2016 Standards of Care

Transcript

1 | VOLUME 39 SUPPLEMENT 1 THE JOURNAL OF CLINICAL AND APPLIED RESEARCH AND EDUCATION JANUARY 2016 WWW.DIABETES.ORG/DIABETESCARE E M L P E P N U T S 1 AMERICAN DIABETES ASSOCIATION STANDARDS OF MEDICAL CARE IN DIABETES—2016 ISSN 0149-5992

2 American Diabetes Association Standards of Medical Care in Diabetes d 2016

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4 Volume 39, Supplement 1 January 2016 ce to express [the journal ’ s] philosophical may suf [T]he simple word Care fi mission. The new journal is designed to promote better patient care by serving the expanded needs of all health professionals committed to the care of patients with diabetes. As such, the American Diabetes Association views as a reaf rmation of Francis Weld Peabody ’ s contention that Diabetes Care fi the secret of the care of the patient is in caring for the patient. ” “ , January-February 1978 Norbert Freinkel, — Diabetes Care EDITOR IN CHIEF William T. Cefalu, MD ASSOCIATE EDITORS EDITORIAL BOARD Rita Rastogi Kalyani, MD, MHS, FACP Nicola Abate, MD George Bakris, MD Rory J. McCrimmon, MBChB, MD, FRCP Silva Arslanian, MD Lawrence Blonde, MD, FACP Harold David McIntyre, MD, FRACP Andrew J.M. Boulton, MD Angelo Avogaro, MD, PhD Gianluca Perseghin, MD Alessio, MD ’ Ananda Basu, MD, FRCP David D Anne L. Peters, MD John B. Buse, MD, PhD Sherita Hill Golden, MD, MHS, FAHA Jonathan Q. Purnell, MD Mary de Groot, PhD Sonia Caprio, MD Peter Reaven, MD Robert Chilton, DO Eddie L. Greene, MD Helena Wachslicht Rodbard, MD Frank B. Hu, MD, MPH, PhD Kenneth Cusi, MD, FACP, FACE David J. Schneider, MD Derek LeRoith, MD, PhD Paresh Dandona, MD, PhD Elizabeth R. Seaquist, MD Robert G. Moses, MD Stefano Del Prato, MD Norbert Stefan, MD Dariush Elahi, PhD Stephen Rich, PhD Jeff Unger, MD Matthew C. Riddle, MD Franco Folli, MD, PhD Ram Weiss, MD, PhD Julio Rosenstock, MD Robert G. Frykberg, DPM, MPH Deborah J. Wexler, MD, MSc William V. Tamborlane, MD W. Timothy Garvey, MD Joseph Wolfsdorf, MD, BCh Katie Weinger, EdD, RN Ronald B. Goldberg, MD Tien Yin Wong, MBBS, FRCSE, FRANZCO, Margaret Grey, DrPH, RN, FAAN Judith Wylie-Rosett, EdD, RD MPH, PhD Richard Hellman, MD AMERICAN DIABETES ASSOCIATION OFFICERS PRESIDENT-ELECT, MEDICINE & SCIENCE CHAIR OF THE BOARD Robin J. Richardson Alvin C. Powers, MD PRESIDENT, MEDICINE & SCIENCE PRESIDENT-ELECT, HEALTH CARE & EDUCATION Desmond Schatz, MD Brenda Montgomery, RN, MSHS, CDE PRESIDENT, HEALTH CARE & EDUCATION SECRETARY/TREASURER-ELECT Margaret A. Powers, PhD, RD, CDE Umesh Verma SECRETARY/TREASURER CHIEF EXECUTIVE OFFICER Lorrie Welker Liang Kevin L. Hagan CHAIR OF THE BOARD-ELECT CHIEF SCIENTIFIC & MEDICAL OFFICER David A. DeMarco, PhD Robert E. Ratner, MD, FACP, FACE The mission of the American Diabetes Association is to prevent and cure diabetes and to improve the lives of all people affected by diabetes.

5 Diabetes Care is a journal for the health care practitioner that is intended to increase knowledge, stimulate research, and promote better management of people with diabetes. To achieve these goals, the journal publishes original research on human studies in the following categories: Clinical Care/Education/Nutrition/ Psychosocial Research, Epidemiology/Health Services Research, Emerging Technologies and Therapeutics, Pathophysiology/Complications, and Cardiovascular and Metabolic Risk. The journal also publishes ADA statements, consensus reports, clinically relevant review articles, letters to the editor, and health/medical news or points of view. Topics covered are of interest to clinically oriented physicians, researchers, epidemiologists, psychologists, diabetes educators, and other health professionals. More information about the journal can be found online at care.diabetesjournals.org. © 2016 by the American Diabetes Association, Inc. All rights reserved. Printed in Copyright the USA. Requests for permission to reuse content should be sent to Copyright Clearance Center at www.copyright.com or 222 Rosewood Dr., Danvers, MA 01923; phone: (978) 750-8400; fax: (978) 646-8600. Requests for permission to translate should be sent to Permissions Editor, American Diabetes Association, at [email protected] The American Diabetes Association reserves the right to reject any advertisement for any reason, which need not be disclosed to the party submitting the advertisement. Commercial reprint orders should be directed to Sheridan Content Services, (800) 635-7181, ext. 8065. Diabetes Care can be ordered by calling toll-free (800) 232-3472, 8:30 A.M. Single issues of to 5:00 P.M. EST, Monday through Friday. Outside the United States, call (703) 549-1500. Rates: $75 in the United States, $95 in Canada and Mexico, and $125 for all other countries. Diabetes Care is available online at care.diabetesjournals.org. Please call the numbers listed above, e-mail [email protected], or visit the online journal for more information about submitting manuscripts, publication charges, ordering reprints, PRINT ISSN 0149-5992 subscribing to the journal, becoming an ADA member, advertising, permission to reuse ONLINE ISSN 1935-5548 ’ content, and the journal s publication policies. PRINTED IN THE USA AMERICAN DIABETES ASSOCIATION PERSONNEL AND CONTACTS PRODUCTION MANAGER EDITORIAL OFFICE DIRECTOR DIRECTOR, MEMBERSHIP/SUBSCRIPTION SERVICES Amy S. Gavin Lyn Reynolds Donald Crowl PEER REVIEW MANAGER PHARMACEUTICAL DIGITAL ADVERTISING TECHNICAL EDITOR Shannon Potts e-Healthcare Solutions Oedipa Rice John Burke EDITORIAL OFFICE SECRETARIES Chief Revenue Of fi cer MANAGING DIRECTOR, MEDIA SALES Raquel Castillo [email protected] Clare Liberis Joan Garrett (609) 882-8887, ext. 149 [email protected] (212) 725-4925, ext. 3448 MANAGING DIRECTOR, SCHOLARLY PHARMACEUTICAL PRINT ADVERTISING JOURNAL PUBLISHING The Jackson-Gaeta Group, Inc. Christian S. Kohler ADVERTISING MANAGER B. Joseph Jackson Julie DeVoss Graff [email protected] DIRECTOR, SCHOLARLY JOURNAL PUBLISHING [email protected] Paul Nalbandian Heather Norton Blackburn (703) 299-5511 [email protected] Tina Auletta EDITORIAL MANAGERS [email protected] ASSOCIATE DIRECTOR, BILLING & COLLECTIONS Valentina Such Nancy C. Baldino Laurie Ann Hall (973) 403-7677

6 January 2016 Volume 39, Supplement 1 — Standards of Medical Care in Diabetes 2016 S60 8. Cardiovascular Disease and Risk S1 Introduction Management S3 Professional Practice Committee Hypertension/Blood Pressure Control 2016 — : S4 Standards of Medical Care in Diabetes Lipid Management Summary of Revisions Antiplatelet Agents 1. Strategies for Improving Care S6 Coronary Heart Disease Diabetes Care Concepts Care Delivery Systems S72 9. Microvascular Complications and Foot Care When Treatment Goals Are Not Met Diabetic Kidney Disease Tailoring Treatment to Vulnerable Populations Diabetic Retinopathy cation and Diagnosis of Diabetes fi 2. Classi S13 Neuropathy Foot Care fi cation Classi Diagnostic Tests for Diabetes 10. Older Adults S81 Categories of Increased Risk for Diabetes (Prediabetes) Overview Type 1 Diabetes Neurocognitive Function Type 2 Diabetes Hypoglycemia Gestational Diabetes Mellitus Treatment Goals Monogenic Diabetes Syndromes Pharmacological Therapy Related Diabetes Cystic Fibrosis – Treatment in Skilled Nursing Facilities S23 3. Foundations of Care and Comprehensive Medical and Nursing Homes Evaluation End-of-Life Care Foundations of Care S86 11. Children and Adolescents Basis for Initial Care Type 1 Diabetes Ongoing Care Management Type 2 Diabetes Diabetes Self-management Education and Support Transition From Pediatric to Adult Care Medical Nutrition Therapy Physical Activity 12. Management of Diabetes in Pregnancy S94 Smoking Cessation: Tobacco and e-Cigarettes Diabetes in Pregnancy Immunization Preconception Counseling Psychosocial Issues Glycemic Targets in Pregnancy Comprehensive Medical Evaluation Management of Gestational Diabetes Mellitus Comorbidities Management of Pregestational Type 1 Diabetes S36 4. Prevention or Delay of Type 2 Diabetes and Type 2 Diabetes in Pregnancy Postpartum Care Lifestyle Modi fi cation Pregnancy and Antihypertensive Drugs Pharmacological Interventions Diabetes Self-management Education and Support S99 13. Diabetes Care in the Hospital 5. Glycemic Targets S39 Hospital Care Delivery Standards Considerations on Admission Assessment of Glycemic Control Glycemic Targets in Hospitalized Patients A1C Testing Antihyperglycemic Agents in Hospitalized A1C Goals Patients Hypoglycemia Standards for Special Situations Intercurrent Illness Treating and Preventing Hypoglycemia S47 6. Obesity Management for the Treatment of Type 2 Self-management in the Hospital Diabetes Medical Nutrition Therapy in the Hospital Look AHEAD Transition From the Acute Care Setting Assessment Diabetes Care Providers in the Hospital Diet, Physical Activity, and Behavioral Therapy Bedside Blood Glucose Monitoring Pharmacotherapy 14. Diabetes Advocacy S105 Bariatric Surgery Advocacy Position Statements 7. Approaches to Glycemic Treatment S52 Professional Practice Committee for the S107 Standards Pharmacological Therapy for Type 1 Diabetes of Medical Care in Diabetes 2016 — Pharmacological Therapy for Type 2 Diabetes S109 Index Bariatric Surgery This issue is freely accessible online at care.diabetesjournals.org. Keep up with the latest information for Diabetes Care and other ADA titles via Facebook (/ADAJournals) and Twitter (@ADA_Journals).

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8 S1 Volume 39, Supplement 1, January 2016 Diabetes Care INTRODUCTION Introduction DOI: 10.2337/dc16-S001 Diabetes Care 2016;39(Suppl. 1):S1 | S2 – diabetes care standards, guidelines, and to diabetes. Workgroup reports fall into Diabetes is a complex, chronic illness re- related documents for over 25 years. fi this category. Scienti c statements are quiring continuous medical care with ADA ’ s clinical practice recommenda- published in the ADA journals and other multifactorial risk-reduction strategies tions are viewed as important resources scienti c/medical publications, as ap- fi beyondglycemic control.Ongoingpatient for health care professionals who care propriate. Scienti fi c statements also self-management education and support ’ for people with diabetes. ADA “ Stan- s undergo a formal review process. are critical to preventing acute complica- dards of Medical Care in Diabetes, ” tions and reducing the risk of long-term Consensus Report position statements, and scienti fi c complications. Signi fi cant evidence exists A consensus report contains a compre- statements undergo a formal review that supports a range of interventions to hensive examination by an expert panel process by ADA ’ s Professional Practice improve diabetes outcomes. fi cor (i.e., consensus panel) of a scienti Committee (PPC) and the Executive s ’ The American Diabetes Association medical issue related to diabetes. A con- Committee of the Board of Directors. s) Standards of Medical Care in (ADA ’ “ sensus report is not an ADA position and The Standards and all ADA position is intended to provide clini- ” Diabetes represents expert opinion only. The cat- c statements, and fi statements, scienti cians, patients, researchers, payers, egory may also include task force and consensus reports are available on the As- and other interested individuals with expert committee reports. The need s Web site at http://professional ’ sociation the components of diabetes care, gen- for a consensus report arises when clini- .diabetes.org/adastatements. eral treatment goals, and tools to eval- cians or scientists desire guidance on a uate the quality of care. The Standards “ Standards of Medical Care in subject for which the evidence is contra- of Care recommendations are not in- Diabetes ” dictory or incomplete. A consensus re- tended to preclude clinical judgment Standards of Care: ADA position state- port is developed following a consensus and must be applied in the context of ment that provides key clinical practice conference where the controversial issue excellent clinical care, with adjustments The PPC performs an recommendations. is extensively discussed. The report for individual preferences, comorbid- extensive literature search and updates s collective anal- ’ represents the panel ities, and other patient factors. For the Standards annually based on the ysis, evaluation, and opinion at that more detailed information about man- quality of new evidence. point in time based in part on the con- agement of diabetes, please refer to ference proceedings. A consensus re- Medical Management of Type 1 Diabe- ADA Position Statement port does not undergo a formal ADA Medical Management of (1) and tes cial ADA A position statement is an of fi review process. Type 2 Diabetes (2). point of view or belief that contains clin- The recommendations include Posi- ical or research recommendations. GRADING OF SCIENTIFIC EVIDENCE screening, diagnost ic, and therapeutic tion statements are issued on scienti c fi fi rst began publishing Since the ADA actions that are known or believed to or medical issues related to diabetes. practice guidelines, there has been con- favorably affect health outcomes of pa- They are published in the ADA journals siderable evolution in the evaluation of tients with diabetes. Many of these in- c/medical publica- fi and other scienti fi c evidence and in the develop- scienti terventions have also been shown to be tions. ADA position statements are typ- ment of evidence-based guidelines. In cost-effective (3). ically based on a systematic review or 2002, the ADA developed a classi cation fi The ADA strives to improve and up- other review of published literature. c fi system to grade the quality of scienti date the Standards of Care to ensure Position statements undergo a formal evidence supporting ADA recommenda- that clinicians, health plans, and policy- review process. They are updated every tions for all new and revised ADA posi- makers can continue to rely on them as 5 years or as needed. tion statements. A recent analysis of the the most authoritative and current evidence cited in the Standards of Care fi ADA Scienti c Statement guidelines for diabetes care. fi cial ADA Ascienti c statement is an of fi found steady improvement in quality ADA STANDARDS, STATEMENTS, point of view or belief that may or may over the past 10 years, with the 2014 AND REPORTS not contain clinical or research recom- Standards for the fi rst time having the The ADA has been actively involved in Scienti mendations. fi c statements con- majority of bulleted recommendations the development and dissemination of tain scholarly synopsis of a topic related -level evidence -or supported by A B was originally approved in 1988. Most recent review/revision: November 2015. ” Standards of Medical Care in Diabetes “ fi t, © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for pro and the work is not altered.

9 Volume 39, Supplement 1, January 2016 Diabetes Care S2 Introduction dence may be equally important but Standards of Medical Care in Diabetes “ ” — Table 1 ADA evidence-grading system for are not as well supported. Of course, Level of evidence is only one component of clin- evidence Description ical decision making. Clinicians care for A Clear evidence from well-conducted, generalizable randomized controlled trials patients, not populations; guidelines that are adequately powered, including must always be interpreted with the in- c Evidence from a well-conducted multicenter trial dividual patient in mind. Individual cir- Evidence from a meta-analysis that incorporated quality ratings in the c analysis cumstances, such as comorbid and rule developed by the ” all or none Compelling nonexperimental evidence, i.e., “ coexisting diseases, age, education, dis- Centre for Evidence-Based Medicine at the University of Oxford values ability, and, above all, patients ’ Supportive evidence from well-conducted randomized controlled trials that are and preferences, must be considered adequately powered, including and may lead to different treatment tar- Evidence from a well-conducted trial at one or more institutions c gets and strategies. Furthermore, con- Evidence from a meta-analysis that incorporated quality ratings in the c ventional evidence hierarchies, such as analysis the one adapted by the ADA, may miss B Supportive evidence from well-conducted cohort studies c Evidence from a well-conducted prospective cohort study or registry nuances important in diabetes care. For Evidence from a well-conducted meta-analysis of cohort studies c example, although there is excellent ev- Supportive evidence from a well-conducted case-control study idence from clinical trials supporting C Supportive evidence from poorly controlled or uncontrolled studies the importance of achieving multiple Evidence from randomized clinical trials with one or more major or three or c risk factor control, the optimal way to fl more minor methodological aws that could invalidate the results achievethisresultislessclear.Itisdif- c Evidence from observational studies with high potential for bias (such as cult to assess each component of fi case series with comparison with historical controls) such a complex intervention. Evidence from case series or case reports c Con fl icting evidence with the weight of evidence supporting the References recommendation Medical 1. American Diabetes Association. Expert consensus or clinical experience E .6thed. Management of Type 1 Diabetes Kaufman FR, Ed. Alexandria, VA, American Di- abetes Association, 2012 Medical 2. American Diabetes Association. Management of Type 2 Diabetes .7thed. Table 1 ) devel- (4). A grading system ( in which clinical trials may be impracti- Burant CF, Young LA, Eds. Alexandria, VA, Amer- oped by the ADA and modeled after ex- icting evi- cal, or in which there is con fl ican Diabetes Association, 2012 isting methods was used to clarify and dence. Recommendations with an A r LE, Chowdhury FM, 3. Li R, Zhang P, Barke codify the evidence that forms the basis rating are based on large well-designed Zhang X. Cost-effectiveness of interventions to for the recommendations. ADA recom- clinical trials or well-done meta-analyses. prevent and control diabetes mellitus: a sys- – tematic review. Diabetes Care 2010;33:1872 B , A mendations are assigned ratings of , Generally, these recommendations 1894 or , depending on the quality of evi- C have the best chance of improving out- 4. Grant RW, Kirkman MS. Trends in the evi- dence. Expert opinion is a separate E comes when applied to the population dence level for the American Diabetes Associa- category for recommendations in which to which they are appropriate. Recom- “ s ’ tion Standards of Medical Care in Diabetes ” 8 – from 2005 to 2014. Diabetes Care 2015;38:6 there is no evidence from clinical trials, mendations with lower levels of evi-

10 PROFESSIONAL PRACTICE COMMITTEE S3 Volume 39, Supplement 1, January 2016 Diabetes Care Professional Practice Committee Diabetes Care 2016;39(Suppl. 1):S3 DOI: 10.2337/dc16-S002 | The Professional Practice Committee for human studies related to each sec- Emma Morton-Eggleston, MD, MPH; (PPC) of the American Diabetes Associ- tion and published since 1 January Margaret A. Powers, PhD, RD, CDE; Stan- “ ation (ADA) is responsible for the 2015. Recommendations were revised Robert E. Ratner, MD; Erinn Rhodes, ” dards of Medical Care in Diabetes basedonnewevidenceor,insome MD, MPH; Amy Rothberg, MD; Sharon position statement, referred to as the cases, to clarify the prior recommenda- D. Solomon, MD; Guillermo E. Umpierrez, “ ” The PPC is a multi- Standards of Care. tion or match the strength of the word- MD; Willy Valencia, MD; and Kristina F. disciplinary expert committee com- ing to the strength of the evidence. A Zdanys, MD. prised of physicians, diabetes educators, table linking the changes in recommen- registered dietitians, and others who dations to new evidence can be re- have expertise in a range of areas, in- viewed at http://professional.diabetes Members of the PPC cluding adult and pediatric endocrinol- .org/SOC. As for all position statements, William H. Herman, MD, MPH (Chair)* ogy, epidemiology, public health, lipid the Standards of Care position state- Thomas W. Donner, MD research, hypertension, preconception ment was reviewed and approved by planning, and pregnancy care. Appoint- the Executive Committee of ADA ’ s R. James Dudl, MD ment to the PPC is based on excellence Board of Directors, which includes Hermes J. Florez, MD, PhD, MPH* in clinical practice and research. Al- health care professi onals, scientists, Judith E. Fradkin, MD though the primary role of the PPC is and lay people. to review and update the Standards of Feedback from the larger clinical Charlotte A. Hayes, MMSc, MS, RD, CDE, Care, it is also responsible for oversee- community was valuable for the 2016 ACSM CCEP ’ ing the review and revisions of ADA s revision of the Standards of Care. Readers Rita Rastogi Kalyani, MD, MHS, FACP c position statements and scienti fi Standards who wish to comment on the Suneil Koliwad, MD, PhD statements. 2016 d are of Medical Care in Diabetes Joseph A. Stankaitis, MD, MPH* The ADA adheres to the Institute of invited to do so at http://professional Medicine Standards for Developing .diabetes.org/SOC. Tracey H. Taveira, PharmD, CDOE, Trustworthy Clinical Practice Guidelines. The ADA funds development of the CVDOE* All members of the PPC are required to Standards of Care and all ADA position Deborah J. Wexler, MD, MSc* icts of interest fl disclose potential con statements out of its general revenues Joseph Wolfsdorf, MB, BCh* with industry and/or other relevant or- and does not use industry support for ganizations. These disclosures are dis- these purposes. The PPC would like to *Subgroup leaders cussed at the onset of each Standards thank the following individuals who of Care revision meeting. Members of the tise in reviewing provided their exper committee, their employer, and their dis- and/or consulting with the committee: ADA Staff closed con fl icts of interest are listed in Lloyd Paul Aiello, MD, PhD; Sheri Jane L. Chiang, MD “ Professional Practice Committee the Colberg-Ochs, PhD; Jo Ellen Condon, RD, (Corresponding author: Standards of Medical Care in for the CDE; Donald R. Coustan, MD; Silvio E. [email protected]) d Diabetes table (see p. S107). ” 2016 Inzucchi, MD; George L. King, MD; Erika Gebel Berg, PhD For the current revision, PPC mem- Shihchen Kuo, RPh, PhD; Ira B. Lamster, DDS, bers systematically searched MEDLINE MMSc; Greg Maynard, MD, MSc, SFHM; Allison T. McElvaine, PhD fi © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for pro t, and the work is not altered.

11 Volume 39, Supplement 1, January 2016 Diabetes Care S4 Standards of Medical Care in Diabetes 2016 : d SUMMARY OF REVISIONS Summary of Revisions | S5 DOI: 10.2337/dc16-S003 – Diabetes Care 2016;39(Suppl. 1):S4 GENERAL CHANGES the ADA added the recommendation screening recommendations. The rec- that people who use continuous glucose ommendation is now to test all adults In alignment with the American Diabe- monitoring and insulin pumps should beginning at age 45 years, regardless tes Association ’ s) position that ’ s(ADA have continued access after they turn of weight. fi diabetes does not de ne people, the 65 years of age. Testing is also recommended for “ will no longer be used word ” diabetic asymptomatic adults of any age who when referring to individuals with dia- Section 6. Obesity Management for are overweight or obese and who have betes in the “ Standards of Medical Care the Treatment of Type 2 Diabetes one or more additional risk factors for ” The ADA will continue to in Diabetes. This new section, which incorporates diabetes. Please refer to Section 2 for “ as an adjective use the term diabetic ” prior recommendations related to bari- testing recommendations for gesta- for complications related to diabetes atric surgery, has new recommenda- tional diabetes mellitus. (e.g., diabetic retinopathy). tions related to the comprehensive For monogenic diabetes syndromes, Although levels of evidence for several assessment of weight in diabetes and there is speci fi c guidance and text on recommendations have been updated, to the treatment of overweight/obesity testing, diagnosing, and evaluating indi- these changes are not included below as fi cation and pharma- with behavior modi viduals and their family members. the clinical recommendations have re- cotherapy. mained the same. Changes in evidence This section also includes a new table Section 3. Foundations of Care and C are not E to level from, for example, of currently approved medications for Comprehensive Medical Evaluation noted below. The Standards of Medical “ Initial Evaluation and Diabe- “ Section 3 the long-term treatment of obesity. contains, in addi- ” 2016 d Care in Diabetes and Section ” tes Management Planning tion to many minor changes that clarify Section 7. Approaches to Glycemic 4 “ Foundations of Care: Education, Nu- fl recommendations or re ect new evidence, Treatment trition, Physical Activity, Smoking Cessa- the following more substantive revisions. Bariatric surgery was removed from this ” tion, Psychosocial Care, and Immunization section and placed in a new section en- from the 2015 Standards were com- SECTION CHANGES titled “ Obesity Management for the bined into one section for 2016 to re- Section 1. Strategies for Improving Care Treatment of Type 2 Diabetes. ” ect the importance of integrating fl This section was revised to include rec- medical evaluation, patient engage- Section 8. Cardiovascular Disease and ommendations on tailoring treatment ment, and ongoing care that highlight Risk Management to vulnerable populations with diabetes, the importance of lifestyle and behav- “ Atherosclerotic cardiovascular disease ” including recommendations for those ioral modi fi cation. The nutrition and (ASCVD) has replaced the former term with food insecurity, cognitive dysfunc- vaccination recomm endations were (CVD), as “ cardiovascular disease ” tion and/or mental illness, and HIV, streamlined to focus on those aspects ASCVD is a more speci fi cterm. and a discussion on disparities related of care most important and most rele- A new recommendation for pharma- to ethnicity, culture, sex, socioeconomic vant to people with diabetes. cological treatment of older adults was differences, and disparities. added. Section 4. Prevention or Delay of To re ect new evidence on ASCVD fl cation and Diagnosis fi Section 2. Classi Type 2 Diabetes risk among women, the recommenda- of Diabetes ect the changing role of technology To re fl The order and discussion of diagnostic tion to consider aspirin therapy in in the prevention of type 2 diabetes, a re- tests (fasting plasma glucose, 2-h plasma 60 years has been women aged . commendation was added encouraging glucoseaftera 75-goralglucose tolerance 50 $ changed to include women aged the use of new technology such as apps test, and A1C criteria) were revised to years. A recommendation was also and text messaging to affect lifestyle make it clear that no one test is preferred added to address antiplatelet use in pa- fi cation to prevent diabetes. modi over another for diagnosis. tients aged , 50 years with multiple risk To clarify the relationship between factors. Section 5. Glycemic Targets Because of the growing number of older age, BMI, and risk for type 2 diabetes A recommendation was made to re- adults with insulin-dependent diabetes, and prediabetes, the ADA revised the fl ect new evidence that adding ezetimibe © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for pro fi t, and the work is not altered.

12 Summary of Revisions S5 care.diabetesjournals.org to moderate-intensity statin provides ad- includes neurocognitive function, hypo- from a recommendation of , 6% (42 ditional cardiovascular bene ts for select fi glycemia, treatment goals, care in skilled mmol/mol) to a target of 6 – 6.5% (42 – individuals with diabetes and should be nursing facilities/nursing homes, and 48 mmol/mol), although depending on considered. end-of-life considerations. hypoglycemia risk the target may be A new table provides ef cacy and fi tightened or relaxed. Section 11. Children and Adolescents dose details on high- and moderate- Glyburide in gestational diabetes The scope of this section is more com- intensity statin therapy. mellitus was deemphasized based on prehensive, capturing the nuances of di- new data suggesting that it may be in- abetes care in the pediatric population. Section 9. Microvascular ferior to insulin and metformin. This includes new recommendations Complications and Foot Care addressing diabetes self-management was changed to “ “ dia- Nephropathy ” Section 13. Diabetes Care in the t, psychosocial education and suppor to emphasize ” betic kidney disease Hospital issues, and treatment guidelines for that, while nephropathy may stem This section was revised to focus solely type 2 diabetes in youth. from a variety of causes, attention is on diabetes care in the hospital setting. The recommendation to obtain a fast- placed on kidney disease that is directly This comprehensive section addresses le in children starting at ing lipid pro fi related to diabetes. There are several hospital care delivery standards, more age 2 years has been changed to age fi minor edits to this section. The signi - detailed information on glycemic tar- cstatement 10 years, based on a scienti fi cant ones, based on new evidence, are gets and antihyperglycemic agents, on type 1 diabetes and cardiovascular as follows: standards for special situations, and disease from the American Heart Asso- Diabetic kidney disease: guidance was transitions from the acute care setting. ciation and the ADA. addedonwhentoreferforrenalre- This section also includes a new table placement treatment and when to refer on basal and bolus dosing recommenda- Section 12. Management of Diabetes to physicians experienced in the care of tions for continuous enteral, bolus en- in Pregnancy diabetic kidney disease. teral, and parenteral feedings. The scope of this section is more com- Diabetic retinopathy: guidance was prehensive, providing new recommen- added on the use of intravitreal anti- dations on pregestational diabetes, Section 14. Diabetes Advocacy VEGF agents for the treatment of Diabetes Care in the School Setting: A “ gestational diabetes mellitus, and gen- center-involved diabetic macular edema, Position Statement of the American Di- eral principles for diabetes management as they were more effective than mono- abetes Association was revised in 2015. ” in pregnancy. therapy or combination therapy with This position statement was previously A new recommendation was added to laser. Diabetes Care in the School and “ called highlight the importance of discussing fam- Day Care Setting. The ADA intentionally ” ily planning and effective contraception Section 10. Older Adults The scope of this section is more compre- separated these two populations be- with women with preexisting diabetes. hensive, capturing the nuances of diabe- cause of the signi fi cant differences in di- A1C recommendations for pregnant tescareinthe older adult population. This abetes care between the two cohorts. women with diabetes were changed,

13 S6 Diabetes Care Volume 39, Supplement 1, January 2016 American Diabetes Association 1. Strategies for Improving Care Diabetes Care 2016;39(Suppl. 1):S6 S12 | DOI: 10.2337/dc16-S004 – Recommendations yle that incorporates patient prefer- A patient-centered communication st c and addresses cultural barriers to ences, assesses literacy and numeracy, B care should be used. and based on evidence-based guide- Treatment decisions should be timely c lines that are tailored to individual patient preferences, prognoses, and co- morbidities. B Care should be aligned with components of the Chronic Care Model to ensure c productive interactions between a prepared proactive practice team and an informed activated patient. A c When feasible, care systems should support team-based care, community involvement, patient registries, and decision support tools to meet patient needs. B DIABETES CARE CONCEPTS In the following sections, different components of the clinical management of patients with (or at risk for) diabetes are reviewed. Clinical practice guidelines are key to improving population health; however, for optimal outcomes, diabetes care must be individualized for each patient. The American Diabetes Association high- 1. STRATEGIES FOR IMPROVING CARE nicians, policymakers, and advocates lights the following three themes that cli should keep in mind: Practice recommendations, whether based on evi- 1. Patient-Centeredness: dence or expert opinion, are intended to guide an overall approach to care. The science and art of medicine c ome together when the clinician is endations for a patient who would not facedwithmakingtreatmentrecomm udies on which guidelines were based. have met eligibility criteria for the st Recognizing that one size does not t all, these Standards provide guid- fi ance for when and how to adapt recommendations. Because patients with r cardiovascular disease, a patient- diabetes have greatly increased risk fo prehensive plan to reduce cardio- centered approach should include a com vascular risk by addressing blood pressure and lipid control, smoking prevention and cessation, weight management, phy sical activity, and healthy lifestyle choices. An increasing proportion of patients with type 1 2. Diabetes Across the Life Span: diabetes are adults. For less salutary reasons, the incidence of type 2 diabetes is increasing in children and young adults. Patients with type 1 diabetes and those with type 2 diabetes are living well into older age, a stage of life for which there is guide therapy. All these demographic little evidence from clinical trials to changes highlight another challenge to high-quality diabetes care, which is the need to improve coordination between clinical teams as patients transition through different stages of the life span. 3. Advocacy for Patients With Diabetes: Advocacy can be de fi ned as active support and engagement to advance a cause or policy. Advocacy is needed to improve Suggested citation: American Diabetes Associa- the lives of patients with (or at risk for) diabetes. Given the tremendous toll that tion.Strategiesforimprovingcare.Sec.1.In obesity, physical inactivity, and smoking have on the health of patients with Standards of Medical Care in Diabetes d 2016 . diabetes, efforts are needed to address and change the societal determinants – Diabetes Care 2016;39(Suppl. 1):S6 S12 at the root of these problems. Within the narrower domain of clinical practice © 2016 by the American Diabetes Association. guidelines, the application of evidence level grading to practice recommenda- Readers may use this article as long as the work tions can help to identify areas that require more research (1). Refer to Section is properly cited, the use is educational and not for pro fi t, and the work is not altered. ” Diabetes Advocacy. “ 14

14 Strategies for Improving Care S7 care.diabetesjournals.org CARE DELIVERY SYSTEMS 1. Healthy lifestyle choices (physical 2. Self-management support activity, healthy eating, tobacco ces- 3. Decision support (basing care on There has been steady improvement in evidence-based, effective care guide- sation, weight management, and ef- the proportion of patients with diabetes lines) fective coping) treated with statins and achieving recom- 4. Clinical information systems (using 2. Disease self-management (taking mended levels of A1C, blood pressure, registries that can provide patient- and managing medications and, when and LDL cholesterol in the last 10 years speci c and population-based fi sup- clinically appropriate, self-monitoring (2). The mean A1C nationally has declined port to the care team) of glucose and blood pressure) 2002 – from 7.6% (60 mmol/mol) in 1999 5. Community resources and policies 3. Prevention of diabetes complica- – to 7.2% (55 mmol/mol) in 2007 2010 (identifying or developing resources tions (self-monitoring of foot health; based on the National Health and Nutri- to support healthy lifestyles) active participation in screening for tion Examination Survey (NHANES), with 6. Health systems (to create a quality- eye, foot, and renal complications; younger adults less likely to meet treat- oriented culture) and immunizations) ment targets compared with older adults (2). This has been accompanied by im- fi ning the roles of the health care Rede High-quality diabet es self-management provements in cardiovascular outcomes delivery team and promoting self- education (DSME) has been shown to andhasledtosubstantialreductionsin management on the part of the patient improve patient self-management, end-stage microvascular complications. are fundamental to the successful imple- satisfaction, and glucose control. Na- Nevertheless, 33 – 49% of patients still mentation of the CCM (8). Collaborative, tional DSME standards call for an inte- do not meet targets for glycemic, blood multidisciplinary teams are best suited to grated approach that includes clinical pressure, or cholesterol control, and provide care for people with chronic con- avioral strategies content and skills, beh only 14% meet targets for all three mea- ditions such as diabetes and to facilitate (goal setting, problem solving), and en- sures and nonsmoking status (2). Evi- self-management (9 – 11). patients ’ gagement with psychosocial concerns dence also suggests that progress in (23). cardiovascular risk factor control (par- Key Objectives ticularly tobacco use) may be slowing The National Diabetes Education Pro- Objective 3: Change the Care System (2,3). Certain patient groups, such as gram (NDEP) maintains an online re- An institutional priority in most success- young adults and patients with complex source (www.betterdiabetescare.nih ful care systems is providing high quality comorbidities, fi nancial or other social .gov) to help health care professionals of care (24). Changes that have been hardships, and/or limited English pro fi - to design and implement more effective shown to increase quality of diabetes ciency, may present particular chal- health care delivery systems for those care include basing care on evidence- lenges to goal-based care (4 6). Even – c objectives, with diabetes. Three speci fi based guidelines (18); expanding the after adjusting for patient factors, with references to literature outlining role of teams to implement more inten- the persistent variation in quality of di- practical strategies to achieve each, are sive disease management strategies abetes care across providers and prac- as follows: (6,21,25); redesigning the care process tice settings indicates that there is Objective 1: Optimize Provider and Team (26); implementing electronic health potential for substantial system-level Behavior record tools (27,28); activating and improvements. Thecareteamshouldprioritizetimely fi - educating patients (29,30); removing and appropriate intensi fi cation of life- Chronic Care Model nancial barriers and reducing patient style and/or pharmacological therapy Numerous interventions to improve ad- out-of-pocket costs for diabetes educa- for patients who have not achieved ben- herence to the recommended standards tion, eye exams, self-monitoring of cial levels of glucose, blood pressure, fi e have been implemented. However, a ma- blood glucose, and necessary medica- or lipid control (12). Strategies such as jor barrier to optimal care is a delivery tions (6); and identifying/developing/ explicit goal setting with patients (13); system that is often fragmented, lacks engaging community resources and identifying and addressing language, nu- clinical information capabilities, dupli- public policy that support healthy life- meracy, or cultural barriers to care (14 – cates services, and is poorly designed for styles (31). 17); integrating evide nce-based guide- the coordinated delivery of chronic care. Initiatives such asthePatient-Centered lines and clinical information tools into The Chronic Care Model (CCM) has been Medical Home show promise for improv- 20); and incor- – the process of care (18 showntobeaneffectiveframeworkfor ing outcomes through coordinated pri- porating care management teams in- improving the quality of diabetes care (7). mary care and offer new opportunities cluding nurses, pharmacists, and other for team-based chronic disease care Six Core Elements providers (21,22) have each been shown (32). Additional strategies to improve di- The CCM includes six core elements for to optimize provider and team behavior abetes care include reimbursement the provision of optimal care of patients and thereby catalyze reductions in A1C, structures that, in contrast to visit-based with chronic disease: blood pressure, and LDL cholesterol. billing, reward the provision of appropriate and high-quality care (33), and incen- 1. Delivery system design (moving Objective 2: Support Patient Behavior tives that accommodate personalized Change care proactive to a reactive from a care goals (6,34). Successful diabetes care requires a sys- delivery system where planned visits tematic approach to supporting patients ’ are coordinated through a team- Optimal diabetes management re- behavior change efforts, including based approach) quires an organized, systematic approach

15 Volume 39, Supplement 1, January 2016 Diabetes Care S8 Strategies for Improving Care TAILORING TREATMENT TO and the involvement of a coordinated pressure, or lipids (40). Although there VULNERABLE POPULATIONS team of dedicated health care profes- are many ways to measure adherence sionals working in an environment where (40), Medicare uses percent of days cov- Health Disparities patient-centered high-quality care is a ered (PDC), which is a measure of the The causes of health disparities are com- priority (6). number of pills prescribed divided by plex and include societal issues such as rst and last prescrip- fi the days between institutional racism, discrimination, socio- WHEN TREATMENT GOALS ARE tions. Adequate ” adherence is de “ fi ned economic status, poor access to health NOT MET as 80% (40). This metric can be used to care, and lack of health insurance. Disparities In general, providers should seek evidence- nd and track poor adherence and help fi are particularly well documented for car- based approaches that improve the to guide system improvement efforts to diovascular disease. clinical outcomes and quality of life of pa- overcome the barriers to adherence. Ethnic/Cultural/Sex/Socioeconomic tients with diabetes. Recent reviews of Barriers to adherence may include pa- Differences quality improvement strategies in diabe- tient factors (remembering to obtain Ethnic, cultural, religious, and sex differ- ed a fi tes care (24,35,36) have not identi or take medications, fears, depression, ences and socioeconomic status may particular approach that is more effective or health beliefs), medication factors affect diabetes prevalence and out- than others. However, the Translating Re- (complexity, multiple daily dosing, comes. Type 2 diabetes develops more search Into Action for Diabetes (TRIAD) cost, or side effects), and system factors frequently in women with prior gesta- study provided objective data from large (inadequate follow-up or support). tional diabetes mellitus (42), in individu- managed care systems demonstrating ef- als with hypertension or dyslipidemia, fi fective tools for speci c targets (6). TRIAD Improving Adherence andincertainracial/ethnicgroups found it useful to divide interventions into Simplifying a complex treatment regi- (African American, Native American, those that affected and processes of care men may improve adherence. Nurse- Hispanic/Latino, and Asian American) (43). intermediate outcomes. directed interventions, home aides, diabetes education, and pharmacy- Access to Health Care Processes of Care derived interventions improved ad- Ethnic, cultural, religious, sex, and socio- Processes of care included periodic test- herence but had a very small effect on economic differences affect health care ing of A1C, lipids, and urinary albumin; outcomes, including metabolic control accessandcomplicationriskinpeople examining the retina and feet; advising (41). Success in overcoming barriers with diabetes. Recent studies have rec- on aspirin use; and smoking cessation. may be achieved if the patient and pro- ommended lowering the BMI cut point TRIADresultssuggestthatproviders vider agree on a targeted treatment for testing for Asian Americans to $ 23 control these activities. Performance fi for a speci c barrier. For example, one 2 (44). Women with diabetes, com- kg/m feedback, reminders, and structured study found that when depression was pared with men with diabetes, have a care (e.g., guidelines, formal case man- identi fi ed as a barrier, agreement on 40% greater risk of incident coronary agement, and patient education re- antidepressant treatment subsequently heart disease (45). Socioeconomic and sources) may in fl uence providers to allowed for improvements in A1C, ethnic inequalities exist in the provision improve processes of care (6). blood pressure, and lipid control (10). of health care to individuals with diabe- Thus, to improve adherence, systems Intermediate Outcomes and tes (46). As a result, children with type 1 should continually monitor and prevent fi cation Treatment Intensi diabetes from racial/ethnic populations or treat poor adherence by identifying For intermediate outcomes, such as with lower socioeconomic status are at barriers and implementing treatments A1C, blood pressure, and lipid goals, risk for poor metabolic control and poor that are barrier speci c and effective. fi tools that improved processes of care cant fi emotional functioning (47). Signi A systematic approach to achieving in- did not perform as well in addressing racial differences and barriers exist in termediate outcomes involves three steps: fi cation barriers to treatment intensi self-monitoring and outcomes (48). and adherence (6). In 35% of cases, un- Adherence should Assess adherence. 1. Addressing Disparities controlled A1C, blood pressure, or lipids be addressed as the fi rst priority. If Therefore, diabetes management re- were associated with a lack of treatment adherence is 80%orabove, then treat- quires individualized, patient-centered, ned as a failure to cation, de fi intensi fi fi cation should be consid- ment intensi and culturally appropriate strategies. To either increase a drug dose or change a ered (e.g., up-titration). If medication overcome disparities, community health drug class (37). Treatment intensi fi ca- up-titration is not a viable option, then workers (49), peers (50,51), and lay lead- tion was associated with improvement consider initiating or changing to a dif- ers (52) may assist in the delivery of in A1C, hypertension, and hyperlipid- ferent medication class. DSME and diabetes self-management emia control (38). A large multicenter to adherence with Explore barriers 2. support services (53). Strong social sup- fi rmed the strong association study con nd a mutu- the patient/caregiver and fi port leads to improved clinical outcomes, between treatment intensi fi cation and ally agreeable approach to overcom- reduced psychosocial symptomatology, improved A1C (39). ing the barriers. and adoption of healthier lifestyles (54). Establish a follow-up plan that con- 3. Structured interventions, tailored to eth- Intermediate Outcomes and rms the planned treatment change fi nic populations that integrate culture, Adherence and assess progress in reaching the In 23% of cases, poor adherence was language, religion, and literacy skills, pos- associated with uncontrolled A1C, blood itively in fl uence patient outcomes (55). target.

16 Strategies for Improving Care S9 care.diabetesjournals.org To decrease disparities, all providers and Additionally, homeless patients with dia- Providers should recognize that FI com- groups are encouraged to use the National betes need secure places to keep their plicates diabetes management and seek s National Voluntary Con- ’ Quality Forum diabetes supplies and refrigerator access local resources that can help patients and sensus Standards for Ambulatory Care d to properly store their insulin. the parents of patients with diabetes to Measuring Healthcare Disparities (56). more regularly obtain nutritious food (59). ciencies. FI and fi Literacy and Numeracy De diabetes are more common among non- Food Insecurity and Hyperglycemia. Hy- Lack of Health Insurance English speaking individuals and those perglycemia is more common in those Not having health insurance affects the with poor literacy and numeracy skills. with diabetes and FI. Reasons for this processes and outcomes of diabetes rtant to consider Therefore, it is impo include the steady consumption of care. Individuals without insurance screening for FI, proper housing, and di- carbohydrate-rich processed foods, coverage for blood glucose monitoring abetes in this population. Programs that binge eating, not lling antidiabetes med- fi supplies have a 0.5% higher A1C than see such patients should work to develop fi ication prescriptions owing to nancial those with coverage (57). The afford- services in multiple languages with the constraint, and anxiety/depression that able care act has improved access to c goal of preventing diabetes and speci fi lead to poor diabetes self-care behaviors. health care; however, many remain building diabetes awareness in people Providers should be well versed in these without coverage. In a recent study of who cannot easily read orwritein English. risk factors for hyperglycemia and take predominantly African American or practical steps to alleviate them in order atients with dia- Hispanic uninsured p Cognitive Dysfunction to improve glucose control. 60% were hypertensive, but betes, 50 – – only 22 37% had systolic blood pres- Recommendations Food Insecurity and Hypoglycemia eatments to under sure controlled by tr Intensive glucose control is not ad- c 130 mmHg (58). Type 1 Diabetes. Individuals with type 1 vised for the improvement of poor diabetes and FI may develop hypoglycemia cognitive function in hyperglycemic Food Insecurity as a result of inadequa te or erratic carbo- B individuals with type 2 diabetes. hydrate consumption following insulin In individuals with poor cognitive c Recommendations administration. Long-acting insulin, as op- c Providers should evaluate hyper- function or severe hypoglycemia, posed to shorter-acting insulin that may glycemia and hypoglycemia in the glycemic therapy should be tailored peak when food is not available, may fi C to avoid signi cant hypoglycemia. context of food insecurity and pro- lowertheriskforhypoglycemiainthose In individuals with diabetes at high c pose solutions accordingly. A with FI. Short-acting insulin analogs, cardiovascular risk, the cardiovascular Providers should recognize that c preferably delivered by a pen, may be bene fi ts of statin therapy outweigh homelessness, poor literacy, and used immediately after consumption A the risk of cognitive dysfunction. poor numeracy often occur with of a meal, whenever food becomes c If a second-generation antipsychotic food insecurity, and appropriate available. Unfortunately, the greater medication is prescribed, changes in resources should be made avail- cost of insulin analogs should be weighed weight, glycemic control, and cho- A able for patients with diabetes. against their potential advantages. Caring lesterol levels should be carefully Food insecurity (FI) is the unreliable for those with type 1 diabetes in the set- monitored and the treatment regi- availability of nutritious food and the ting of FI may mirror “ sick day ” manage- men should be reassessed. C inability to consistently obtain food ment protocols. Dementia without resorting to socially unaccept- Those with type 2 diabe- Type 2 Diabetes. The most severe form of cognitive able practices. Over 14% (or one out of tes and FI can develop hypoglycemia for dysfunction is dementia. A recent meta- every seven people in the U.S.) are food similar reasons after taking certain oral analysis of prospective observational stud- insecure. The rate is higher in some hypoglycemic agents. If using a sulfonyl- iesinpeoplewithdiabetesshoweda73% racial/ethnic minority groups including e preferred choice urea, glipizide is th increased risk of all types of dementia, a African American a nd Latino popula- due to the shorter half-life. Glipizide 56% increased risk of Alzheimer dementia, tions, in low-income households, and can be taken immediately before meal and 127% increased risk of vascular de- in homes headed by a single mother. FI consumption, thus limiting its tendency mentia compared with individuals without may involve a tradeoff between purchas- to produce hypoglycemia as compared diabetes (60). The reverse is also true: peo- ing nutritious food for inexpensive and with longer-acting sulfonylureas (e.g., ple with Alzheimer dementia are more more energy- and carbohydrate-dense glyburide). likely to develop diabetes than people processed foods. without Alzheimer dementia. In people with FI, interventions should Homelessness. Homelessness often ac- focus on preventing diabetes and, in companies the most severe form of FI. In those with type 2 Hyperglycemia. those with diabetes, limiting hyperglyce- Therefore, providers who care for those diabetes, the degree and duration of mia and preventing hypoglycemia. The with FI who are uninsured and homeless hyperglycemia are related to dementia. risk for type 2 diabetes is increased two- and individuals with poor literacy and nu- More rapid cognitive decline is associated fold in those with FI. The risks of uncontrolled meracy should be well versed or have with both increased A1C and longer du- hyperglycemia and severe hypoglycemia access to social workers to facilitate tem- ration of diabetes (61). The Action to are increased in those with diabetes who porary housing for their patients as a Control Cardiovascular Risk in Diabetes are also food insecure. (ACCORD) study found that each 1% means to prevent and control diabetes.

17 Volume 39, Supplement 1, January 2016 Diabetes Care S10 Strategies for Improving Care higher A1C level was associated with analysis showed a signi cantly increased fi progression toward diabetes. Among lower cognitive function in individuals risk of incident depression (relative risk HIV patients with diabetes, preventive with type 2 diabetes (62). However, the 1.15), and, in turn, depression was 5 [RR] health care using an approach similar ACCORD study found no difference in fi associated with a signi cantly increased to that used in patients without HIV is cognitive outcomes between intensive risk of diabetes (RR 5 1.6) (71). Depression critical to reduce the risks of microvas- and standard glycemic control, support- and psychosocial issues are discussed cular and macrovascular complications. ing the recommendation that intensive “ more extensively in Section 3 Founda- For patients with HIV and ARV- glucose control should not be advised for tions of Care and Comprehensive Medical associated hyperglycemia, it may be the improvement of cognitive function in ” Evaluation. appropriate to consider discontinuing individuals with type 2 diabetes (63). the problematic ARV agents if safe and Medications effective alternatives are available (76). Hypoglycemia. In type 2 diabetes, severe Diabetes medications are effective, re- itutions, carefully Before making ARV subst hypoglycemia is associated with reduced gardless of mental health status. Treat- consider the possible effect on HIV viro- cognitive function, and those with poor ments for depression are effective in logical control and the potential adverse cognitive function have more severe hy- patients with diabetes, and treating de- effects of new ARV agents. In some cases, poglycemia. In a long-term study of older pression may improve short-term glyce- antidiabetes agents may still be necessary. patients with type 2 diabetes, individuals mic control (72). If a second-generation with one or more recorded episode of antipsychotic medication is prescribed, References severe hypoglycemia had a stepwise in- changes in weight, glycemic control, and 1. Grant RW, Kirkman MS. Trends in the evi- crease in risk of dementia (64). Likewise, dence level for the American Diabetes Associa- cholesterol levels should be carefully the ACCORD trial found that as cognitive ” “ tion s ’ Standards of Medical Care in Diabetes monitored and the treatment regimen function decreased, the risk of severe hy- from 2005 to 2014. Diabetes Care 2015;38:6 – 8 should be reassessed if signi fi cant changes 2. Ali MK, Bullard KM, Saaddine JB, Cowie CC, poglycemia increased (65). Tailoring gly- are noted (73). Awareness of an individu- Imperatore G, Gregg EW. Achievement of goals cemic therapy may help to prevent al le, especially if an in- s medication pro fi ’ in U.S. diabetes care, 1999-2010. N Engl J Med hypoglycemia in individuals with cogni- dividual takes psychotropic medications, is 1624 – 2013;368:1613 tive dysfunction. 3. Wang J, Geiss LS, Cheng YJ, et al. Long-term key to effective management. and recent progress in blood pressure levels In one study, adherence to the Nutrition. among U.S. adults with diagnosed diabetes, Diabetes Care in Patients With HIV Mediterranean diet correlated with im- 1988-2008. Diabetes Care 2011;34:1579 – 1581 proved cognitive function (66). However, Recommendation 4. Kerr EA, Heisler M, Krein SL, et al. Beyond a recent Cochrane review found insuf fi - comorbidity counts: how do comorbidity type c Patients with HIV should be screened cient evidence to recommend any dietary fl uence diabetes patients ’ treat- and severity in for diabetes and prediabetes with a ment priorities and s elf-management? J Gen change for the prevention or treatment of fasting glucose level before starting Intern Med 2007;22:1635 – 1640 cognitive dysfunction (67). antiretroviral therapy and 3 months 5. Fernandez A, Schillinger D, Warton EM, et al. after starting or changing it. If initial Given the controversy over a po- Statins. Language barriers, physician-patient language screening results are normal, check- concordance, and glycemic control among in- tential link between statins and demen- sured Latinos with diabetes: the Diabetes Study ing fasting glucose each year is ad- tia, it is worth noting that a Cochrane of Northern California (DISTANCE). J Gen Intern vised. If prediabetes is detected, systematic review has reported that data 176 – Med 2011;26:170 continue to measure levels every do not support an adverse effect of sta- 6. TRIAD Study Group. Health systems, patients – 6 months to monitor for pro- 3 tins on cognition. The U.S. Food and Drug factors, and quality of care for diabetes: a syn- gression to diabetes. E Administration (FDA) postmarketing sur- thesis of ndings from the TRIAD study. Diabe- fi – 947 tes Care 2010;33:940 veillance databases have also revealed a 7. Stellefson M, Dipnarine K, Stopka C. The Diabetes risk is increased with certain low reporting rate for cognitive-related Chronic Care Model and diabetes management protease inhibitors (PIs) and nucleoside adverse events, including cognitive dys- in US primary care settings: a systematic review. reverse transcriptase inhibitors (NRTIs). function ordementia, with statin therapy, Prev Chronic Dis 2013;10:E26 New-onset diabetes is estimated to occur similar to rates seen with other com- 8. Coleman K, Austin BT, Brach C, Wagner EH. in more than 5% of HIV-infected patients monly prescribed cardiovascular medica- Evidence on the Chronic Care Model in the on PIs, whereas more than 15% may have new millennium. Health Aff (Millwood) 2009; tions (68). Therefore individuals with 85 28:75 – prediabetes (74). PIs are associated with diabetes and a high risk for cardiovascular 9. Piatt GA, Anderson RM, Brooks MM, et al. insulin resistance and may also lead to disease should be placed on statin ther- 3-year follow-up of clinical and behavioral apoptosis of pancreatic -cells. NRTIs b apy regardless of cognitive status. improvements following a multifaceted diabe- also affect fat distribution (both lipohy- tescare intervention:resultsofa randomizedcon- pertrophy and lipoatrophy), which is as- Mental Illness trolled trial. Diabetes Educ 2010;36:301 309 – Severe mental disorder that includes sociated with insulin resistance. 10. Katon WJ, Lin EHB, Von Korff M, et al. Col- laborative care for patients with depression and schizophrenia, bipolar disorder, and de- Individuals with HIV are at higher risk – chronic illnesses. N Engl J Med 2010;363:2611 pression is increased 1.7-fold in people for developing prediabetes and diabetes 2620 with diabetes (69). The prevalence of on antiretroviral (ARV) therapies, so a 11. Parchman ML, Zeber JE, Romero RR, Pugh three times higher – type 2 diabetes is two proper screening protocol is recom- JA. Risk of coronary artery disease in type 2 di- in people with schizophrenia, bipolar dis- mended (75). In those with prediabetes, abetes and the delivery of care consistent with order, and schizoaffective disorder than weight loss through healthy nutrition the chronic care model in primary care settings: in the general population (70). A meta- 1134 a STARNet study. Med Care 2007;45:1129 – and physical activity may reduce the

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Battersby M, Von Korff M, Schaefer J, et al. 45. Peters SA, Huxley RR, Woodward M. Diabe- compared with current treatment guidelines. Twelve evidence-based principles for implement- tes as risk factor for incident coronary heart – Diabetes Educ 2011;37:78 84 ing self-management support in primary care. Jt 14. Schillinger D, Piette J, Grumbach K, et al. disease in women compared with men: a sys- Comm J Qual Patient Saf 2010;36:561 – 570 tematic review and meta-analysis of 64 cohorts Closing the loop: physician communication 30. Grant RW, Wald JS, Schnipper JL, et al. Practice- including 858,507 individuals and 28,203 coro- with diabetic patients who have low health lit- linked online personal health records for type 2 1551 nary events. Diabetologia 2014;57:1542 – eracy. Arch Intern Med 2003;163:83 – 90 diabetes mellitus: a randomized controlled trial. ́ 15. Rosal MC, Ockene IS, Restrepo A, et al. Ran- erez I, Olry de Labry- 46. Ricci-Cabello I, Ruiz-P 1782 – Arch Intern Med 2008;168:1776 ́ ́ domized trial of a literacy-sensitive, culturally arquez-Calder on S. Do social inequal- Lima A, M 31. Pullen-Smith B, Carter-Edwards L, Leathers tailored diabetes self-management interven- ities exist in terms of the prevention, diagnosis, KH. Community health ambassadors: a model treatment, control and monitoring of diabetes? tion for low-income Latinos: Latinos en Control. for engaging community leaders to promote A systematic review. Health Soc Care Commu- – 844 Diabetes Care 2011;34:838 better health in North Carolina. J Public Health 16. Osborn CY, Cavanaugh K, Wallston KA, et al. 587 – nity 2010;18:572 S81 – Manag Pract 2008;14(Suppl.):S73 Health literacy explains racial disparities in di- 47. Borschuk AP, Everhart RS. Health disparities 32. Bojadzievski T, Gabbay RA. Patient-centered abetes medication adherence. J Health Com- among youth with type 1 diabetes: a systematic medical home and diabetes. Diabetes Care 2011; review of the current literature. Fam Syst Health – 278 mun 2011;16(Suppl. 3):268 34:1047 – 1053 17. Rothman R, Malone R, Bryant B, Horlen C, 313 2015;33:297 – 33. Rosenthal MB, Cutler DM, Feder J. The ACO DeWalt D, Pignone M. The relationship between 48. Campbell JA, Walker RJ, Smalls BL, Egede d striking the balance between participa- rules literacy and glycemic control in a diabetes LE. Glucose control in diabetes: the impact of tion and transformative potential. N Engl J Med disease-management program. Diabetes Educ racial differences on monitoring and outcomes. 2011;365:e6 – 482 Endocrine 2012;42:471 – 273 2004;30:263 34. Washington AE, Lipstein SH. The Patient- Connor PJ, Bodkin NL, Fradkin J, et al. Di- ’ 18. O 49. Shah M, Kaselitz E, Heisler M. The role of d promoting Centered Outcomes Research Institute abetes performance measures: current status community health workers in diabetes: update better information, decisions, and health. N Engl J and future directions. Diabetes Care 2011;34: on current literature. Curr Diab Rep 2013;13: Med 2011;365:e31 – 1651 1659 171 – 163 35. Shojania KG, Grimshaw JM. Evidence-based 19. Garg AX, Adhikari NKJ, McDonald H, et al. 50. Heisler M, Vijan S, Makki F, Piette JD. Di- quality improvement: the state of the science. Effects of computerized clinical decision sup- abetes control with reciprocal peer support ver- – 150 Health Aff (Millwood) 2005;24:138 port systems on practitioner performance and sus nurse care management: a randomized trial. 36. Shojania KG, Ranji SR, Shaw LK, et al. Closing patient outcomes: a systematic review. JAMA – 515 Ann Intern Med 2010;153:507 the quality gap: a critical analysis of quality im- 51. Long JA, Jahnle EC, Richardson DM, 1238 – 2005;293:1223 provement strategies (vol. 2: diabetes care). 20. Smith SA, Shah ND, Bryant SC, et al.; Evi- Loewenstein G, Volpp KG. Peer mentoring and Rockville, MD, Agency for Healthcare Research dens Research Group. Chronic Care Model and fi nancial incentives to improve glucose control and Quality, 2004 (Report no. 04-0051-2. AHRQ shared care in diabetes: randomized trial of an in African American veterans: a randomized tri- Technical Reviews) electronic decision support system. Mayo Clin al. Ann Intern Med 2012;156:416 – 424 37. Schmittdiel JA, Uratsu CS, Karter AJ, et al. 52. Foster G, Taylor SJC, Eldridge SE, Ramsay J, 757 – Proc 2008;83:747 ’ Why don t diabetes patients achieve recom- 21. Jaffe MG, Lee GA, Young JD, Sidney S, Go fi Grif ths CJ. Self-management education pro- mended risk factor targets? Poor adherence AS. Improved blood pressure control associated grammes by lay leaders for people with chronic versus lack of treatment intensi cation. J Gen fi with a large-scale hypertension program. JAMA conditions. Cochrane Database Syst Rev 2007;4: 594 – Intern Med 2008;23:588 705 – 2013;310:699 CD005108 38. Selby JV, Uratsu CS, Fireman B, et al. Treat- 22. Stone RA, Rao RH, Sevick MA, et al. Active 53. Siminerio L, Ruppert KM, Gabbay RA. Who ment intensi cation and risk factor control: to- fi care management supported by home telemo- can provide diabetes self-management sup- ward more clinically relevant quality measures. nitoring in veterans with type 2 diabetes: the port in primary care? Findings from a random- 402 – Med Care 2009;47:395 DiaTel randomized cont rolled trial. Diabetes ized controlled trial. Diabetes Educ 2013;39: 39. Raebel MA, Ellis JL, Schroeder EB, et al. In- 484 – Care 2010;33:478 – 705 713 tensi cation of antihyperglycemic therapy among fi 23. Powers MA, Bardsley J, Cypress M, et al. 54. Strom JL, Egede LE. The impact of social patients with incident diabetes: a Surveillance Diabetes self-management education and sup- support on outcomes in adult patients with Prevention and Management of Diabetes Mellitus port in type 2 diabetes: a joint position state- type 2 diabetes: a systematic review. Curr (SUPREME-DM) study. Pharmacoepidemiol Drug ment of the American Diabetes Association, the Diab Rep 2012;12:769 781 – – Saf 2014;23:699 710 55. Zeh P, Sandhu HK, Cannaby AM, Sturt JA. American Association of Diabetes Educators, 40. Raebel MA, Schmittdiel J, Karter AJ, The impact of culturally competent diabetes and the Academy of Nutrition and Dietetics. Di- Konieczny JL, Steiner JF. Standardizing terminol- care interventions for improving diabetes- abetes Care 2015;38:1372 1382 – nitions of medication adherence and fi ogy and de 24. Tricco AC, Ivers NM, Grimshaw JM, et al. related outcomes in ethnic minority groups: a persistence in research employing electronic da- Effectiveness of quality improvement strategies – systematic review. Diabet Med 2012;29:1237 tabases. Med Care 2013;51(Suppl. 3):S11 – S21 on the management of diabetes: a systematic 1252 41. Vermeire E, Wens J, Van Royen P, Biot Y, 56. National Quality Forum. National Voluntary review and meta-analysis. Lancet 2012;379: Hearnshaw H, Lindenmeyer A. Interventions Consensus Standards for Ambulatory Care d 2252 – 2261 for improving adherence to treatment recom- 25. Peikes D, Chen A, Schore J, Brown R. Effects Measuring Healthcare Disparities [Internet], mendations in people with type 2 diabetes mel- of care coordination on hospitalization, quality 2008. Available from https://www.qualityforum litus. Cochrane Database Syst Rev 2005;2: of care, and health care expenditures among .org/Publications/2008/03/National_Voluntary_ CD003638 Consensus_Standards_for_Ambulatory_Care% fi ciaries: 15 randomized trials. Medicare bene 42. Kim C, Newton KM, Knopp RH. Gestational E2%80%94Measuring_Healthcare_Disparities JAMA 2009;301:603 – 618 diabetes and the incidence of type 2 diabetes: a 26. Feifer C, Nemeth L, Nietert PJ, et al. Differ- .aspx. Accessed 2 September 2015 systematic review. Diabetes Care 2002;25: ent paths to high-quality care: three archetypes 57. Bowker SL, Mitchell CG, Majumdar SR, Toth 1862 1868 – of top-performing practice sites. Ann Fam Med EL, Johnson JA. Lack of insurance coverage for 43. Hutchinson RN, Shin S. Systematic review of health disparities for cardiovascular diseases testing supplies is associated with poorer 241 – 2007;5:233

19 Volume 39, Supplement 1, January 2016 Diabetes Care S12 Strategies for Improving Care glycemic control in patients with type 2 diabe- 64. Whitmer RA, Karter AJ, Yaffe K, Quesenberry depression and bipolar disorder. World Psychi- CP Jr, Selby JV. Hypoglycemic episodes and risk of – 136 atry 2015;14:119 43 – tes. CMAJ 2004;171:39 dementia in older patients with type 2 diabetes 71. Mezuk B, Eaton WW, Albrecht S, Golden SH. 58. Baumann LC, Chang M-W, Hoebeke R. Clinical – mellitus. JAMA 2009;301:1565 1572 Depression and type 2 diabetes over the lifespan: a outcomes for low-income adults with hyperten- 65. Punthakee Z, Miller ME, Launer LJ, et al.; meta-analysis. Diabetes Care 2008;31:2383 – 2390 sion and diabetes. Nurs Res 2002;51:191 – 198 tigators; ACCORD- ACCORD Group of Inves 72. Baumeister H, Hutter N, Bengel J. Psycho- 59. Seligman HK, Schillinger D. Hunger and so- MIND Investigators. Poor cognitive function logical and pharmacological interventions for cioeconomic disparities in chronic disease. N and risk of severe hypoglycemia in type 2 dia- depression in patients with diabetes mellitus – 9 Engl J Med 2010;363:6 betes: post hoc epidemiologic analysis of the and depression. Cochrane Database Syst Rev 60. Gudala K, Bansal D, Schifano F, Bhansali A. ACCORD trial. Diabetes Care 2012;35:787 793 – 2012;12:CD008381 Diabetes mellitus and risk of dementia: a meta- 66. Scarmeas N, Stern Y, Mayeux R, Manly JJ, 73. American Diabetes Association; American analysis of prospective observational studies. J Schupf N, Luchsinger JA. Mediterranean diet Psychiatric Association; American Association 650 Diabetes Investig 2013;4:640 – and mild cognitive impairment. Arch Neurol of Clinical Endocrinologists; North American As- 61. Rawlings AM, Sharrett AR, Schneider AL, 225 2009;66:216 – sociation for the Study of Obesity. Consensus et al. Diabetes in midlife and cognitive change 67. Ooi CP, Loke SC, Yassin Z, Hamid T-A. Car- development conference on antipsychotic over 20 years: a cohort study. Ann Intern Med bohydrates for improving the cognitive per- drugs and obesity and diabetes. Diabetes Care 2014;161:785 793 – formance of independent-living older adults 2004;27:596 – 601 62. Cukierman-Yaffe T, Gerstein HC, Williamson ́ with normal cognition or mild cognitive impair- 74. Dub e MP. Disorders of glucose metabo- JD, et al.; Action to Control Cardiovascular Risk ment. Cochrane Database Syst Rev 2011;4: lism in patients infected with human immuno- in Diabetes-Memory in Diabetes (ACCORD- CD007220 de fi ciency virus. Clin Infect Dis 2000;31: MIND) Investigators. Relationship between 68. Richardson K, Schoen M, French B, et al. 1467 – 1475 baseline glycemic control and cognitive func- Statins and cognitive function: a systematic re- 75. Schambelan M, Benson CA, Carr A, et al.; tion in individuals with type 2 diabetes and 697 – view. Ann Intern Med 2013;159:688 International AIDS Society-USA. Management other cardiovascular risk factors: the action to 69. Osborn DPJ, Wright CA, Levy G, King MB, of metabolic complications associated with control cardiovascular risk in diabetes-memory Deo R, Nazareth I. Relative risk of diabetes, dys- antiretroviral therapy for HIV-1 infection: rec- in diabetes (ACCORD-MIND) trial. Diabetes lipidaemia, hypertension and the metabolic syn- ommendations of an International AIDS Society- Care 2009;32:221 – 226 drome in people with severe mental illnesses: fi USA panel. J Acquir Immune De c Syndr 2002;31: 63. Launer LJ, Miller ME, Williamson JD, et al.; systematic review and metaanalysis. BMC Psy- 275 257 – ACCORD MIND investigators. Effects of intensive chiatry 2008;8:84 76. Wohl DA, McComsey G, Tebas P, et al. glucose lowering on brain structure and function 70. Correll CU, Detraux J, De Lepeleire J, De Current concepts in the diagnosis and man- in people with type 2 diabetes (ACCORD MIND): a Hert M. Effects of antipsychotics, antidepres- agement of metabolic complications of HIV randomised open-label substudy. Lancet Neurol sants and mood stabilizers on risk for physi- infection and its therapy. Clin Infect Dis 977 – 2011;10:969 cal diseases in people with schizophrenia, 653 – 2006;43:645

20 Diabetes Care Volume 39, Supplement 1, January 2016 S13 American Diabetes Association 2. Classi fi cation and Diagnosis of Diabetes DOI: 10.2337/dc16-S005 | Diabetes Care 2016;39(Suppl. 1):S13 S22 – CLASSIFICATION ed into the following general categories: Diabetes can be classi fi -cell destruction, usually leading to absolute insulin 1. Type 1 diabetes (due to b 2. CLASSIFICATION AND DIAGNOSIS OF DIABETES ciency) fi de 2. Type 2 diabetes (due to a progressive loss of insulin secretion on the background of insulin resistance) 3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes) c types of diabetes due to other causes, e.g., monogenic diabetes syn- fi 4. Speci dromes (such as neonatal diabetes and maturity-onset diabetes of the young brosis), and drug- or fi [MODY]), diseases of the exocrine pancreas (such as cystic chemical-induced diabetes (such as with glucocorticoid use, in the treatment of HIV/AIDS or after organ transplantation) This section reviews most common forms of diabetes but is not comprehensive. For additional information, see the American Diabetes Association (ADA) position state- “ cation of Diabetes Mellitus ment fi (1). Diagnosis and Classi ” Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical presentation and disease progression may vary considerably. Classi fi cation is im- portant for determining therapy, but some individuals cannot be clearly classi fi ed as having type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms of type 2 diabetes occurring only in adults and type 1 diabetes only in children are no longer accurate, as both diseases occur in both cohorts. Occasionally, patients with type 2 diabetes may present with diabetic ketoacidosis (DKA). Children with type 1 diabetes typically present with the hallmark symptoms of polyuria/polydipsia and approximately one-third with DKA (2). The onset of type 1 diabetes may be more variable in adults, and they may not present with the classic symptoms seen in culties in distinguishing diabetes type may occur in all age- children. Although dif fi groups at onset, the true diagnosis becomes more obvious over time. DIAGNOSTIC TESTS FOR DIABETES , either the fasting Diabetes may be diagnosed based on the plasma glucose criteria plasma glucose (FPG) or the 2-h plasma glucose (2-h PG) value after a 75-g oral A1C criteria (1,3) ( Table 2.1 ). glucose tolerance test (OGTT) or the The same tests are used to screen for and diagnose diabetes and to detect individ- fi ed anywhere along the spectrum of uals with prediabetes. Diabetes may be identi clinical scenarios: in seemingly low-risk individuals who happento have glucose testing, in individuals tested based on diabetes risk assessment, and in symptomatic patients. Fasting and 2-Hour Plasma Glucose Suggested citation: American Diabetes Associa- The FPG and 2-h PG may be used to diagnose diabetes ( ). The concordance Table 2.1 cation and diagnosis of diabetes. fi tion. Classi between the FPG and 2-h PG tests is imperfect, as is the concordance between A1C Sec. 2. In Standards of Medical Care in rmed that, compared fi and either glucose-based test. Numerous studies have con Diabetes d 2016 . Diabetes Care 2016;39(Suppl. 1): – S13 S22 with FPG cut points and A1C, the 2-h PG value diagnoses more people with diabetes. © 2016 by the American Diabetes Association. A1C Readers may use this article as long as the work fi ed by the NGSP The A1C test should be performed using a method that is certi is properly cited, the use is educational and not (www.ngsp.org) and standardized or traceable to the Diabetes Control and t, and the work is not altered. fi for pro

21 Volume 39, Supplement 1, January 2016 cation and Diagnosis of Diabetes fi S14 Classi Diabetes Care the test result that is above the diagnos- Criteria for the diagnosis of diabetes — Table 2.1 tic cut point should be repeated. The di- FPG fi ned as no caloric intake for at least 8 h.* $ 126 mg/dL (7.0 mmol/L). Fasting is de agnosis is made on the basis of the OR rmed test. For example, if a patient fi con 200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed as described by 2-h PG $ meets the diabetes criterion of the A1C the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in 6.5%[48mmol/mol])but not $ (two results water.* 126 mg/dL [7.0 mmol/L]), that , FPG ( OR person should nevertheless be consid- A1C $ 6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is ered to have diabetes. NGSP certi fi ed and standardized to the DCCT assay.* Since all the tests have preanalytic and OR analytic variability, it is possible that an In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma abnormalresult(i.e.,abovethe diagnostic $ glucose 200 mg/dL (11.1 mmol/L). threshold), when repeated, will produce a *In the absence of unequivocal hyperglycemia, results should be con rmed by repeat testing. fi value below the diagnostic cut point. This scenario is least likely for A1C, more likely for FPG, and most likely for the 2-h PG, Complications Trial (DCCT) reference as- of fructosamine and glycated albumin and especially if the glucose samples remain say. Although point-of-care A1C assays lower levels of 1,5-anhydroglucitol, sug- at room temperature and are not centri- may be NGSP certi ciency testing fi fi ed, pro gesting that their glycemic burden (partic- fuged promptly. Barring laboratory error, is not mandated for performing the test, ularly postprandially) may be higher (8). such patients will likely have test results so use of point-of-care assays for diagnos- Moreover, the association of A1C with near the margins of the diagnostic thresh- tic purposes is not recommended. risk for complications is similar in African old. The health care professional should The A1C has several advantages com- Americans and non-Hispanic whites (9). follow the patient closely and repeat the pared with the FPG and OGTT, including Hemoglobinopathies/Anemias 6 months. – test in 3 greater convenience (fasting not re- Interpreting A1C levels in the presence of quired), greater preanalytical stability, certain hemoglobinopathies and anemia CATEGORIES OF INCREASED RISK and less day-to-day perturbations during or patients with an may be problematic. F FOR DIABETES (PREDIABETES) stress and illness. However, these advan- abnormal hemoglobin but normal red blood Recommendations tages may be offset by the lower sensitiv- cell turnover, such as those with the sickle c Testing to assess risk for future di- ity of A1C at the designated cut point, cell trait, an A1C assay without interference abetes in asymptomatic people greater cost, limited availability of A1C from abnormal hemoglobins should be should be considered in adults of testing in certain regions of the develop- used. An updated list of interferences is any age who are overweight or ing world, and the imperfect correlation available at www.ngsp.org/interf.asp. 2 or $ 23 25 kg/m obese (BMI $ between A1C and average glucose in cer- 2 Red Blood Cell Turnover in Asian Americans) and kg/m tain individuals. National Health and In conditions associated with increased who have one or more additional Nutrition Examination Survey (NHANES) red blood cell turnover, such as pregnancy B risk factors for diabetes. data indicate that an A1C cut point of (second and third trimesters), recent blood c For allpatients, testingshouldbegin fi es one- 6.5% (48 mmol/mol) identi $ loss or transfusion, erythropoietin therapy, at age 45 years. B third fewer cases of undiagnosed diabe- or hemolysis, only blood glucose criteria c If tests are normal, repeat testing tes than a fasting glucose cut point of should be used to diagnose diabetes. carried out at a minimum of 3-year $ 126 mg/dL (7.0 mmol/L) (4). C intervals is reasonable. It is important to take age, race/ Con fi rming the Diagnosis c To test for prediabetes, fasting ethnicity, and anemia/hemoglobinop- Unless there is a clear clinical diagnosis plasma glucose, 2-h plasma glucose athies into consideration when using (e.g., patient in a hyperglycemic crisis or after 75-g oral glucose tolerance test, the A1C to diagnose diabetes. with classic symptoms of hyperglycemia B and A1C are equally appropriate. Age $ 200 and a random plasma glucose c In patients with prediabetes, iden- The epidemiological studies that formed mg/dL [11.1 mmol/L]), a second test is re- tify and, if appropriate, treat other the basis for recommending A1C to di- rmation. It is recom- fi quired for con cardiovascular disease risk factors. B agnose diabetes included only adult mended that the same test be repeated c Testing to detect prediabetes should populations. Therefore, it remains un- without delay using a new blood sample be considered in children and ado- clear if A1C and the same A1C cut point for con fi rmation because there will be a lescents who are overweight or should be used to diagnose diabetes in greater likelihood of concurrence. For ex- obese and who have two or more children and adolescents (4,5). ample, if the A1C is 7.0% (53 mmol/mol) additional risk factors for diabetes. E Race/Ethnicity and a repeat result is 6.8% (51 mmol/mol), ’ race/ A1C levels may vary with patients rmed. If fi the diagnosis of diabetes is con ethnicity (6,7). For example, African Amer- two different tests (such as A1C and FPG) Description icans may have higher A1C levels than are both above the diagnostic threshold, In 1997 and 2003, the Expert Committee non-Hispanic whites despite similar fast- rms the diagnosis. On the this also con fi fi on the Diagnosis and Classi cation of Di- abetes Mellitus (10,11) recognized a ing and postglucose load glucose levels. other hand, if a patient has discordant group of individuals whose glucose African Americans also have higher levels results from two different tests, then

22 cation and Diagnosis of Diabetes S15 fi Classi care.diabetesjournals.org levels did not meet the criteria for di- islet cell autoanti bodies and autoanti- Hence, it is reasonable to consider an abetes but were too high to be consid- bodies to insulin, GAD (GAD65), the ty- 46 mmol/mol) – 6.4% (39 – A1C range of 5.7 is the term ” Prediabetes “ ered normal. , and b rosine phosphatases IA-2 and IA-2 as identifying individuals with prediabe- used for individuals with impaired fast- fi ZnT8. Type 1 diabetes is de ned by one tes. As with those with IFG and/or IGT, ing glucose (IFG) and/or impaired glu- or more of these autoimmune markers. – 6.4% individuals with an A1C of 5.7 cose tolerance (IGT) and indicates an The disease has strong HLA associations, (39 – 46 mmol/mol) should be informed increased risk for the future develop- with linkage to the DQA and DQB genes. of their increased risk for diabetes and ment of diabetes. IFG and IGT should These HLA-DR/DQ alleles can be either CVD and counseled about effective strate- not be viewed as clinical entities in their predisposing or protective. “ Pre- gies to lower their risks (see Section 4 own right but rather risk factors for di- b -cell destruction is quite Therateof vention or Delay of Type 2 Diabetes ” ). abetes ( Table 2.2 ) and cardiovascular variable, being rapid in some individu- Similar to glucose measurements, the con- disease (CVD). IFG and IGT are associ- als (mainly infants and children) and tinuum of risk is curvilinear, so as A1C rises, ated with obesity (especially abdominal slow in others (mainly adults). Children the diabetes risk rises disproportionately or visceral obesity), dyslipidemia with and adolescents may present with ke- (12). Aggressive interventions and vigilant high triglycerides and/or low HDL cho- toacidosis as the fi rst manifestation of follow-up should be pursued for those lesterol, and hypertension. the disease. Others have modest fast- considered at very high risk (e.g., those ing hyperglycemia that can rapidly 6.0% [42 mmol/mol]). with A1C . change to severe hyperglycemia and/or Table 2.3 summarizes the categories Diagnosis In 1997 and 2003, the Expert Committee ketoacidosis with infection or other of prediabetes and the criteria Table 2.2 fi cation of Di- on the Diagnosis and Classi stress. Adults may retain suf -cell fi cient b for prediabetes testing. For recommen- ned IFG as abetes Mellitus (10,11) de fi function to prevent ketoacidosis for dations regarding risk factors and – FPG levels 100 6.9 – 125 mg/dL (5.6 many years; such individuals eventually – screening for prediabetes, see pp. S17 mmol/L) and IGT as 2-h PG after 75-g become dependent on insulin for survival S18 ( Testing for Type 2 Diabetes and Pre- “ – 11.0 OGTT levels 140 199 mg/dL (7.8 – and are at risk for ketoacidosis. At this diabetes in Asymptomatic Adults ” and mmol/L). It should be noted that the latter stage of the disease, there is little “ Testing for Type 2 Diabetes and Pre- World Health Organization (WHO) and or no insulin secretion, as manifested by ). diabetes in Children and Adolescents ” numerous diabetes organizations de ne fi low or undetectable levels of plasma C- TYPE 1 DIABETES the IFG cutoff at 110 mg/dL (6.1 mmol/L). peptide. Immune-mediated diabetes Recommendations As with the glucose measures, several commonly occurs in childhood and ado- Blood glucose rather than A1C should c prospective studies that used A1C to lescence, but it can occur at any age, even be used to diagnose acute onset of predict the progression to diabetes in the 8th and 9th decades of life. type 1 diabetes in individuals with demonstrated a strong, continuous as- Autoimmune destruction of b -cells E symptoms of hyperglycemia. sociation between A1C and subsequent has multiple genetic predispositions c Inform the relatives of patients with diabetes. In a systematic review of and is also related to environmental fac- type 1 diabetes of the opportunity 44,203 individuals from 16 cohort stud- tors that are still poorly de fi ned. Al- to be tested for type 1 diabetes risk, ies with a follow-up interval averaging though patients are not typically obese but only in the setting of a clinical – 5.6 years (range 2.8 12 years), those when they present with type 1 diabetes, research study. E 6.0% (37 – – with an A1C between 5.5 42 obesity should not preclude the diagno- mmol/mol) had a substantially in- sis. These patients are also prone to creased risk of diabetes (5-year inci- other autoimmune disorders such as Diagnosis dence from 9% to 25%). An A1C range Hashimoto thyroiditis, celiac disease, In a patient with acute symptoms, mea- of 6.0 48 mmol/mol) had a – 6.5% (42 – Graves disease, Addison disease, viti- surement of blood glucose is part of the 5-year risk of developing diabetes be- ligo, autoimmune hepatitis, myasthenia nition of diabetes (classic symptoms of fi de tween25%and50%andarelative gravis, and pernicious anemia. hyperglycemia or hyperglycemic crisis plus risk 20 times higher compared with an 200 mg/dL a random plasma glucose $ A1C of 5.0% (31 mmol/mol) (12). In a Idiopathic Type 1 Diabetes [11.1 mmol/L]). In these cases, knowing Some forms of type 1 diabetes have no community-based study of African the blood glucose level is critical because, known etiologies. These patients have American and non-Hispanic white adults in addition to con rming that symptoms fi permanent insulinopenia and are prone without diabetes, baseline A1C was a are due to diabetes, this will inform man- to ketoacidosis, but have no evidence of stronger predictor of subsequent diabe- agement decisions. Some providers may b -cell autoimmunity. Although only a tes and cardiovascular events than fast- also want to know the A1C to determine minority of patients with type 1 diabetes ing glucose (13). Other analyses suggest how long a patient has had hyperglycemia. fall into this category, of those who do, that an A1C of 5.7% (39 mmol/mol) is most are of African or Asian ancestry. associated with a diabetes risk similar Immune-Mediated Diabetes “ insulin- This form, previously called Individuals with this form of diabetes to that of the high-risk participants in dependent diabetes ” or “ juvenile-onset suffer from episodic ketoacidosis and the Diabetes Prevention Program (DPP) – diabetes, accounts for 5 ” 10% of diabe- exhibit varying degrees of insulin de fi - (14), and A1C at baseline was a strong tes and is due to cellular-mediated auto- ciency between episodes. This form of predictor of the development of glucose- immune destruction of the pancreatic diabetes is strongly inherited and is not fi ned diabetes during the DPP and its de -cells. Autoimmune markers include b HLA associated. An absolute requirement follow-up (15).

23 Volume 39, Supplement 1, January 2016 Diabetes Care fi S16 Classi cation and Diagnosis of Diabetes being conducted to test various meth- — Criteria for testing for diabetes or prediabetes in asymptomatic adults Table 2.2 ods of preventing type 1 diabetes in 2 2 $ 23 kg/m in or 1. Testing should be considered in all adults who are overweight (BMI $ 25 kg/m those with evidence of autoimmunity Asian Americans) and have additional risk factors: (www.clinicaltrials.gov). c physical inactivity rst-degree relative with diabetes c fi high-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, c TYPE 2 DIABETES c Islander) fi Paci Recommendations women who delivered a baby weighing c . 9 lb or were diagnosed with GDM hypertension ( c $ 140/90 mmHg or on therapy for hypertension) c Testing to detect type 2 diabetes in , 35 mg/dL (0.90 mmol/L) and/or a triglyceride level 250 mg/dL c . HDL cholesterol level asymptomatic people should be con- (2.82 mmol/L) sidered in adults of any age who are c women with polycystic ovary syndrome overweight or obese (BMI $ 25 c A1C $ 5.7% (39 mmol/mol), IGT, or IFG on previous testing 2 2 $ in Asian Amer- 23 kg/m or kg/m other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis c icans) and who have one or more nigricans) B additional risk factors for diabetes. history of CVD c For all patients, testing should be- c 2. For all patients, testing should begin at age 45 years. B gin at age 45 years. 3. If results are normal, testing should be repeated at a minimum of 3-year intervals, with If tests are normal, repeat testing c consideration of more frequent testing depending on initial results (e.g., those with prediabetes should be tested yearly) and risk status. carried out at a minimum of 3-year C intervals is reasonable. c To test for type 2 diabetes, fasting plasma glucose, 2-h plasma glucose for insulin replacement therapy in af- type 1 diabetes within 10 years and 84% after 75-g oral glucose tolerance test, fected patients may be intermittent. fi within 15 years (19,20). These ndings are and A1C are equally appropriate. B cant because, while the highly signi fi c In patients with diabetes, identify German group was recruited from off- Testing for Type 1 Diabetes Risk and, if appropriate, treat other car- The incidence and prevalence of type 1 spring of parents with type 1 diabetes, diovascular disease risk factors. B diabetes is increasing (16). Patients with the Finnish and American groups were c Testing to detect type 2 diabetes type 1 diabetes often present with acute recruited from the general population. should be considered in children symptoms of diabetes and markedly el- ndings in all three fi Remarkably, the andadolescentswhoareoverweight evated blood glucose levels, and ap- groups were the same, suggesting that or obese and who have two or more proximately one-third are diagnosed the same sequence of events led to clin- additional risk factors for diabetes. E with life-threatening ketoacidosis (2). ” ical disease in both “ sporadic and famil- Several studies indicate that measuring ial cases of type 1 diabetes. islet autoantibodies in relatives of those Although there is currently a lack of Description with type 1 diabetes may identify individ- accepted screening programs, one Type 2 diabetes, previously referred to uals who are at risk for developing type 1 should consider referring relatives of ” as “ non or – insulin-dependent diabetes diabetes (17). Such testing, coupled with those with type 1 diabetes for antibody “ adult-onset diabetes, ” accounts for education about diabetes symptoms and testing for risk assessment in the setting 90 95% of all diabetes. This form en- – close follow-up in an observational clini- of a clinical research study (http://www2 compasses individuals who have insulin ca- fi cal study, may enable earlier identi .diabetestrialnet.org). Widespread clini- resistance and usually relative (rather tion of type 1 diabetes onset (18). There cal testing of asymptomatic low-risk in- ciency. At fi than absolute) insulin de is evidence to suggest that early diagnosis dividuals is not currently recommended least initially, and often throughout may limit acute complications (19). due to lack of approved therapeutic in- their lifetime, these individuals may A recent study reported the risk of pro- terventions. Higher-risk individuals may not need insulin treatment to survive. gression to type 1 diabetes from the be tested, but only in the context of a There are various causes of type 2 di- time of seroconversion to autoantibody clinical research setting. Individuals abetes. Although the speci c etiologies fi positivity in three pediatric cohorts from who test positive will be counseled are not known, autoimmune destruction Finland, Germany, and the U.S. Of the 585 about the risk of developing diabetes, of -cells does not occur, and patients do b children who developed more than two diabetes symptoms, and DKA preven- not have any of the other known causes autoantibodies, nearly 70% developed tion. Numerous clinical studies are of diabetes. Most, but not all, patients with type 2 diabetes are overweight or obese. Excess weight itself causes some — Categories of increased risk for diabetes (prediabetes)* Table 2.3 degree of insulin resistance. Patients who FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG) are notobese oroverweightbytraditional OR weight criteria may have an increased 2-h PG in the 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT) percentage of body fat distributed pre- OR dominantly in the abdominal region. – – 46 mmol/mol) A1C 5.7 6.4% (39 Ketoacidosis seldom occurs sponta- *For all three tests, risk is continuous, extending below the lower limit of the range and neously in type 2 diabetes; when seen, becoming disproportionately greater at the higher end of the range. it usually arises in association with the

24 cation and Diagnosis of Diabetes S17 fi Classi care.diabetesjournals.org stress of another illness such as infec- (sensitivity of 80%) for nearly all Asian individuals to identify those with predi- tion. Type 2 diabetes frequently goes American subgroups (with levels slightly abetes or diabetes might seem reason- undiagnosed for many years because hy- lower for Japanese Americans). This able, rigorous clinical trials to prove the 2 makes a rounded cut point of 23 kg/m perglycemia develops gradually and, at effectiveness of such screening have not practical. In determining a single BMI cut earlier stages, is often not severe enough beenconducted andareunlikely tooccur. point,it is importanttobalancesensitivity for the patient to notice the classic diabe- A large European randomized con- fi city so as to provide a valuable and speci tes symptoms. Nevertheless, even undi- trolled trial compared the impact of screening tool without numerous false agnosed patients are at increased risk of screening for diabetes and intensive positives. An argument can be made to developing macrovascular and microvas- multifactorial intervention with that of push the BMI cut point to lower than cular complications. screening and routine care (22). General 2 in favor of increased sensitivity; 23 kg/m Whereas patients with type 2 diabetes practice patients between the ages of however, this would lead to an unaccept- may have insulin levels that appear nor- 69 years were screened for diabetes – 40 ably low speci fi city(13.1%).Datafromthe mal or elevated, the higher blood glucose and randomly assigned by practice to 2 WHO also suggest that a BMI $ 23 kg/m levels in these patients would be expected intensive treatment of multiple risk fac- fi should be used to de ne increased risk to result in even higher insulin values had tors or routine diabetes care. After 5.3 in Asian Americans (27). The nding fi their b -cell function been normal. Thus, years of follow-up, CVD risk factors were that half of diabetes in Asian Americans insulin secretion is defective in these pa- cantly improved fi modestly but signi is undiagnosed suggeststhattestingis not tients and insuf cient to compensate for fi with intensive treatment compared occurring at lower BMI thresholds (21). insulin resistance. Insulin resistance may with routine care, but the incidence of Evidence also suggests that other improve with weight reduction and/or fi rst CVD events or mortality was not tfromlower populations may bene fi pharmacological treatment of hypergly- cantly different between the signi fi BMI cut points. For example, in a large cemia but is seldom restored to normal. groups (22). The excellent care provided multiethnic cohort study, for an equiva- The risk of developing type 2 diabetes to patients in the routine care group and lent incidence rate of diabetes, a BMI of increases with age, obesity, and lack of the lack of an unscreened control arm 2 in non-Hispanic whites was 30 kg/m physical activity. It occurs more fre- ’ limited the authors ability to prove that 2 in Afri- equivalent to a BMI of 26 kg/m quently in women with prior GDM, in screening and early intensive treatment can Americans (28). those with hypertension or dyslipidemia, impact outcomes. Mathematical model- and in certain racial/ethnic subgroups ts fi ing studies suggest that major bene Medications (African American, American Indian, are likely to accrue from the early diag- Certain medications, such as glucocorti- Hispanic/Latino, and Asian American). It nosis and treatment of glycemia and car- coids, thiazide diuretics, and atypical an- is often associated with a strong genetic diovascular risk factors in type 2 diabetes tipsychotics (29), are known to increase predisposition, more so than type 1 dia- (23); moreover, screening, beginning at the risk of diabetes and should be con- betes. However, the genetics of type 2 age 30 or 45 years and independent sidered when ascertaining a diagnosis. diabetes is poorly understood. of risk factors, may be cost-effective , $11,000 per quality-adjusted life- ( Diagnostic Tests year gained) (24). Testing for Type 2 Diabetes and FPG, 2-h PG after 75-g OGTT, and A1C ations regarding Additional consider Prediabetes in Asymptomatic Adults are equally appropriate for testing .It Prediabetes and type 2 diabetes meet cri- testing for type 2 diabetes and predia- should be noted that the tests do not teria for conditions in which early detec- betes in asymptomatic patients include necessarily detect diabetes in the same tion is appropriate. Both conditions are the following: individuals. The ef cacy of interventions fi common and impose signi fi cant clinical for primary prevention of type 2 diabe- Age and public health burdens. There is often tes (30,31) has primarily been demon- Testing recommendations for diabetes a long presymptomatic phase before the strated among individuals with IGT, not in asymptomatic adults are listed in diagnosis of type 2 diabetes. Simple tests for individuals with isolated IFG or for Table 2.2 . Age is a major risk factor for to detect preclinical disease are readily fi ned by A1C those with prediabetes de diabetes. Testing should begin at age 45 available. The duration of glycemic burden criteria. years for all patients. is a strong predictor of adverse outcomes. Testing Interval BMI and Ethnicity There are effective interventions that pre- The appropriate interval between tests is Testing should be considered in adults vent progression from prediabetes to dia- not known (32). The rationale for the 2 and one $ 25 kg/m of any age with BMI betes (see Section 4 “ Prevention or Delay 3-year interval is that with this interval, or more additional risk factors for dia- ” of Type 2 Diabetes )andreducetheriskof the number of false-positive tests that re- betes. However, recent data (25) and diabetes complications (see Section 8 rmatory testingwillbereduced fi quire con evidence from the ADA position state- Cardiovascular Disease and Risk Man- “ and individuals with false-negative tests ment “ BMI Cut Points to Identify At-Risk “ and Section 9 ” Microvascular agement will be retested before substantial time Asian Americans for Type 2 Diabetes Complications and Foot Care ). ” elapses and complications develop (32). Screening (26) suggest that the BMI ” Approximately one-quarter of people Community Screening cut point should be lower for the Asian with diabetes in the U.S. and nearly half Ideally, testing should be carried out American population. For diabetes of Asian and Hispanic Americans with within a health care setting because of screening purposes, the BMI cut points diabetes are undiagnosed (21). Al- 2 the need for follow-up and treatment. fall consistentlybetween23 and 24 kg/m though screening of asymptomatic

25 Volume 39, Supplement 1, January 2016 Diabetes Care cation and Diagnosis of Diabetes fi S18 Classi Community testing outside a health care 1. One-step ” 75-g OGTT or “ using the oral glucose tolerance setting is not recommended because Two-step ” approach with a 50-g (non- 2. “ test and clinically appropriate non- people with positive tests may not fasting) screen followed by a 100-g E pregnancy diagnostic criteria. seek, or have access to, appropriate OGTT for those who screen positive c Women with a history of gesta- follow-up testing and care. Community tional diabetes mellitus should Different diagnostic criteria will identify testing may also be poorly targeted; i.e., have lifelong screening for the de- different degrees of maternal hyperglyce- it may fail to reach the groups most at velopment of diabetes or predia- mia and maternal/fetal risk, leading some risk and inappropriately test those at B betes at least every 3 years. experts to debate, and disagree on, opti- very low risk or even those who have Women with a history of gesta- c mal strategies for the diagnosis of GDM. already been diagnosed. tional diabetes mellitus found to have prediabetes should receive Testing for Type 2 Diabetes and One-Step Strategy lifestyle interventions or metfor- Prediabetes in Children and In the 2011 Standards of Care (39), the min to prevent diabetes. A Adolescents fi rst time recommended ADA for the In the last decade, the incidence and that all pregnant women not known to prevalence of type 2 diabetes in ado- have prior diabetes undergo a 75-g fi De nition lescents has increased dramatically, es- OGTT at 24 – 28 weeks of gestation, based fi ned as any Formanyyears,GDMwasde pecially in ethnic populations (16). on a recommendation of the Interna- fi degree of glucose intolerance that was rst Recent studies question the validity of tional Association of the Diabetes and recognized during pregnancy (10), regard- A1C in the pediatric population, espe- Pregnancy Study Groups (IADPSG) (40). less of whether the condition may have pre- cially among certain ethnicities, and ned diagnostic cut points fi The IADPSG de dated the pregnancy or persisted after the suggest OGTT or FPG as more suitable for GDM as the average glucose values nition facilitated a uni- fi pregnancy. This de diagnostic tests (33). However, many of (fasting, 1-h, and 2-h PG) in the HAPO form strategy for detection and classi fi cation these studies do not recognize that di- study at which odds for adverse out- of GDM, but it was limited by imprecision. abetes diagnostic criteria are based on comes reached 1.75 times the estimated The ongoing epidemic of obesity and comes, and valida- long-term health out odds of these outcomes at the mean glu- diabetes has led to more type 2 diabetes tions are not currently available in the cose levels of the study population. This in women of childbearing age, with an in- pediatric population (34). The ADA ac- one-step strategy was anticipated to sig- crease in the number of pregnant women knowledges the limited data support- ni fi cantly increase the incidence of GDM with undiagnosed type 2 diabetes (37). Be- ing A1C for diagnosing type 2 diabetes – – (from 5 20%), primarily be- 6% to 15 cause of the number of pregnant women in children and adolescents. Although cause only one abnormal value, not two, with undiagnosed type 2 diabetes, it is rea- A1C is not recommended for diagnosis cient to make the diagnosis. became suf fi sonable to test women with risk factors for bro- fi of diabetes in children with cystic The ADA recognized that the anticipated ) at their initial type 2 diabetes ( Table 2.2 sisorsymptomssuggestiveofacuteon- increase in the incidence of GDM would prenatal visit, using standard diagnostic set of type 1 diabetes and only A1C have signi fi cant impacton the costs, med- Table 2.1 ).Womenwithdiabetes criteria ( assays without interference are appro- ical infrastructure capacity, and potential fi in the fi rst trimester would be classi ed as priate for children with hemoglobinopa- of preg- ” medicalization “ for increased having type 2 diabetes. GDM is diabetes thies, the ADA continues to recommend nancies previously categorized as normal, diagnosed in the second or third trimester A1C for diagnosis of type 2 diabetes in but recommended these diagnostic crite- of pregnancy that is not clearly either ed recom- this cohort (35,36). The modi fi ria changes in the context of worrisome type 1 or type 2 diabetes (see Section 12 mendations of the ADA consensus worldwide increases in obesity and diabe- ). ” Management of Diabetes in Pregnancy “ Type 2 Diabetes in Children “ report tes rates with the intent of optimizing are summarized in ” and Adolescents gestational outcomes for women and Diagnosis Table 2.4 . their offspring. GDM carries risks for the mother and ne- onate. Not all adverse outcomes are of fi The expected bene ts to these preg- equal clinical importance. The Hypergly- nancies and offspring are inferred from GESTATIONAL DIABETES cemia and Adverse Pregnancy Outcome intervention trials that focused on MELLITUS women with lower levels of hyperglyce- (HAPO) study (38), a large-scale (25,000 Recommendations mia than identi fi ed using older GDM di- pregnant women) multinational cohort c Test for undiagnosed type 2 diabe- agnostic criteria and that found modest study, demonstrated that risk of adverse rst prenatal visit in fi tes at the fi ts including reduced rates of bene maternal, fetal, and neonatal outcomes those with risk factors, using stan- large-for-gestational-age births and pre- continuously increased as a function of B dard diagnostic criteria. eclampsia (41,42). It is important to maternal glycemia at 24 28 weeks, even – c Test for gestational diabetes mel- 90% of women being – note that 80 within ranges previously considered nor- litus at 24 – 28 weeks of gestation treated for mild GDM in two random- mal for pregnancy. For most complica- in pregnant women not previously tions, there was no threshold for risk. ized controlled trials (whose glucose val- A known to have diabetes. These results have led to careful reconsid- ues overlapped with the thresholds c Screen women with gestational di- eration of the diagnostic criteria for GDM. recommended by the IADPSG) could abetesmellitusforpersistentdiabe- )canbeaccom- Table 2.5 GDM diagnosis ( be managed with lifestyle therapy 12 weeks postpartum, – tes at 6 alone. Data are lacking on how the plished with either of two strategies:

26 cation and Diagnosis of Diabetes S19 fi Classi care.diabetesjournals.org Testing for type 2 diabetes or prediabetes in asymptomatic children* — Table 2.4 c Because a diagnosis of maturity- Criteria onset diabetes of the young may c Overweight (BMI . 85th percentile for age and sex, weight for height . 85th percentile, or impact therapy and lead to identi- . weight 120% of ideal for height) fi cation of other affected family Plus any two of the following risk factors: members, consider referring indi- Family history of type 2 diabetes in rst- or second-degree relative fi c viduals with diabetes not typical of c Islander) c Race/ethnicity (Native American, African American, Latino, Asian American, Paci fi type 1 or type 2 diabetes and oc- Signs of insulin resistance or conditions associated with insulin resistance (acanthosis c curing in successive generations nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational- age birth weight) (suggestive of an autosomal dom- ’ Maternal history of diabetes or GDM during the child c s gestation inant pattern of inheritance) to a Age of initiation: age 10 years or at onset of puberty, if puberty occurs at a younger age E specialist for further evaluation. Frequency: every 3 years # *Persons aged 18 years. -cell Monogenic defects that cause b dysfunction, such as neonatal diabetes and MODY, represent a small fraction of treatment of lower levels of hyperglyce- its guidelines in 2013 and supported the patients with diabetes ( , 5%). These mia affects a mother ’ sriskforthedevel- two-step approach (45). forms of diabetes are frequently charac- opment of type 2 diabetes in the future Future Considerations terized by onset of hyperglycemia at an s risk for obesity, di- ’ and her offspring fl icting recommendations from The con early age (generally before age 25 years). abetes, and other metabolic dysfunc- expert groups underscore the fact that tion. Additional well-designed clinical Neonatal Diabetes there are data to support each strategy. studies are needed to determine the op- Neonatal diabetes is a monogenic form of The decision of which strategy to imple- timal intensity of monitoring and treat- rst 6 months of fi diabetes with onset in the ment must therefore be made based on ment of women with GDM diagnosed by life. It can be mistaken for the more com- the relative values placed on factors that the one-step strategy. mon type 1 diabetes, but type 1 diabetes have yet to be measured (e.g., cost t – fi bene rarely occurs before 6 months of age. Neo- estimation, willingness to change prac- Two-Step Strategy natal diabetes can either be transient or tice based on correlation studies rather In 2013, the National Institutes of Health permanent. The most common genetic than clinical intervention trial results, rel- (NIH) convened a consensus develop- defect causing transient disease is a defect ative role of cost considerations, and avail- ment conference on diagnosing GDM. on ZAC/HYAMI imprinting, whereas per- cally, nationally, and able infrastructure lo The 15-member panel had representatives manent neonatal diabetes is most com- internationally). cology, maternal- from obstetrics/gyne monly an autosomal dominant defect in As the IADPSG criteria have been adop- fetal medicine, pediatrics, diabetes re- the gene encoding the Kir6.2 subunit of ted internationally, further evidence has search, biostatistics, and other related channel. Correct diagnosis -cell K b the emerged to support improved pregnancy ATP elds to consider diagnostic criteria (43). fi has important implications, because chil- outcomes with cost savings (46) and may The panel recommended the two-step dren with neonatal diabetes due to muta- be the preferred approach. In addition, approach of screening with a 1-h 50-g tions affecting Kir6.2 should be treated pregnancies complicated by GDM per glucose load test (GLT) followed by a 3-h with sulfonylureas rather than insulin. IADPSG criteria, but not recognized as 100-g OGTT for those who screen posi- such, have comparable outcomes to preg- tive, a strategy commonly used in the U.S. Maturity-Onset Diabetes of the Young nancies diagnosed as GDM by the more MODYischaracterizedbyimpairedinsulin Key factors reported in the NIH pan- stringent two-step criteria (47). There secretion with minimal or no defects in el s decision-making process were the ’ remains strong consensus that estab- insulin action. It is inherited in an autoso- lack of clinical trial interventions dem- lishing a uniform approach to diagnosing mal dominant pattern. Abnormalities at onstrating the bene ts of the one-step fi fi t patients, caregivers, GDM will bene six genetic loci on different chromosomes strategy and the potential negative con- and policymakers. Longer-term outcome fi ed to date. The most have been identi sequences of identifying a large new studies are currently under way. group of women with GDM, including common form (MODY 3) is associated with mutations on chromosome 12 in a medicalization of pregnancy with in- MONOGENIC DIABETES hepatic transcription factor referred to as creased interventions and costs. More- SYNDROMES a and hepatocyte nuclear factor (HNF)-1 over, screening with a 50-g GLT does not Recommendations also referred to as transcription factor-1 require fasting and is therefore easier to c All children diagnosed with diabe- (TCF-1). The second most common form accomplish for many women. Treat- rst 6 months of life fi tes in the (MODY 2) is associated with mutations in ment of higher threshold maternal should have genetic testing. B the glucokinase gene on chromosome 7p fi hyperglycemia, as identi ed by the two- Maturity-onset diabetes of the c and results in a defective glucokinase mol- step approach, reduces rates of neonatal young should be considered in indi- ecule. Glucokinase converts glucose to macrosomia, large-for-gestational-age viduals who have mild stable fasting glucose-6-phosphate, the metabolism of births (44), and shoulder dystocia, with- hyperglycemia and multiple family out increasing small-for-gestational-age which, in turn, stimulates insulin secretion members with diabetes not charac- b by the -cell. The less common forms of births. The American College of Obstetri- E teristic of type 1 or type 2 diabetes. MODY result from mutations in other cians and Gynecologists (ACOG) updated

27 Volume 39, Supplement 1, January 2016 cation and Diagnosis of Diabetes fi S20 Classi Diabetes Care occurring in about 20% of adolescents Screening for and diagnosis of GDM Table 2.5 — – 50% of adults. Diabetes in this and 40 One-step strategy population, compared with individuals Perform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 and with type 1 or type 2 diabetes, is asso- 2h,at24 28 weeks of gestation in women not previously diagnosed with overt diabetes. – ciated with worse nutritional status, The OGTT should be performed in the morning after an overnight fast of at least 8 h. fl ammatory lung dis- more severe in The diagnosis of GDM is made when any of the following plasma glucose values are met or ease, and greater mortality. Insulin in- exceeded: suf ciency is the primary defect in fi c Fasting: 92 mg/dL (5.1 mmol/L) 1 h: 180 mg/dL (10.0 mmol/L) c -cell CFRD. Genetically determined b c 2 h: 153 mg/dL (8.5 mmol/L) function and insulin resistance associ- Two-step strategy ammation fl ated with infection and in – Step 1: Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h, at 24 28 may also contribute to the develop- weeks of gestation in women not previously diagnosed with overt diabetes. ment of CFRD. Milder abnormalities $ If the plasma glucose level measured 1 h after the load is 140 mg/dL* (7.8 mmol/L), proceed of glucose tolerance are even more to a 100-g OGTT. common and occur at earlier ages Step 2: The 100-g OGTT should be performed when the patient is fasting. than CFRD. Although screening for di- The diagnosis of GDM is made if at least two of the following four plasma glucose levels abetes before the age of 10 years can (measured fasting and 1 h, 2 h, 3 h after the OGTT) are met or exceeded: identify risk for progression to CFRD Carpenter/Coustan (55) NDDG (56) or in those with abnormal glucose toler- ance, no bene fi t has been established 105 mg/dL (5.8 mmol/L) 95 mg/dL (5.3 mmol/L) Fasting c with respect to weight, height, BMI, 180 mg/dL (10.0 mmol/L) c 1 h 190 mg/dL (10.6 mmol/L) 165 mg/dL (9.2 mmol/L) c 155 mg/dL (8.6 mmol/L) 2 h or lung function. Continuous glucose c 145 mg/dL (8.0 mmol/L) 140 mg/dL (7.8 mmol/L) 3 h monitoring may be more sensitive than OGTT to detect risk for progres- NDDG, National Diabetes Data Group. *The ACOG recommends a lower threshold of 135 mg/dL (7.5 mmol/L) in high-risk ethnic populations with higher prevalence of GDM; some experts also sion to CFRD, but evidence linking recommend 130 mg/dL (7.2 mmol/L). continuous glucose monitoring results tolong-termoutcomesislacking without typical clinical features of , transcription factors, including HNF-4 a and its use is not recommended for type 2 diabetes , insulin promoter factor-1 (IPF-1), HNF-1 b screening (50). and NeuroD1. CRFD mortality has signi fi cantly de- – RELATED CYSTIC FIBROSIS creased over time, and the gap in mor- Diagnosis DIABETES brosis patients tality between cystic fi A diagnosis of MODY should be consid- with and without diabetes has consider- Recommendations ered in individuals who have atypical di- ably narrowed (51). There are limited fi Annual screening for cystic c brosis – abetes and multiple family members clinical trial data on therapy for CFRD. related diabetes with oral glucose with diabetes not characteristic of The largest study compared three regi- tolerance test should begin by age type 1 or type 2 diabetes. These individ- mens: premeal insulin aspart, repagli- 10 years in all patients with cystic uals should be referred to a specialist for brosis fi nide, or oral placebo in cystic fi brosis who do not have cystic further evaluation. Readily available patients with diabetes or abnormal B fi brosis – related diabetes. commercial genetic testing now enables glucose tolerance. Participants all had c A1C as a screening test for cystic a genetic diagnosis. It is important to cor- weight loss in the year preceding treat- brosis fi – related diabetes is not rectly diagnose one of the monogenic ment; however, in the insulin-treated B recommended. forms of diabetes because these patients group, this pattern was reversed, and related – c Patients with cystic fi brosis may be incorrectly diagnosed with type 1 patients gained 0.39 ( 6 0.21) BMI units diabetes should be treated with or type 2 diabetes, leading to suboptimal ( P 5 0.02). The repaglinide-treated insulin to attain individualized gly- treatment regimens and delays in diag- group had initial weight gain, but this cemic goals. A nosing other family members (48,49). was not sustained by 6 months. The pla- In patients with cystic fi c brosis and The diagnosis of monogenic diabetes cebo group continued to lose weight impaired glucose tolerance with- should be considered in children with (52). Insulin remains the most widely fi out con rmed diabetes, prandial fi ndings: the following used therapy for CFRD (53). insulin therapy should be consid- ○ Recommendations for the clinical rst Diabetes diagnosed within the fi B ered to maintain weight. management of CFRD can be found in 6monthsoflife Beginning 5 years after the diagnosis c ○ the ADA position statement Clinical “ f diabetes but with- Strong family history o related diabetes, of cystic – fi brosis Care Guidelines for Cystic Fibrosis – out typical features of type 2 diabetes annual monitoring for complications Related Diabetes: A Position Statement (nonobese, low-risk ethnic group) E of diabetes is recommended. ○ – 150 Mild fasting hyperglycemia (100 of the American Diabetes Association 8.5 mmol/L]), especially if – mg/dL [5.5 and a Clinical Practice Guideline of brosis fi Cystic related diabetes – the Cystic Fibrosis Foundation, En- young and nonobese ○ (CFRD) is the most common comor- dorsed by the Pediatric Endocrine Diabetes with negative diabetes- Society ” (54). associated autoantibodies and brosis, fi bidity in people with cystic

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Di- docrinol 2012;2012:31 body levels and their incorporation into an 1311 – abetes Care 2011;34:1306 autoantibody risk score in relatives of type 1 35. Kester LM, Hey H, Hannon TS. Using hemo- 6. Ziemer DC, Kolm P, Weintraub WS, et al. diabetic patients. Diabetes Care 2013;36: globin A1c for prediabetes and diabetes diagno- Glucose-independent, black-white differences in 2620 2615 – sis in adolescents: can adult recommendations hemoglobin A1c levels: a cross-sectional analysis be upheld for pediatric use? J Adolesc Health 21. Menke A, Casagrande S, Geiss L, Cowie CC. 777 – of 2 studies. Ann Intern Med 2010;152:770 – 2012;50:321 323 Prevalence of and trends in diabetes among 7. Kumar PR, Bhansali A, Ravikiran M, et al. Util- adults in the United States, 1988-2012. JAMA 36. Wu E-L, Kazzi NG, Lee JM. Cost-effectiveness ity of glycated hemoglobin in diagnosing type 1029 2015;314:1021 – of screening strategies for identifying pediatric di- 2 diabetes mellitus: a community-based study. n SJ, Borch-Johnsen K, Davies MJ, et al. abetes mellitus and dysglycemia. JAMA Pediatr fi 22. Grif – 2835 J Clin Endocrinol Metab 2010;95:2832 Effect of early intensive multifactorial therapy 39 – 2013;167:32 8. Selvin E, Steffes MW, Ballantyne CM, on 5-year cardiovascular outcomes in individu- 37. Lawrence JM, Contreras R, Chen W, Sacks Hoogeveen RC, Coresh J, Brancati FL. Racial dif- als with type 2 diabetes detected by screening DA. Trends in the prevalence of preexisting di- ferences in glycemic markers: a cross-sectional (ADDITION-Europe): a cluster-randomised trial. abetes and gestational diabetes mellitus analysis of community-based data. Ann Intern Lancet 2011;378:156 – 167 among a racially/ethnically diverse population Med 2011;154:303 309 – 23. Herman WH, Ye W, Grif fi nSJ,etal.Early of pregnant women, 1999-2005. Diabetes Care 9. Selvin E, Rawlings AM, Bergenstal RM, detection and treatment of type 2 diabetes re- 2008;31:899 – 904 Coresh J, Brancati FL. No racial differences in duce cardiovascular morbidity and mortality: a the association of glycated hemoglobin with 38. Metzger BE, Lowe LP, Dyer AR, et al.; HAPO simulation of the results of the Anglo-Danish- kidney disease and cardiovascular outcomes. Study Cooperative Research Group. Hyperglyce- Dutch Study of Intensive Treatment in People Diabetes Care 2013;36:2995 3001 – mia and adverse pregnancy outcomes. N Engl J With Screen-Detected Diabetes in Primary Care 10. Expert Committee on the Diagnosis and – 2002 Med 2008;358:1991 (ADDITION-Europe). Diabetes Care 2015;38: cation of Diabetes Mellitus. Report of fi Classi 39. American Diabetes Association. Standards 1449 1455 – the Expert Committee on the Diagnosis and d 2011. Diabetes of medical care in diabetes 24. Kahn R, Alperin P, Eddy D, et al. Age at ini- fi cation of Diabetes Mellitus. Diabetes Classi S61 – Care 2011;34(Suppl. 1):S11 tiation and frequency of screening to detect Care 1997;20:1183 – 1197 40. Metzger BE, Gabbe SG, Persson B, et al.; type 2 diabetes: a cost-effectiveness analysis. 11. Genuth S, Alberti KG, Bennett P, et al.; Expert International Association of Diabetes and 1374 Lancet 2010;375:1365 – cation of fi Committee on the Diagnosis and Classi Pregnancy Study Groups Consensus Panel. 25. Araneta MR, Kanaya AM, Hsu WC, et al. Opti- Diabetes Mellitus. Follow-up report on the diag- International Association of Diabetes and mum BMI cut points to screen Asian Americans for nosis of diabetes mellitus. Diabetes Care 2003;26: Pregnancy Study Groups recommendations – type 2 diabetes. Diabetes Care 2015;38:814 820 3167 – 3160 fi on the diagnosis and classi cation of hyper- 12. Zhang X, Gregg EW, Williamson DF, et al. 26. Hsu WC, Araneta MR, Kanaya AM, Chiang glycemia in pregnancy. Diabetes Care 2010; A1C level and future risk of diabetes: a system- JL, Fujimoto W. BMI cut points to identify at-risk – 682 33:676 atic review. Diabetes Care 2010;33:1665 – 1673 Asian Americans for type 2 diabetes screening. Eunice 41. Landon MB, Spong CY, Thom E, et al.; 13. Selvin E, Steffes MW, Zhu H, et al. Glycated Diabetes Care 2015;38:150 158 – National Institute of Child Kennedy Shriver hemoglobin, diabetes, and cardiovascular risk Health and Human Development Maternal-Fetal 27. WHO Expert Consultation. Appropriate in nondiabetic adults. N Engl J Med 2010;362: Medicine Units Network. A multicenter, ran- body-mass index for Asian populations and its – 811 800 domized trial of treatment for mild gestational implications for policy and intervention strate- 14. Ackermann RT, Cheng YJ, Williamson DF, – 1348 diabetes. N Engl J Med 2009;361:1339 gies. Lancet 2004;363:157 – 163 Gregg EW. Identifying adults at high risk for di- 42. Crowther CA, Hiller JE, Moss JR, McPhee AJ, 28. Chiu M, Austin PC, Manuel DG, Shah BR, Tu abetes and cardiovascular disease using hemo- Jeffries WS, Robinson JS; Australian Carbohy- JV. Deriving ethnic-speci fi c BMI cutoff points for globin A1c National Health and Nutrition drate Intolerance Study in Pregnant Women assessing diabetes risk. Diabetes Care 2011;34: Examination Survey 2005-2006. Am J Prev (ACHOIS) Trial Group. Effect of treatment of 1748 – 1741 Med 2011;40:11 17 – gestational diabetes mellitus on pregnancy out- 29. Erickson SC, Le L, Zakharyan A, et al. New- 15. Diabetes Prevention Program Research 2486 comes. N Engl J Med 2005;352:2477 – onset treatment-dependent diabetes mellitus Group. HbA1c as a predictor of diabetes and 43. Vandorsten JP, Dodson WC, Espeland MA, and hyperlipidemia associated with atypical an- as an outcome in the Diabetes Prevention Pro- et al. NIH consensus development confer- tipsychotic use in older adults without schizo- gram: a randomized clinical trial. Diabetes Care ence: diagnosing gestational diabetes melli- phrenia or bipolar disorder. J Am Geriatr Soc 2015;38:51 – 58 tus. NIH Consens State Sci Statements 2013; – 479 2012;60:474 29:1 31 – 30. Knowler WC, Barrett-Connor E, Fowler SE, 16. Dabelea D, Mayer-Davis EJ, Saydah S, et al.; 44. Horvath K, Koch K, Jeitler K, et al. Effects of et al.; Diabetes Prevention Program Research SEARCH for Diabetes in Youth Study. Prevalence treatment in women with gestational diabetes Group. Reduction in the incidence of type 2 di- of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA 2014; mellitus: systematic review and meta-analysis. abetes with lifestyle intervention or metformin. 311:1778 – 1786 BMJ 2010;340:c1395 – N Engl J Med 2002;346:393 403

29 Volume 39, Supplement 1, January 2016 Diabetes Care cation and Diagnosis of Diabetes fi S22 Classi 45. Committee on Practice Bulletins Obstetrics. – 49. Rubio-Cabezas O, Hattersley AT, Njølstad Therapy trial. Diabetes Care 2009;32:1783 – Practice Bulletin No. 137: gestational diabetes PR, et al.; International Society for Pediatric 1788 416 – mellitus. Obstet Gynecol 2013;122:406 and Adolescent Diabetes. ISPAD Clinical Practice 53. Onady GM, Stol fi A. Insulin and oral agents ́ ́ aenz S, Torrej on MJ, et al. Intro- 46. Duran A, S Consensus Guidelines 2014. The diagnosis and brosis-related diabetes. for managing cystic fi duction of IADPSG criteria for the screening and management of monogenic diabetes in children Cochrane Database Syst Rev 2013;7:CD004730 diagnosis of gestational diabetes mellitus re- and adolescents. Pediatr Diabetes 2014;15 54. Moran A, Brunzell C, Cohen RC, et al.; CFRD sultsinimprovedpre gnancy outcomes at a – (Suppl. 20):47 64 Guidelines Committee. Clinical care guidelines lower cost in a large cohort of pregnant women: 50. Ode KL, Moran A. New insights into cystic fi for cystic brosis-related diabetes: a position the St. Carlos Gestational Diabetes Study. fi brosis-related diabetes in children. Lancet Di- statement of the American Diabetes Associa- Diabetes Care 2014;37:2442 2450 – 58 – abetes Endocrinol 2013;1:52 tion and a clinical practice guideline of the Cystic 47. Ethridge JK Jr, Catalano PM, Waters TP. Peri- 51. Moran A, Dunitz J, Nathan B, Saeed A, Fibrosis Foundation, endorsed by the Pediatric natal outcomes associated with the diagnosis of Holme B, Thomas W. Cystic fi brosis-related di- Endocrine Society. Diabetes Care 2010;33: gestational diabetes made by the International abetes: current trends in prevalence, incidence, – 2708 2697 Association of the Diabetes and Pregnancy Study and mortality. Diabetes Care 2009;32:1626 – 55. Carpenter MW, Coustan DR. Criteria for – Groups criteria. Obstet Gynecol 2014;124:571 1631 screening tests for gestational diabetes. Am J 578 52. Moran A, Pekow P, Grover P, et al.; Cystic 773 Obstet Gynecol 1982;144:768 – 48. Hattersley A, Bruining J, Shield J, Njolstad P, Fibrosis Related Diabetes Therapy Study Group. 56. National Diabetes Data Group. Classi ca- fi Donaghue KC. The diagnosis and management of Insulin therapy to improve BMI in cystic fi brosis- tion and diagnosis of di abetes mellitus and monogenic diabetes in children and adolescents. related diabetes without fasting hyperglycemia: other categories of glucose intolerance. Diabe- 42 – Pediatr Diabetes 2009;10(Suppl. 12):33 results of the Cystic Fibrosis Related Diabetes tes 1979;28:1039 – 1057

30 Diabetes Care Volume 39, Supplement 1, January 2016 S23 American Diabetes Association 3. Foundations of Care and Comprehensive Medical Evaluation DOI: 10.2337/dc16-S006 Diabetes Care 2016;39(Suppl. 1):S23 – | S35 The foundations of care include self-management education, nutrition, counseling, physical activity, smoking cessation, immunizations, psychosocial care, and med- ications (covered in other sections). The comprehensive medical evaluation in- cludes the initial and ongoing evaluations, assessment of complications, management of comorbid conditions, and engagement of the patient throughout the process. 3. FOUNDATIONS OF CARE FOUNDATIONS OF CARE Optimal diabetes management starts with laying down the foundations of care. The health care provider must take a holistic approach in providing care, accounting for s life circumstances. A team approach to diabetes man- all aspects of the patient ’ agement facilitates a comprehensive assessment and development of a plan that s values and circumstances. The investment of time and ’ addresses the patient ally expedite, care delivery and achieve collaboration can facilitate, and potenti and maintain outcomes. The initial clinical evaluation should be as comprehensive as possible as the pa- tient will now have to address behavioral, dietary, lifestyle, and pharmaceutical interventions to effectively manage this newly identi ed chronic condition. The fi ) will provide Table 3.1 components for the comprehensive medical evaluation ( the health care team with information necessary to optimally support a patient with diabetes. In addition to the medical history and physical examination, labora- tory tests, nutrition, and psychosocial assessments should be obtained. Patient Engagement ” As discussed in Section 1 “ Strategies for Improving Care, the Chronic Care Model (CCM) has been shown to be an effective framework for improving the quality of – 3). This is a patient-centered approach to care that requires a close diabetes care (1 working relationship between the patient and clinicians involved in care planning and delivery. The foundation of successful diabetes management includes ongoing individual lifestyle and behavioral changes, engagement of the patient, and assess- s level of understanding about the disease and level of pre- ment of the patient ’ paredness for self-management. BASIS FOR INITIAL CARE Diabetes self-management education (DS ME), diabetes self-management sup- py (MNT), counseling on smoking cessa- port (DSMS), medical nutrition thera tion, education on physical activity, guidance on routine immunizations, and of diabetes management. Patients psychosocial care are the cornerstone should be referred for such services if not readily available in the clinical care setting, i.e., referral for DSME, DSMS, MNT, and emotional health con- cerns. Additionally, specialty and lif estyle change services and programs may Suggested citation: American Diabetes Associa- tion. Foundations of care and comprehensive Table 3.2 ). Patients should also re ceive recommended preven- cial ( fi be bene medical evaluation. Sec. 3. In Standards of Med- tive care services (e.g., cancer screening and immunizations); referral for smok- ical Care in Diabetes d 2016 . Diabetes Care ing cessation, if needed; and podiatric, ophthalmological, and dental referrals. S35 2016;39(Suppl. 1):S23 – als with diabetes are screened for com- Clinicians should ensure that individu © 2016 by the American Diabetes Association. plications and comorbidities. Identifyi ng and implementing the initial approach Readers may use this article as long as the work to glycemic control with the patient is one part, not the sole aspect, of the is properly cited, the use is educational and not fi t, and the work is not altered. for pro comprehensive care strategy.

31 Volume 39, Supplement 1, January 2016 S24 Foundations of Care and Comprehensive Medical Evaluation Diabetes Care psychosocial care). Various strategies — Table 3.1 Components of the comprehensive diabetes medical evaluation and techniques should be used to enable Medical history patients to self-manage diabetes, includ- c Age and characteristics of onset of diabetes (e.g., diabetic ketoacidosis, asymptomatic nding) laboratory fi ing providing education on problem- c Eating patterns, nutritional status, weight history, and physical activity habits; nutrition solving skills for all aspects of diabetes education and behavioral support history and needs management. Treatment goals and plans Presence of common comorbidities, psychosocial problems, and dental disease c should be individualized and take patient c Screen for depression using PHQ-2 (PHQ-9 if PHQ-2 is positive) or Edinburgh Postnatal preferences into account. In developing Depression Scale (EPDS) the plan, health care providers should c Screen for diabetes distress using DDS or PAID-1 ’ s age, school/work consider the patient History of smoking, alcohol consumption, and substance use c c Diabetes education, self-management, and support history and needs schedule and conditions, physical activ- c Review of previous treatment regimens and response to therapy (A1C records) ity, eating patterns, social situation, cul- Results of glucose monitoring and patient s use of data c ’ tural factors, diabetes complications, Diabetic ketoacidosis frequency, severity, and cause c health priorities, other medical condi- c Hypoglycemia episodes, awareness, and frequency and causes tions, preferences for care and self- c History of increased blood pressure, increased lipids, and tobacco use management, and life expectancy. c Microvascular complications: retinopathy, nephropathy, and neuropathy (sensory, including history of foot lesions; autonomic, including sexual dysfunction and gastroparesis) DIABETES SELF-MANAGEMENT Macrovascular complications: coronary heart disease, cerebrovascular disease, and c EDUCATION AND SUPPORT peripheral arterial disease Physical examination Recommendations c Height, weight, and BMI; growth and pubertal development in children and adolescents In accordance with the national c Blood pressure determination, including orthostatic measurements when indicated c standards for diabetes self-man- Fundoscopic examination c agement education (DSME) and c Thyroid palpation Skin examination (e.g., for acanthosis nigricans, insulin injection or infusion set insertion c support (DSMS), all people with di- sites) abetes should participate in DSME c Comprehensive foot examination to facilitate the knowledge, skills, Inspection c and ability necessary for diabetes c Palpation of dorsalis pedis and posterior tibial pulses self-care and in DSMS to assist with Presence/absence of patellar and Achilles re fl exes c implementing and sustaining skills Determination of proprioception, vibration, and mono fi lament sensation c and behaviors needed for ongoing Laboratory evaluation self-management, both at diagnosis c A1C, if the results are not available within the past 3 months If not performed/available within the past year c B andasneededthereafter. c le, including total, LDL, and HDL cholesterol and triglycerides, as needed Fasting lipid pro fi Effective self-management, im- c c Liver function tests proved clinical outcomes, health Spot urinary albumin – to – creatinine ratio c status, and quality of life are key fi ltration rate c Serum creatinine and estimated glomerular outcomes of DSME and DSMS and Thyroid-stimulating hormone in patients with type 1 diabetes or dyslipidemia or women c should be measured and moni- aged . 50 years tored as part of care. C DSME and DSMS should be patient c centered, respectful, and respon- ONGOING CARE MANAGEMENT with diabetes must assume an active sive to individual patient prefer- People with diabetes should receive role in their care. ences, needs, and values, which medical care from a collaborative, inte- The patient, family, physician, and A should guide clinical decisions. grated team with diabetes expertise. other members of the health care team c DSME and DSMS programs should This team may include physicians, nurse should formulate the management plan. have the necessary elements in practitioners, physician assistants, Integral components of the management their curricula that are needed to nurses, dietitians, exercise specialists, plan include the foundations of care prevent the onset of diabetes. pharmacists, dentists, podiatrists, and (DSME, DSMS, MNT, smoking cessation, DSME and DSMS programs should mental health professionals. Individuals physical activity, immunizations, and therefore tailor their content spe- cally when prevention of diabe- ci fi tes is the desired goal. B c Because DSME and DSMS can re- Referrals for initial care management — Table 3.2 Eye care professional for annual dilated eye exam c sult in cost savings and improved c Family planning for women of reproductive age ,DSMEandDSMS B outcomes c Registered dietitian for MNT should be adequately reimbursed E by third-party payers. DSME/DSMS c c Dentist for comprehensive dental and periodontal examination DSME and DSMS are the ongoing c Mental health professional, if indicated processes of facilitating the knowledge,

32 Foundations of Care and Comprehensive Medical Evaluation S25 care.diabetesjournals.org skills, and ability necessary for diabetes (10,13), healthy coping (14,15), and types of diabetes and be supportive of self-care. These pro cesses incorporate lower costs (16,17). Better outcomes their implementation. See Table 3.3 for the needs, goals, and life experiences were reported for DSME interventions fi c nutrition recommendations. speci of the person with diabetes. The overall that were longer ( 10 h) and included . Goals of Medical Nutrition Therapy objectives of DSME and DSMS are to follow-up support (DSMS) (18,19), were for Adults With Diabetes support informed decision making, culturally (20,21) and age appropriate 1. To promote and support healthful eat- self-care behaviors, problem solving, (22,23), were tailored to individual ing patterns, emphasizing a variety of and active collaboration with the health needs and preferences, and addressed nutrient-dense foods in appropriate care team to improve clinical outcomes, psychosocial issues and incorporated portion sizes, in order to improve health status, and quality of life in a behavioral strategies (5,14,24,25). Both cally to fi overall health and speci cost-effective manner (4). individual and group approaches have ○ Achieve and maintain body weight DSME and DSMS are essential ele- been found effective (12,26). There is goals ments of diabetes care (5,6), and the growing evidence for the role of com- ○ Attain individualized glycemic, current national standards for DSME munity health workers (27), as well as blood pressure, and lipid goals and DSMS (4) are based on the evidence peer (27 29) and lay (30) leaders, in pro- – ○ Delay or prevent complications of of their bene ts. Education helps people fi viding ongoing support. diabetes with diabetes to initiate effective self- DSME is associated with increased pri- 2. To address individual nutrition needs management and cope with diabetes mary and preventive service use based on personal and cultural prefer- rst diagnosed. Ongoing fi when they are (16,31,32) and lower acute, inpatient hos- ences, health literacy and numeracy, DSMS helps people with diabetes to pital service use (11). Patients who partic- access to healthful foods, willingness e self-management maintain effectiv ipate in DSME are more likely to follow and ability to make behavioral changes, throughout a lifetime of diabetes as best practice treatment recommenda- andbarrierstochange they face new challenges and as treat- tions, particularly among the Medicare 3. To maintain the pleasure of eating by ment advances become available. population, and have lower Medicare providing nonjudgmental messages The DSME and DSMS algorithm de- and insurance claim costs (17,31). about food choices nes four critical time points for DSME fi 4. To provide an individual with diabe- Reimbursement and DSMS delivery (7): tes with practical tools for develop- DSME and DSMS, when provided by a 1. At diagnosis ing healthful eating patterns rather program that meets the national stan- 2. Annually for assessment of educa- than focusing on individual macronu- dards (4) and is recognized by the Amer- tion, nutrition, and emotional needs trients, micronutrients, or single ican Diabetes Association (ADA) or other 3. When new complicating factors arise foods approval bodies, are reimbursed as part fl that in uence self-management of the Medicare program as overseen by 4. When transitions in care occur MNT is an integral component of diabe- the Centers for Medicare & Medicaid Ser- tes prevention, management, and self- vices. DSME is also covered by most Current best practice of DSME is a skill- management education. All individuals health insurance plans. Although DSMS based approach that focuses on helping with diabetes should receive individual- has been shown to be instrumental for those with diabetes to make informed ized MNT, preferably provided by a reg- improving outcomes and can be provided self-management choices (4,5). DSME has istered dietitian who is knowledgeable via phone calls and telehealth, it currently changed from a didactic approach that c fi and skilled in providing diabetes-speci has limited reimbursement as compared focusedonprovidinginformationtoem- MNT. MNT delivered by a registered di- with in-person follow-up to DSME. powerment models that focus on helping 1% – etitian shows A1C decreases of 0.3 those with diabetes to make informed self- 37) for people with type 1 diabetes (35 – MEDICAL NUTRITION THERAPY management decisions (5). Diabetes care – 2% for people with type 2 di- and 0.5 For many individuals with diabetes, the has shifted to an approach that is more 41). – abetes (38 most challenging part of the treatment patient centered and places the person plan is determining what to eat. It is the Weight Management with diabetes and his or her family at the Intensive lifestyle programs with fre- position of the ADA that there is not a center of the care model, working in col- quent follow-up are required to achieve ts-all eating pattern for individ- one-size- fi laboration with health care professionals. cant reductions in excess body signi fi uals with diabetes. The ADA recognizes Patient-centered care is respectful of and weight and improve clinical indicators. the integral role of MNT in overall diabe- responsive to individual patient prefer- There is strong and consistent evidence tes management and recommends that ences, needs, and values. It ensures that that obesity management can delay pro- each person with diabetes be actively en- patient values guide all decision making (8). gression from prediabetes to type 2 di- gaged in self-management, education, fi ts type 2 abetes (42,43) and bene and treatment planning with his or her ts Evidence for the Bene fi diabetes treatment. health care team, including the collabora- Studies have found that DSME is associ- In overweight and obese patients tive development of an individualized ated with improved diabetes knowl- with type 2 diabetes, modest weight eating plan (33,34). Therefore, it is impor- edge, improved self-care behaviors (4), ned as sustained reduction of fi loss, de tant that each member of the health care lower A1C (6,9,10), lower self-reported 5% of initial body weight, has been team be knowledgeable about nutrition weight (11,12), improved quality of life showntoimproveglycemiccontrol therapy principles for people with all

33 Volume 39, Supplement 1, January 2016 Diabetes Care S26 Foundations of Care and Comprehensive Medical Evaluation Table 3.3 Nutrition therapy recommendations — Recommendations Topic Evidence rating c A An individualized MNT program, preferably provided by a registered dietitian, is Effectiveness of nutrition therapy recommended for all people with type 1 or type 2 diabetes. A For people with type 1 diabetes or those with type 2 diabetes who are prescribed c fl a exible insulin therapy program, education on how to use carbohydrate counting or estimation to determine mealtime insulin dosing can improve glycemic control. xed, having a consistent pattern of B c fi For individuals whose daily insulin dosing is carbohydrate intake with respect to time and amount can result in improved glycemic control and a reduced risk of hypoglycemia. C A simple and effective approach to glycemia and weight management c emphasizing healthy food choices and portion control may be more helpful for those with type 2 diabetes who are not taking insulin, who have limited health literacy or numeracy, and who are elderly and prone to hypoglycemia. B c Because diabetes nutrition therapy can result in cost savings E B and improved , A , outcomes (e.g., A1C reduction) A , MNT should be adequately reimbursed by E insurance and other payers. A cation and Modest weight loss achievable by the combination of lifestyle modi fi c Energy balance fi ts overweight or obese adults with type 2 the reduction of energy intake bene diabetes and also those at risk for diabetes. Interventional programs to facilitate this process are recommended. c As there is no single ideal dietary distribution of calories among carbohydrates, E Eating patterns and macronutrient fats, and proteins for people with diabetes, macronutrient distribution should be distribution individualized while keeping total calorie and metabolic goals in mind. c Carbohydrate intake from whole grains, vegetables, fruits, legumes, and dairy B ber and lower in glycemic load, fi products, with an emphasis on foods higher in should be advised over other sources, especially those containing sugars. People with diabetes and those at risk should avoid sugar-sweetened beverages c A , B B in order to control weight and reduce their risk for CVD and fatty liver and should minimize the consumption of sucrose-containing foods that have the A capacity to displace healthier, more nutrient-dense food choices. In individuals with type 2 diabetes, ingested protein appears to increase insulin B c Protein response without increasing plasma glucose concentrations. Therefore, carbohydrate sources high in protein should not be used to treat or prevent hypoglycemia. Whereas data on the ideal total dietary fat content for people with diabetes are B c Dietary fat inconclusive, an eating plan emphasizing elements of a Mediterranean-style diet rich in monounsaturated fats may improve glucose metabolism and lower CVD risk and can be an effective alternative to a diet low in total fat but relatively high in carbohydrates. sh (EPA and , c Eating foods rich in long-chain omega-3 fatty acids, such as fatty A fi B DHA) and nuts and seeds (ALA), is recommended to prevent or treat CVD ; B cial role for omega-3 dietary fi however, evidence does not support a bene supplements. A c There is no clear evidence that dietary supplementation with vitamins, minerals, C Micronutrients and herbal supplements herbs, or spices can improve diabetes, and there may be safety concerns regarding the long-term use of antioxidant supplements such as vitamins E and C and carotene. C c Adults with diabetes who drink alcohol should do so in moderation (no more Alcohol than one drink per day for adult women and no more than two drinks per day for adult men). c Alcohol consumption may place people with diabetes at increased risk for B delayed hypoglycemia, especially if taking insulin or insulin secretagogues. Education and awareness regarding the recognition and management of delayed hypoglycemia are warranted. As for the general population, people with diabetes should limit sodium c B Sodium , consumption to 2,300 mg/day, although further restriction may be indicated for those with both diabetes and hypertension.

34 Foundations of Care and Comprehensive Medical Evaluation S27 care.diabetesjournals.org and to reduce the need for glucose- omega-3 fatty acids did not improve glyce- from meal to meal and improving glycemic 46). Weight lowering medications (44 – mic control in individuals with type 2 di- control (36,51,57,58). For individuals on a loss can be attained with lifestyle programs abetes (53). Randomized controlled trials fi xed daily insulin schedule, meal planning that achieve a 500 750 kcal/day energy – also do not support recommending fi should emphasize a relatively xed carbo- 1,500 kcal/day cit or provide fi de 1,200 – ; omega-3 supplements for primary or sec- hydrate consumption pattern with respect for women and 1,500 – 1,800 kcal/day for ondarypreventionofCVD(69 – 73). People to both time and amount (34). By men, adjusted for the individual ’ s baseline with diabetes should be advised to follow contrast, a simpler diabetes meal planning ts may be body weight. Although bene fi the guidelines for the general population approach emphasizing portion control and seen with as little as 5% weight loss, sus- forthe recommended intakes of saturated healthful food choices may be better $ 7% is optimal. tained weight loss of trans fat, dietary cholesterol, and fat (64). suited for some elderly individuals, those These diets may differ in the types of trans In general, fats should be avoided. with cognitive dysfunction, and those for foods they restrict (such as high-fat or whom there are concerns over health lit- Sodium high-carbohydrate foods) but are effec- 36,38,51,57). – eracy and numeracy (34 As for the general population, people with tive if they create the necessary energy diabetes should limit their sodium con- de 50). The diet choice should cit (47 – fi Protein sumption to , 2,300 mg/day. Lowering be based on the patients health status ’ For individuals without evidence of dia- sodium intake (i.e., 1,500 mg/day) may and preferences. he evidence is incon- betic kidney disease, t bene fi t blood pressure in certain circum- clusive about recommending an ideal stances (74). The American Heart Associa- Carbohydrates amount of protein for optimizing glycemic tion recommends 1,500 mg/day for Studies examining the ideal amount of control or for improving one or more CVD African Americans; people diagnosed carbohydrate intake for people with dia- risk measures (53). Therefore, these goals with hypertension, diabetes, or chronic betes are inconclusive, although monitor- should be individualized. For those with di- kidney disease; and people over 51 years ing carbohydrate intake and considering abetic kidney disease (with albuminuria, of age (75). However, other studies (76,77) thebloodglucoseresponsetodietarycar- fi reduced estimated glomerular ltration have recommended caution for universal bohydrate are key for improving post- rate), dietary protein should be maintained sodium restriction to 1,500 mg in this pop- prandial glucose control (51,52). The at the recommended daily allowance of ulation. Sodium intake recommendations literature concerning glycemic index and 0.8 g/kg body weight per day. Reducing should take into account palatability, avail- glycemic load in individuals with diabetes the amount of dietary protein below ability, affordability, and the dif culty of fi is complex. Although in some studies low- the recommended daily allowance is achieving low-sodium recommendations ering the glycemic load of consumed not recommended because it does not in a nutritionally adequate diet (78). carbohydrates has d emonstrated A1C alter glycemic measures, cardiovascular For complete discussion and refer- reductions of 0.2% to 2 0.5% (53,54), a 2 risk measures, or the rate at which glo- ences of all recommendations, see the systematic review (53) found that whole- fi ltration rate declines (59,60). merular ADA position statement “ Nutrition Ther- grain consumption was not associated In individuals with type 2 diabetes, in- apy Recommendations for the Manage- with improvements in glycemic control gested protein may enhance the insulin ” ment of Adults With Diabetes (34). in type 2 diabetes. One study did fi nd a response to dietary carbohydrates (61). t of whole-grain intake in potential bene fi Therefore, carbohydrate sources high in PHYSICAL ACTIVITY reducing mortality and cardiovascular dis- protein should not be used to treat or pre- ease (CVD) among individuals with type 2 vent hypoglycemia. The effects of protein Recommendations diabetes (55). As for all Americans, indi- intake on blood glucose levels in type 1 c Children with diabetes or predia- viduals with diabetes should be encour- diabetes are less clear. betes should be encouraged to en- ned carbohydrates fi aged to replace re gage in at least 60 min of physical and added sugars with whole grains, Fats B activity each day. Limited research exists concerning the legumes, vegetables, and fruits. The con- c Adults with diabetes should be ad- ideal amount of fat for individuals with di- sumption of sugar-sweetened beverages visedtoperformatleast150min/ abetes. The Institute of Medicine has nonfat “ or ” low-fat “ and ” products with week of moderate-intensity aerobic de fi ned an acceptable macronutrient dis- high amounts of re ned grains and added fi physical activity (50 – 70% of maxi- tribution range for all adults for total fat of sugars should be discouraged (56). mum heart rate), spread over at least – 35% of energy with no tolerable upper 20 Individuals with type 1 or type 2 diabe- 3 days/week with no more than 2 ned (62). The type of fatty fi intake level de tes taking insulin at mealtimes should be consecutive days without exercise. A acids consumed is more important than offered intensive education on coupling All individuals, including those with c total amount of fat when looking at meta- insulin administration with carbohydrate diabetes, should be encouraged to bolic goals and CVD risk (63 65). Multiple – intake. For people whose meal schedules reduce sedentary time, particularly randomized controlled trials including pa- or carbohydrate consumption is variable, by breaking up extended amounts tients with type 2 diabetes have reported regular counseling to help them to under- of time ( B 90 min) spent sitting. . that a Mediterranean-style eating pattern stand the complex relationship between In the absence of contraindications, c – (63,66 68), rich in monounsaturated fats, carbohydrate intake and insulin needs, as adults with type 2 diabetes should be can improve both glycemic control and well as the carbohydrate-counting ap- encouraged to perform resistance blood lipids. However, a systematic review proach to meal planning, can assist them training at least twice per week. A concluded that dietary supplements with with effectively modifying insulin dosing

35 Volume 39, Supplement 1, January 2016 Diabetes Care S28 Foundations of Care and Comprehensive Medical Evaluation Physical activity is a general term that over age 18 years do 150 min/week of careful history being aware of the atyp- includes all movement that increases en- moderate-intensity or 75 min/week of ical presentation of coronary artery dis- ergy use and is an important part of the vigorous-intensity aerobic physical activ- ease in patients with diabetes and assess diabetes management plan. Exercise is a ity, or an equivalent combination of the other cardiovascular risk factors. Cer- fi c form of physical activity more speci two. In addition, the guidelines suggest tainly, high-risk patients should be en- that is structured and designed to im- that adults do muscle-strengthening activ- couraged to start with short periods of fi tness. Although both prove physical ities that involve all major muscle groups 2 low-intensity exercise and slowly in- are important, exercise has been shown or more days/week. The guidelines sug- crease the intensity and duration. Pro- to improve blood glucose control, reduce gest that adults over age 65 years or those viders should assess patients for cardiovascular risk factors, contribute to with disabilities follow the adult guide- conditions that might contraindicate weight loss, and improve well-being. lines if possible or, if this is not possible, certain types of exercise or predis- Physical activity is as important for those be as physically active as they are able. pose to injury, such as uncontrolled with type 1 diabetes asitisfor thegeneral Recent evidence supports that all indi- hypertension, autonomic neuropathy, fi c role in pre- population, but its speci viduals, including those with diabetes, peripheral neuropathy, a history of venting diabetes complications and con- should be encouraged to reduce the ated proliferative foot lesions, and untre trolling blood glucose is not as clear as it is amount of time spent being sedentary retinopathy. The patient ’ s age and pre- for those with type 2 diabetes. (e.g., working at a computer, watching vious physical activity level should be Furthermore, regular exercise may TV), particularly, by breaking up extended considered. The provider should cus- prevent type 2 diabetes in high-risk in- amounts of time ( . 90 min) spent sitting tomize the exercise regimen to the Pre- “ dividuals (43,79,80) (see Section 4 y standing or walking (87). fl by brie ’ s needs. Those with compli- individual vention or Delay of Type 2 Diabetes ” ). cations may require a more thorough Structured exercise interventions of at evaluation (81). Physical Activity and Glycemic least 8 weeks duration have been ’ Control Hypoglycemia showntolowerA1Cbyanaverageof On the basis of physical activity studies In individuals taking insulin and/or insu- 0.66% in people with type 2 diabetes, that include people with diabetes, it is lin secretagogues, physical activity may fi cant change in BMI even with no signi reasonable to recommend that people cause hypoglycemia if the medication onsiderable data (80). There are also c cally bene t with diabetes will speci fi fi dose or carbohydrate consumption is fi for the health bene ts (e.g., increased from following the U.S. Department of not altered. Individuals on these thera- tness, muscle strength, fi cardiovascular ’ physical ac- Health and Human Services pies may need to ingest some added improved insulin sensitivity, etc.) of reg- tivity guidelines. For example, studies in- carbohydrate if pre-exercise glucose lev- ular exercise for those with type 1 dia- cluded in the meta-analysis of the effects els are , 100 mg/dL (5.6 mmol/L), de- betes (81). Higher levels of exercise ofexercise interventions on glycemiccon- pending on whether they can lower intensity are associated with greater im- trol (80) reported a mean of 3.4 sessions/ insulin levels during the workout (such fi provements in A1C and in tness (82). week, with a mean of 49 min/session. as with an insulin pump or reduced pre- Other bene fi ts include slowing the de- Clinical trials have provided strong evi- exercise insulin dosage), the time of day cline in mobility among overweight pa- dence for the A1C-lowering value of resis- exercise is done, and the intensity and Exercise and tients with diabetes (83). “ tance training in older adults with type 2 duration of the activity. Hypoglycemia is Type 2 Diabetes: The American College tof fi diabetes (84) and for an additive bene less common in patients with diabetes of Sports Medicine and the American combined aerobic and resistance exercise who are not treated with insulin or in- Diabetes Association: Joint Position in adults with type 2 diabetes (88,89). If sulin secretagogues, and no preventive Statement ” (84) reviews the evidence not contraindicated, patients with type 2 measures for hypoglycemia are usually fi ts of exercise in people for the bene diabetes should be encouraged to do at advised in these cases. Intense activities with type 2 diabetes. least two weekly sessions of resistance ex- may actually raise blood glucose levels ercise (exercise with free weights or instead of lowering them (91). Exercise and Children weight machines), with each session con- As is recommended for all children, chil- sisting of at least one set of fi ve or more c Exercise in the Presence of Speci fi dren with diabetes or prediabetes should different resistance exercises involving the Long-term Complications of Diabetes be encouraged to engage in at least 60 largemusclegroups(84). Retinopathy minofphysicalactivityeachday.Included If proliferative diabetic retinopathy or se- in the 60 min each day, children should Pre-exercise Evaluation vere nonproliferative diabetic retinopa- engage in vigorous-intensity aerobic ac- Car- As discussed more fully in Section 8 “ thy is present, then vigorous-intensity tivity, muscle-strengthening activities, diovascular Disease and Risk Manage- aerobic or resistance exercise may be and bone-strengthening activities at least the best protocol for screening ” ment, contraindicated because of the risk of 3 of those days (85). asymptomatic patients with diabetes triggering vitreous hemorrhage or retinal forcoronaryarterydiseaseremains detachment (92). unclear. The ADA consensus report Frequency and Type of Physical Peripheral Neuropathy Screening for Coronary Artery Disease “ Activity Decreased pain sensation and a higher The U.S. Department of Health and Hu- (90) con- ” in Patients With Diabetes ’ man Services physical activity guidelines pain threshold in the extremities result cluded that routine testing is not recom- in an increased risk of skin breakdown, for Americans (86) suggest that adults mended. Providers should perform a

36 Foundations of Care and Comprehensive Medical Evaluation S29 care.diabetesjournals.org infection, and Charcot joint destruction Results from epidemiological, case-control, Administer hepatitis B vaccine to c with some forms of exercise. There- and cohort studies provide convincing ev- unvaccinated adults with diabetes fore, a thorough assessment should idence to support the causal link between who are aged 19 – 59 years. C be done to ensure that neuropathy cigarette smoking and health risks (97). c Consider administering hepatitis B does not alter kinesthetic or propriocep- Other studies of individuals with diabetes vaccine to unvaccinated adults tive sensation during physical activity. consistently demonstrate that smokers 60 $ with diabetes who are aged Studies have shown that moderate- (and people exposed to secondhand years. C intensity walking may not lead to an smoke) have a heightened risk of CVD, increased risk of foot ulcers or reulcera- premature death, and microvascular As for the general population, all chil- tion in those with peripheral neuropa- complications. Smoking may have a role dren and adults with diabetes should re- thy who use proper footwear (93). In in the development of type 2 diabetes ceive routine vaccinations (105,106) addition, 150 min/week of moderate (98). One study in smokers with newly fi according to age-speci c recommenda- exercise was reported to improve out- diagnosed type 2 diabetes found that tions (see the adult vaccination sched- comes in patients with milder forms smoking cessation was associated with available from http://www.cdc.gov/ ule of neuropathy (94). All individuals with amelioration of metabolic parameters vaccines/schedules/hcp/imz/adult.html peripheral neuropathy should wear and reduced blood pressure and albumin- child and adolescent vaccina- and the proper footwear and examine their uria at 1 year (99). available from http:// tion schedule feet daily to detect lesions early. Any- The routine and thorough assessment www.cdc.gov/vaccines/schedules/hcp/ one with a foot injury or open sore of tobacco use is essential to prevent imz/child-adolescent.html). weight- should be restricted to non – smoking or encourage cessation. Nu- The Centers for Disease Control and bearing activities. merous large randomized clinical trials Prevention (CDC) Advisory Committee cacy and cost- have demonstrated the ef fi Autonomic Neuropathy on Immunization Practices recommends effectiveness of brief counseling in smoking Autonomic neuropathy can increase the uenza and pneumococcal vaccines fl in cessation, including the use of telephone risk of exercise-induced injury or ad- for all individuals with diabetes (http:// quit lines,in reducingtobaccouse.Forthe verse events through decreased cardiac www.cdc.gov/vaccines/schedules). patient motivated to quit, the addition of responsiveness to exercise, postural hy- pharmacological therapy to counseling uenza fl In potension, impaired thermoregulation, is more effective than either treatment uenza is a common, preventable in- fl In impaired night vision due to impaired alone. Special considerations should in- fectious disease associated with high papillary reaction, and greater suscepti- clude assessment of level of nicotine mortality and morbidity in vulnerable bility to hypoglycemia (95). Cardiovas- dependence, which is associated with populations, such as the young and cular autonomic neuropathy is also an fi dif culty in quitting and relapse (100). the elderly and people with chronic independent risk factor for cardiovascu- Although some patients may gain weight diseases. Regardless of sex, race, and lar death and silent myocardial ischemia in the period shortly after smoking ces- socioeconomic statu s, adults with dia- (96). Therefore, individuals with dia- sation, recent research has demon- – betes 25 64yearsofagewhodiedare betic autonomic neuropathy should un- strated that this weight gain does not four times more likely to have pneu- dergo cardiac investigation before t re- fi diminish the substantial CVD bene fl monia and in uenza recorded on their beginning physical activity more intense alized from smoking cessation (101). death certi cates than adults without fi than that to which they are accustomed. Nonsmokers should be advised not to diabetes who died at comparable ages Albuminuria and Nephropathy use e-cigarettes. (107). In a case-control series, the in- Physical activity can acutely increase uri- There are norigorousstudies that have fl uenza vaccine was shown to reduce nary protein excretion. However, there e-cigarettes are a demonstrated that diabetes-related hospital admission is no evidence that vigorous-intensity healthier alternative to smoking or that uepidemics fl by as much as 79% during exercise increases the rate of progres- e-cigarettes can facilitate smoking cessa- (108). sion of diabetic kidney disease, and tion. More extensive research of their fi there appears to be no need for speci c short- and long-term effects is needed Pneumococcal Pneumonia exercise restrictions for people with di- to determine their safety and their car- Like in uenza, pneumococcal pneumo- fl abetic kidney disease (92). diopulmonary effects in comparison nia is a common, preventable disease. with smoking and standard approaches People with diabetes may be at in- SMOKING CESSATION: TOBACCO 104). to smoking cessation (102 – creased risk for the bacteremic form of AND e-CIGARETTES pneumococcal infection and have been reported to have a high risk of nosoco- Recommendations IMMUNIZATION mial bacteremia, with a mortality rate c Advise all patients not to use ciga- as high as 50% (109). All patients with Recommendations rettes, other tobacco products, or diabetes 2 years of age and older should Provide routine vaccinations for c A e-cigarettes. receive the pneumococcal polysaccha- Include smoking cessation coun- c children and adults with diabetes ride vaccine 23 (PPSV23). There is suf - fi seling and other forms of treat- as for the general population ac- cient evidence to support that people ment as a routine component of cording to age-related recommen- with diabetes have appropriate sero- diabetes care. B dations. C logic and clinical responses to these

37 Volume 39, Supplement 1, January 2016 Diabetes Care S30 Foundations of Care and Comprehensive Medical Evaluation vaccinations. The ADA endorses the appropriate services. A systematic re- cant fi with depression without signi CDC advisory panel recommendation view and meta-analysis showed that - fi DD, and those with DD without signi that both pneumococcal conjugate vac- psychosocial interventions modestly cant depression. Understanding the cine 13 (PCV13) and PPSV23 should be fi but signi cantly improved A1C (stan- category in which a particular patient administered routinely in series to all 2 0.29%) dardized mean difference belongs facilitates a customized care 65 years. adults aged $ and mental health outcomes. However, approach that may include DSME, there was a limited association be- DSMS, cognitive therapy, or treatment Hepatitis B tween the effects on A1C and mental for depression (psychotherapy and/ Compared with the general population, health, and no intervention characteris- or psychotropic medications). The people with type 1 or type 2 diabetes t on both outcomes fi tics predicted bene screening of all patients with diabetes have higher rates of hepatitis B. This (114). with the Patient Health Questionnaire-2 may be due to contact with infected (PHQ-2) and either the Diabetes Dis- blood or through improper equipment Screening tress Scale (DDS) or Problem Areas in use (glucose monitoring devices or in- Key opportunities for psychosocial Diabetes (PAID)-1 scale can help to fected needles). Because of the higher screening occur at diabetes diagnosis, facilitate this (24,123,124). likelihood of transmission, hepatitis B during regularly scheduled manage- Other issues known to affect self- vaccine is recommended for adults ment visits, during hospitalizations, management and health outcomes with diabetes. with new onset of complications, or include attitudes about the illness, ex- when problems with glucose control, pectations for medical management and PSYCHOSOCIAL ISSUES quality of life, or self-management are outcomes, anxiety, general and diabetes- identi fi ed. Patients are likely to exhibit nancial, related quality of life, resources ( fi Recommendations psychological vulnerability at diagnosis, social, and emotional) (125), and psychi- The patient c s psychological and ’ when their medical status changes atric history (126). social situation should be ad- (e.g., end of the honeymoon period), dressedinthemedicalmanage- when the need for intensi ed treat- fi Referral to a Mental Health Specialist ment of diabetes. B ment is evident, and when complica- Indications for referral to a mental c Psychosocial screening and follow- tions are discovered. Depression health specialist familiar with diabetes up may include, but are not lim- 25% of people with diabe- ; 20 affects – management may include possibility of ited to, attitudes about the illness, tes (115). Individuals with both diabe- self-harm, gross disregard for the med- expectations for medical man- tes and major depressive disorder ical regimen (by self or others) (127), agement and outcomes, affect/ have a twofold increased risk for new- depression, overall stress related to mood, general and diabetes-related onset myocardial infarction compared work-life balance, debilitating anxiety quality of life, resources ( fi nancial, with either disease state alone (116). (alone or with depression), indications social, and emotional), and psy- There appears to be a bidirectional re- of an eating disorder (128), or cognitive E chiatric history. lationship between both diabetes (117) functioning that signi cantly impairs fi c Routinely screen for psychoso- and metabolic syndrome (118) and judgment. It is preferable to incorpo- cial problems such as depression, depression. rate psychological assessment and diabetes-related distress, anxiety, treatment into routine care rather eating disorders, and cognitive im- than waiting for a speci fi c problem or Diabetes Distress pairment. B Diabetes-related distress (DD) is dis- deterioration in metabolic or psycho- $ 65 years) Older adults (aged c tinct from depressive disorders and is logical status (24,119). In the second Di- with diabetes should be consid- 121) in people – very common (119 abetes Attitudes, Wishes and Needs ered for evaluation of cognitive with diabetes and their family mem- fi cant DD was re- (DAWN2) study, signi function and depression screening fi bers (113). DD refers to signi cant neg- ported by 45% of the participants, but and treatment. B ative psychological reactions related only 24% reported that their health care c Patients with comorbid diabetes to emotional burdens and worries spe- team asked them how diabetes affected and depression should receive a ’ ctoanindividual fi ci sexperiencein their life (119). stepwise collaborative care ap- having to manage a severe, compli- Although the clinician may not feel proach for the management of de- cated, and demanding chronic dis- quali ed to treat psychological prob- fi A pression. – 122). Its ease such as diabetes (120 – lems (129), optimizing the patient Emotional well-being is an important part prevalence is reported to be 18 – 45%, provider relationship as a foundation of diabetes care and self-management. with an incidence of 38 – 48% over 18 may increase the likelihood of the pa- Psychological and social problems can months. High levels of distress are tient accepting referral for other ser- impair the individual 112) or – s (110 ’ fi cantly linked to medication non- signi vices. Collaborative care interventions s (113) ability to carry out ’ family adherence (122), higher A1C, lower and a team approach have demonstrated diabetes care tasks and therefore com- cacy, and poorer dietary and self-ef fi ef fi cacy in diabetes and depression promise health status. There are oppor- exercise behaviors ( 15,120). The clini- (130,131). Interv entions to enhance tunities for the clinician to routinely cian needs to understand that individuals self-management and address severe assess psychosocial status in a timely may fall into one of three categories: distress have demonstrated ef fi cacy and ef fi cient manner for referral for those with depression and DD, those in DD (15).

38 Foundations of Care and Comprehensive Medical Evaluation S31 care.diabetesjournals.org Obstructive Sleep Apnea COMPREHENSIVE MEDICAL For patients with type 2 diabetes with Age-adjusted rates of obstructive sleep EVALUATION fracture risk factors, thiazolidinediones - fi apnea, a risk factor for CVD, are signi glucose cotransporter – (148) and sodium Recommendations cantly higher (4- to 10-fold) with obe- 2 inhibitors should beavoidedastheir use A complete medical evaluation should sity, especially with central obesity has been associated with a higher risk of be performed at the initial visit to (139). The prevalence of obstructive fractures (149). fi c rm the diagnosis and classify Con sleep apnea in the population with B diabetes. Low Testosterone in Men type 2 diabetes may be as high as 23% Detect diabetes complications and c Mean levels of testosterone are lower in (140). In obese participants enrolled in E potential comorbid conditions. men with diabetes compared with age- the Action for Health in Diabetes (Look Review previous treatment and c matched men without diabetes, but AHEAD) trial, it exceeded 80% (141). risk factor control in patients obesity is a major confounder (150). Sleep apnea treatment signi fi cantly im- E with established diabetes. Treatment in asymptomatic men is con- proves quality of life and blood pressure Begin patient engagement in the c troversial. The evidence that testoster- control. The evidence for a treatment formulation of a care manage- one replacement affects outcomes is effect on glycemic control is mixed ment plan. B mixed, and recent guidelines do not rec- (142). B Develop a plan for continuing care. c ommend testing and treating men with- Cancer out symptoms (151). Diabetes (possibly only type 2 diabetes) is associated with increased risk of Periodontal Disease Besides assessing diabetes-related cancers of the liver, pancreas, endome- Periodontal disease is more severe, but complications and comorbidities, clini- trium, colon/rectum, breast, and blad- not necessarily more prevalent, in pa- cians and their patients need to be der (143). The association may result tients with diabetes than in those with- aware of other common conditions from shared risk factors between out (152). Current evidence suggests that affect people with diabetes. Im- type 2 diabetes and cancer (older age, that periodontal disease adversely af- proved disease prevention and treat- obesity, and physical inactivity) but fects diabetes outcomes, although evi- ment mean that people with diabetes may also be due to hyperinsulinemia ts remains dence for treatment bene fi are living longer and developing heart or hyperglycemia (144). Patients with controversial (136). failure, fatty liver disease, obstructive diabetes should be encouraged to un- d conditions sleep apnea, and arthritis Hearing Impairment dergo recommended age- and sex-ap- that affect people with diabetes more Hearing impairment, both in high-frequency propriate cancer screenings and to often than age-matched people without and low/mid-frequency ranges, is more able cancer risk fac- fi reduce their modi diabetes and that may complicate dia- common in people with diabetes than tors (smoking, obesity, and physical in- 136). betes management (132 – in those without, perhaps due to neu- activity). Adults who develop type 1 diabetes ropathyand/orvasculardisease.Ina may develop additional autoimmune dis- Fractures National Health and Nutrition Examina- orders including thyroid or adrenal dys- - c hip fracture risk is signi Age-speci fi fi tion Survey (NHANES) analysis, hearing function and celiac disease, although the cantly increased in both type 1 (relative impairment was about twice as preva- risk ofcoexistingautoimmunityislowerin risk 6.3) and type 2 (relative risk 1.7) di- lent in people with diabetes compared adults than for youth with type 1 diabe- abetes in both sexes (145). Type 1 dia- with those without, after adjusting for tes. For additional details on autoimmune betes is associated with osteoporosis, age and other risk factors for hearing Children and “ conditions, see Section 11 but in type 2 diabetes, an increased impairment (153). ” Adolescents. risk of hip fracture is seen despite higher bone mineral density (BMD) (146). In Cognitive Impairment COMORBIDITIES - fi Diabetes is associated with a signi three large observational studies of cantly increased risk and rate of cogni- older adults, femoral neck BMD T-score Fatty Liver Disease Elevations of hepatic transaminase con- tive decline and an increased risk of and the World Health Organization Frac- centrations are signi cantly associated fi dementia (154,155). In a 15-year pro- ture Risk Assessment Tool (FRAX) score with higher BMI, waist circumference, spective study of community-dwelling were associated with hip and nonspine and triglyceride levels and lower HDL . 60 years, the presence people aged fractures. Fracture risk was higher in cholesterol levels. In a prospective anal- of diabetes at baseline signi fi cantly participants with diabetes compared ysis, diabetes was signi fi cantly associ- increased the age- and sex-adjusted with those without diabetes for a given ated with incident nonalcoholic chronic incidence of all-cause dementia, Alz- T-score and age for a given FRAX score liver disease and with hepatocellular heimer disease, and vascular dementia (147). Providers should assess fracture carcinoma (137). Interventions that im- compared with rates in those with history and risk factors in older patients prove metabolic abnormalities in pa- normal glucose tolerance (156). In a with diabetes and recommend measure- tients with diabetes (weight loss, substudy of the Action to Control Car- ment of BMD if appropriate for the pa- glycemic control, and treatment with diovascular Risk in Diabetes (ACCORD) s age and sex. Fracture prevention tient ’ c drugs for hyperglycemia or dys- fi speci clinical trial, there were no differences strategies for people with diabetes are cial for fatty lipidemia) are also bene fi in cognitive outcomes between the in- the same as for the general population liver disease (138). tensive and standard glycemic control and include vitamin D supplementation.

39 Volume 39, Supplement 1, January 2016 Diabetes Care S32 Foundations of Care and Comprehensive Medical Evaluation 30. Foster G, Taylor SJ, Eldridge SE, Ramsay J, mellitus. Cochrane Database Syst Rev 2005;2: groups, although there was signi fi - Grif fi ths CJ. Self-management education pro- CD003417 cantly less of a decrement in total brain 13. Cochran J, Conn VS. Meta-analysis of qual- grammes by lay leaders for people with chronic volume,asmeasuredbyMRI,inpartic- ity of life outcomes following diabetes self- conditions. Cochrane Database Syst Rev 2007;4: ipants in the intensive arm (157). The management training. Diabetes Educ 2008;34: CD005108 effects of hyperglycemia and insulin on 31. Duncan I, Birkmeyer C, Coughlin S, Li QE, 815 – 823 14. Thorpe CT, Fahey LE, Johnson H, Deshpande Sherr D, Boren S. Assessing the value of diabetes the brain are areas of intense research M, Thorpe JM, Fisher EB. Facilitating healthy 760 – education. Diabetes Educ 2009;35:752 interest. 32. 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41 Volume 39, Supplement 1, January 2016 Diabetes Care S34 Foundations of Care and Comprehensive Medical Evaluation patients with type 2 diabetes. Diabet Med 2007; 99. Voulgari C, Katsilambros N, Tentolouris N. Diabetes Association. Exercise and type 2 diabe- – 54 24:48 Smoking cessation predicts amelioration of mi- tes: the American College of Sports Medicine 112. Anderson RJ, Freedland KE, Clouse RE, croalbuminuria in newly diagnosed type 2 dia- and the American Diabetes Association: joint Lustman PJ. The prevalence of comorbid depres- betes mellitus: a 1-year prospective study. position statement. Di abetes Care 2010;33: sion in adults with diabetes: a meta-analysis. Metabolism 2011;60:1456 – 1464 e147 e167 – 100. Ranney L, Melvin C, Lux L, McClain E, Lohr 85. Janssen I, Leblanc AG. Systematic review of 1078 – Diabetes Care 2001;24:1069 113. Kovacs Burns K, Nicolucci A, Holt RIG, KN. Systematic review: smoking cessation inter- t- fi fi ts of physical activity and the health bene et al.; DAWN2 Study Group. Diabetes Attitudes, vention strategies for adults and adults in spe- ness in school-aged children and youth. Int J Wishes and Needs second study (DAWN2): cial populations. Ann Intern Med 2006;145: Behav Nutr Phys Act 2010;7:40 86. U.S. Department of Health and Human cross-national benchmarking indicators for fam- 845 856 – 101. Clair C, Rigotti NA, Porneala B, et al. Asso- Services. 2008 physical activity guidelines ily members living with people with diabetes. ciation of smoking cessation and weight change for Americans [Internet], 2008. Available 788 Diabet Med 2013;30:778 – 114. Harkness E, Macdonald W, Valderas J, with cardiovascular disease among adults with from http://www.health.gov/paguidelines/ Coventry P, Gask L, Bower P. Identifying psycho- and without diabetes. JAMA 2013;309:1014 – guidelines/default.aspx. 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Diabetes Care 2013;36:376 nating Committee, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiol- sociation. Screening for coronary artery disease 382 118. Pan A, Keum N, Okereke OI, et al. Bidirec- in patients with diabetes. Diabetes Care 2007; ogy, and Council on Quality of Care and Out- tional association between depression and comes Research. Electronic cigarettes: a policy – 30:2729 2736 91. American Diabetes Association, JDRF. metabolic syndrome: a systematic review and statement from the American Heart Associa- American Diabetes Association/JDRF Type 1 meta-analysis of epidemiological studies. Dia- tion. Circulation 2014;130:1418 – 1436 105. Strikas RA; Centers for Disease Control .PetersA,LaffelL,Eds. Diabetes Sourcebook – betes Care 2012;35:1171 1180 119. Nicolucci A, Kovacs Burns K, Holt RIG, and Prevention (CDC); Advisory Committee on Alexandria, VA, American Diabetes Associa- et al.; DAWN2 Study Group. Diabetes Attitudes, Immunization Practices (ACIP); ACIP Child/Ado- tion, 2013 92. Colberg SR. Exercise and Diabetes: A Clini- Wishes and Needs second study (DAWN2): lescent Immunization Work Group. Advisory cian g Physical Activity. ’ s Guide to Prescribin cross-national benchmarking of diabetes-related Committee on Immunization Practices recom- Alexandria, VA, American Diabetes Association, psychosocial outcomes for people with diabetes. mended immunization schedules for persons 2013 777 – Diabet Med 2013;30:767 d United States, 2015. aged 0 through 18 years 93. Lemaster JW, Reiber GE, Smith DG, 120. Fisher L, Hessler DM, Polonsky WH, MMWR Morb Mortal Wkly Rep 2015;64:93 94 – Heagerty PJ, Wallace C. Daily weight-bearing Mullan J. When is diabetes distress clinically 106. Kim DK, Bridges CB, Harriman KH; Centers activity does not increase the risk of diabetic meaningful? Establishing cut points for the Di- for Disease Control and Prevention (CDC); Advi- foot ulcers. 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42 Foundations of Care and Comprehensive Medical Evaluation S35 care.diabetesjournals.org 126. Zhang X, Norris SL, Gregg EW, Cheng YJ, with risk of fracture in older adults with type 2 hepatocellular carcinoma. Gastroenterology Beckles G, Kahn HS. Depressive symptoms and 2192 – diabetes. JAMA 2011;305:2184 2004;126:460 468 – mortality among persons with and without di- 148. Kahn SE, Zinman B, Lachin JM, et al.; Di- 138. American Gastroenterological Associa- – abetes. Am J Epidemiol 2005;161:652 660 abetes Outcome Progression Trial (ADOPT) tion. American Gastroenterological Association 127. Rubin RR, Peyrot M. Psychological issues Study Group. Rosiglitazone-associated fractures medical position statement: nonalcoholic fatty and treatments for people with diabetes. J Clin in type 2 diabetes: an Analysis from A Diabetes – liver disease. Gastroenterology 2002;123:1702 Psychol 2001;57:457 – 478 Outcome Progression Trial (ADOPT). Diabetes 1704 128. Young-Hyman DL, Davis CL. 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43 S36 Diabetes Care Volume 39, Supplement 1, January 2016 American Diabetes Association 4. Prevention or Delay of Type 2 Diabetes DOI: 10.2337/dc16-S007 | S38 Diabetes Care 2016;39(Suppl. 1):S36 – Recommendations c Patients with prediabetes should be referred to an intensive diet and physical activity behavioral counseling program adhering to the tenets of the Diabetes Prevention Program (DPP) targeting a loss of 7% of body weight and should increase their moderate-intensity physical activity (such as brisk walking) to at least 150 min/week. A Follow-up counseling and maintenance programs should be offered for long- c B term success in preventing diabetes. c Based on the cost-effectiveness of diabetes prevention, such programs should B be covered by third-party payers. Metformin therapy for prevention of type 2 diabetes should be considered in c 2 , those aged . those with prediabetes, especially in those with BMI 35 kg/m A , 60 years, and women with prior gestational diabetes mellitus. c At least annual monitoring for the development of diabetes in those with prediabetes is suggested. E Screening for and treatment of modi able risk factors for cardiovascular dis- fi c B ease is suggested. c Diabetes self-management education and support programs are appropriate venues for people with prediabetes to receive education and support to de- 4. PREVENTION OR DELAY OF TYPE 2 DIABETES B velop and maintain behaviors that can prevent or delay the onset of diabetes. Technology-assisted tools including Internet-based social networks, distance c learning, DVD-based content, and mobile applications can be useful elements of effective lifestyle modi cation to prevent diabetes. B fi LIFESTYLE MODIFICATION hat individuals at high risk for develop- Randomized controlled trials have shown t ing type 2 diabetes (impaired fasting glucose, impaired glucose tolerance, or both) cantly decrease the rate of diabetes onset with particular interventions can signi fi fi 7). These include intensive lifestyle modi – (1 cation programs that have been showntobeveryeffective( ; 58% reduction after 3 years). Follow-up of all three large studies of lifestyle intervention ha s shown sustained reduction in the rate of tion at 20 years in the Da Qing study (8), conversion to type 2 diabetes: 43% reduc abetes Prevention Study (DPS) (9), and 43% reduction at 7 years in the Finnish Di 34% reduction at 10 years in the U.S. Diabetes Prevention Program Outcomes Study (DPPOS) (10). A cost-effectiveness model suggested that lifestyle interventions in the Diabetes Prevention Program (DPP) are cost-effective (11). Actual cost data from the DPP and DPPOS also con fi rm this (12). Group delivery of DPP content into community settings has the potential to reduce overall program costs while still producing weight loss and diabetes risk reduction (13,14). The Centers for Disease Control and Prevention (CDC) helps to coordinate the National Diabetes Prevention Program, a resource designed to bring evidence-based lifestyle change programs Suggested citation: American Diabetes Associa- ties (http://www.cdc.gov/diabetes/ for preventing type 2 diabetes to communi tion. Prevention or delay of type 2 diabetes. Sec. prevention/index.htm). 4. In 2016 . Standards of Medical Care in Diabetes d Given the clinical trial results and the known risks of progression from prediabetes Diabetes Care 2016;39(Suppl. 1):S36 – S38 6.4% (39 to diabetes, people with an A1C 5.7 46 mmol/mol), impaired glucose – – © 2016 by the American Diabetes Association. tolerance, or impaired fasting glucose should be counseled on lifestyle changes Readers may use this article as long as the work weight loss and moderate-intensity with goals similar to those of the DPP (7% is properly cited, the use is educational and not for pro fi t, and the work is not altered. physical activity of at least 150 min/week).

44 Prevention or Delay of Type 2 Diabetes S37 care.diabetesjournals.org Nutrition PHARMACOLOGICAL health care providers should inform As for people with diabetes (see Section 3 INTERVENTIONS ts in or- fi at-risk patients of these bene Foundations of Care and Comprehen- “ der to motivate them to engage Pharmacological agents, such as metfor- ” sive Medical Evaluation ), evidence sup- in regular moderate-intensity physical a -glucosidase inhibitors, orlistat, min, ports the importance of maintaining a activity. and thiazolidinediones, have each healthy diet in order to prevent diabetes Moderate exercise, such as brisk been shown to decrease incident dia- onset. Unlike past recommendations walking or other activities of equivalent betes to various degrees. Metformin that focused on simply reducing total di- intensity, has been also observed to im- has the strongest evidence base and etary fat and cholesterol consumption, prove insulin sensitivity and reduce ab- demonstrated long-term safety as more recent evidence argues against dominal fat content in children and pharmacological therapy for diabetes the preventative effects of lowering fat young adults (22,23). The DPP included prevention (34). For other drugs, cost, and cholesterol intake across the board 150 min/week of moderate-intensity ex- side effects, and durable ef fi cacy re- and supports instead that the quality of ercise and showed bene cial effect on fi quire consideration. fats consumed in the diet is more impor- glycemia in those with prediabetes (1). Metformin was less effective than tant than the total quantity of dietary fat . Both resistance training and endurance fi cation in the DPP and lifestyle modi For example, recent work supports the cial ef- fi exercise appear to have bene DPPOS but may be cost-saving over a Mediterranean diet, which is relatively fects on waist circumference, insulin 10-year period (12). It was as effective rich in monounsaturated fats, as a means sensitivity, and thus diabetes risk fi as lifestyle modi cation in participants 2 to help to prevent type 2 diabetes (15). (24,25). The preventative effects of exer- but not signi - fi with BMI 35 kg/m $ Studies evaluating glycemic index to cise appear to extend to the prevention cantly better than placebo in those recommendations guide carbohydrate of gestational diabetes mellitus (GDM) over 60 years of age (1). In the DPP, have been inconsistent (16,17); however, as well (26). for women with a history of GDM, met- data suggest that consumption of a diet fi formin and intensive lifestyle modi ca- enriched in whole grains is helpful in pre- Prevention of Cardiovascular Disease tion led to an equivalent 50% reduction venting type 2 diabetes (18). Finally, in- People with prediabetes often have other in diabetes risk (35), and both inter- creased consumption of nuts (19) and cardiovascular risk factors, such as obe- ventions remained highly effective berries (20) in the context of a diet high sity, hypertension, and dyslipidemia during a 10-year follow-up period in vegetables and whole fruits has been and are at increased risk for cardiovas- (36). Metformin may be recommended correlated with reduced diabetes risk. In- cular disease events. While treatment for high-risk individuals (e.g., those dividualized medical nutrition therapy goals for people with prediabetes are with a history of GDM, those who are “ Foundations of Care and (see Section 3 thesameasforthegeneralpopulation, very obese, and/or those with more for ” Comprehensive Medical Evaluation increased vigilance is warranted to severe or progressive hyperglycemia) more detailed information) has been identify and treat these and other risk and/or those with rising A1C despite shown to be effective in lowering A1C in factors (e.g., smoking). lifestyle intervention. individuals diagnosed with prediabetes (7). This indicates that nutritional inter- Technology Assistance to Deliver DIABETES SELF-MANAGEMENT ventions are potentially effective in stav- Lifestyle Modi fi cation EDUCATION AND SUPPORT ing off the progression toward type 2 Technology may be an effective means diabetes (e.g., individuals showing signs As for those with established diabetes, the to deliver the core components of the of metabolic syndrome). standards for diabetes self-management DPP (27,28). Initial studies have vali- education and support (see Section 3 dated DVD-based content delivery Foundations of Care and Comprehen- “ (29). This has been corroborated in a Physical Activity and Exercise sive Medical Evaluation ) can also apply ” Physical activity and exercise are impor- primary care patient population (30). to the education and support of people tant for those living with diabetes (see Recent studies support content delivery with prediabetes. Currently, there are Section 3 “ Foundations of Care and Com- through virtual small groups (31), Internet- cant barriers to the provision of fi signi ), but they prehensive Medical Evaluation ” driven social networks (32,33), cellular education and support to those with pre- have also been evaluated for diabetes pre- phones, and other mobile devices. Mo- diabetes. However, the strategies for vention. Physical activity is a more general bile applications for weight loss and di- supporting successful behavior change term that covers all types of activity, abetes prevention have been validated and the healthy behaviors recom- whereas exercise refers to structured or for their ability to reduce A1C in the mended for people with prediabetes planned activities. Although not well stud- s Di- ’ setting of prediabetes (33). The CDC are comparable to those for diabetes. ied in isolation, exercise and physical ac- abetes Prevention Recognition Program Although reimbursement remains a tivity have been validated to prevent or (DPRP) (http://www.cdc.gov/diabetes/ barrier, studies show that providers of delay diabetes development as part of a on/index.htm) has prevention/recogniti diabetes self-management education comprehensive approach to lifestyle mod- begun to certify electronic and mobile and support are particularly well equip- fi cation (21). These studies suggest that i health-based modalities as effective ve- pedtoassistpeoplewithprediabetesin while exercise treatment programs may hicles for DPP-style prevention content developing and maintaining behaviors not reduce body weight, programs of suf- that may be considered alongside more that can prevent or delay the onset of fi cient intensity have been shown to de- traditional face-to-face and coach-driven diabetes (7,37). crease diabetes risk (21). Therefore, programs.

45 Volume 39, Supplement 1, January 2016 Diabetes Care S38 Prevention or Delay of Type 2 Diabetes in obese adolescent boys: a randomized, con- 13. Ackermann RT, Finch EA, Brizendine E, References trolled trial. Diabetes 2012;61:2787 2795 – Zhou H, Marrero DG. Translating the Diabetes 1. Knowler WC, Barrett-Connor E, Fowler SE, 26. Russo LM, Nobles C, Ertel KA, Chasan-Taber Prevention Program into the community. The et al.; Diabetes Prevention Program Research L, Whitcomb BW. Physical activity interventions DEPLOY Pilot Study. Am J Prev Med 2008;35: Group. Reduction in the incidence of type 2 di- in pregnancy and risk of gestational diabetes 357 – 363 abetes with lifestyle intervention or metformin. mellitus: a systematic review and meta-analysis. 14. Balk EM, Earley A, Raman G, Avendano EA, 403 – N Engl J Med 2002;346:393 Obstet Gynecol 2015;125:576 582 – Pittas AG, Remington PL. Combined diet and 2. Buchanan TA, Xiang AH, Peters RK, et al. muthu S, Squires A, 27. Levine DM, Savari physical activity promotion programs to prevent b -cell function and Preservation of pancreatic Nicholson J, Jay M. Technology-assisted weight type 2 diabetes among persons at increased risk: prevention of type 2 diabetes by pharmacolog- loss interventions in primary care: a systematic a systematic review for the Community Preven- ical treatment of insulin resistance in high-risk 117 review. J Gen Intern Med 2015;30:107 – tive Services Task Force. Ann Intern Med 2015; – 2803 Hispanic women. Diabetes 2002;51:2796 28. Allen JK, Stephens J, Patel A. Technology- – 163:437 451 3. Chiasson J-L, Josse RG, Gomis R, Hanefeld M, ́ ́ assisted weight management interventions: 15. Salas-Salvad oJ,Bull oM,BabioN,etal.; Karasik A, Laakso M; STOP-NIDDM Trial Re- systematic review of clinical trials. Telemed J E PREDIMED Study Investigators. Reduction in search Group. Acarbose for prevention of 1120 – Health 2014;20:1103 the incidence of type 2 diabetes with the Med- type 2 diabetes mellitus: the STOP-NIDDM 29. Kramer MK, Kriska AM, Venditti EM, et al. A iterranean diet: results of the PREDIMED-Reus 2077 randomised trial. Lancet 2002;359:2072 – novel approach to diabetes prevention: evalua- nutrition intervention randomized trial. Diabe- ’ 4. Lin JS, O Connor E, Evans CV, Senger CA, tion of the Group Lifestyle Balance program de- tes Care 2011;34:14 19 – Rowland MG, Groom HC. Behavioral counseling livered via DVD. Diabetes Res Clin Pract 2010; 16. Bhupathiraju SN, Tobias DK, Malik VS, et al. to promote a healthy lifestyle in persons with – e63 90:e60 Glycemic index, glycemic load, and risk of type 2 cardiovascular risk factors: a systematic review 30. Ma J, Yank V, Xiao L, et al. Translating the diabetes: results from 3 large US cohorts and an for the U.S. Preventive Services Task Force. Ann Diabetes Prevention Program lifestyle interven- updated meta-analysis. Am J Clin Nutr 2014; 578 – Intern Med 2014;161:568 tion for weight loss into primary care: a random- 232 – 100:218 ̈ 5. Paulweber B, Valensi P, Lindstr om J, et al. A ized trial. JAMA Intern Med 2013;173:113 121 – 17. Sacks FM, Carey VJ, Anderson CAM, et al. European evidence-based guideline for the pre- 31. Azar KMJ, Aurora M, Wang EJ, Muzaffar A, Effects of high vs low glycemic index of dietary vention of type 2 diabetes. Horm Metab Res Pressman A, Palaniappan LP. Virtual small carbohydrate on cardiovascular disease risk fac- S36 – 2010;42(Suppl. 1):S3 groups for weight management: an innovative tors and insulin sensitivity: the OmniCarb ran- 6. Diabetes Preventi on Program Research delivery mechanism for evidence-based lifestyle 2541 domized clinical trial. JAMA 2014;312:2531 – as a predictor of diabetes and as Group. HbA 1c ̈ interventions among obese men. Transl Behav arvinen R, Aromaa A, 18. Montonen J, Knekt P, J an outcome in the Diabetes Prevention Pro- – 44 Med 2015;5:37 ber intake and fi Reunanen A. Whole-grain and gram: a randomized clinical trial. Diabetes 32. Sepah SC, Jiang L, Peters AL. Translating the the incidence of type 2 diabetes. Am J Clin Nutr – Care 2015;38:51 58 Diabetes Prevention Program into an online so- – 629 2003;77:622 7. Parker AR, Byham-Gray L, Denmark R, Winkle cial network: validation against CDC standards. 19. Afshin A, Micha R, Khatibzadeh S, PJ. The effect of medical nutrition therapy by a 443 – Diabetes Educ 2014;40:435 Mozaffarian D. Consumption of nuts and legumes registered dietitian nutritionist in patients with 33. Sepah SC, Jiang L, Peters AL. Long-term out- and risk of incident ischemic heart disease,stroke, prediabetes participating in a randomized con- comes of a Web-based diabetes prevention pro- and diabetes: a systematic review and meta- trolled clinical research trial. J Acad Nutr Diet gram: 2-year results of a single-arm longitudinal analysis. Am J Clin Nutr 2014;100:278 – 288 1748 – 2014;114:1739 study. J Med Internet Res 2015;17:e92 20. Mursu J, Virtanen JK, Tuomainen T-P, Nurmi 8. Li G, Zhang P, Wang J, et al. The long-term 34. Group TDPPR; Diabetes Prevention Pro- T, Voutilainen S. Intake of fruit, berries, and effect of lifestyle interventions to prevent dia- gram Research Group. Long-term safety, tol- vegetables and risk of type 2 diabetes in Finnish betes in the China Da Qing Diabetes Prevention erability, and weight loss associated with men: the Kuopio Ischaemic Heart Disease Risk Study: a 20-year follow-up study. Lancet 2008; metforminintheDiabetesPreventionPro- 333 Factor Study. Am J Clin Nutr 2014;99:328 – 1789 – 371:1783 gram Outcomes Study. Diabetes Care 2012; 21. Swift DL, Johannsen NM, Lavie CJ, Earnest ̈ om J, Ilanne-Parikka P, Peltonen M, 9. Lindstr 35:731 – 737 CP, Church TS. The role of exercise and physical et al.; Finnish Diabetes Prevention Study Group. 35. Ratner RE, Christophi CA, Metzger BE, et al.; activity in weight loss and maintenance. Prog Sustained reduction in the incidence of type 2 Diabetes Prevention Program Research Group. 447 Cardiovasc Dis 2014;56:441 – diabetes by lifestyle intervention: follow-up of Prevention of diabetes in women with a history 22. Fedewa MV, Gist NH, Evans EM, Dishman the Finnish Diabetes Prevention Study. Lancet of gestational diabetes: effects of metformin RK. Exercise and insulin resistance in youth: a 2006;368:1673 1679 – and lifestyle interventions. J Clin Endocrinol e174 – meta-analysis. Pediatrics 2014;133:e163 10. Knowler WC, Fowler SE, Hamman RF, et al.; 4779 – Metab 2008;93:4774 23. Davis CL, Pollock NK, Waller JL, et al. Exer- Diabetes Prevention Program Research Group. 36. Aroda VR, Christophi CA, Edelstein SL, et al.; cise dose and diabetes risk in overweight and 10-year follow-up of diabetes incidence and Diabetes Prevention Program Research Group. obese children: a randomized controlled trial. weight loss in the Diabetes Prevention Program The effect of lifestyle intervention and metfor- 1112 – JAMA 2012;308:1103 Outcomes Study. Lancet 2009;374:1677 1686 – eld GS, et al. Ef- fi 24. Sigal RJ, Alberga AS, Gold min on preventing or delaying diabetes among 11. Herman WH, Hoerger TJ, Brandle M, et al.; women with and without gestational diabetes: fects of aerobic training, resistance training, or Diabetes Prevention Program Research Group. both on percentage body fat and cardiometa- the Diabetes Prevention Program outcomes The cost-effectiveness of lifestyle modi cation fi bolic risk markers in obese adolescents: the study 10-year follow-up. J Clin Endocrinol or metformin in preventing type 2 diabetes in Metab 2015;100:1646 – 1653 healthy eating aerobic and resistance training adults with impaired glucose tolerance. Ann In- 37. Butcher MK, Vanderwood KK, Hall TO, in youth randomized clinical trial. JAMA Pediatr – 332 tern Med 2005;142:323 – 2014;168:1006 1014 Gohdes D, Helgerson SD, Harwell TS. Capacity 12. Diabetes Prevention Program Research 25. Lee S, Bacha F, Hannon T, Kuk JL, Boesch C, of diabetes education programs to provide both Group. The 10-year cost-effectiveness of life- diabetes self-management education and to im- Arslanian S. Effects of aerobic versus resistance style intervention or metformin for diabetes exercise without caloric restriction on abdomi- plement diabetes prevention services. J Public prevention: an intent-to-treat analysis of the nal fat, intrahepatic lipid, and insulin sensitivity Health Manag Pract 2011;17:242 – 247 – DPP/DPPOS. Diabetes Care 2012;35:723 730

46 Diabetes Care Volume 39, Supplement 1, January 2016 S39 American Diabetes Association 5. Glycemic Targets Diabetes Care 2016;39(Suppl. 1):S39 S46 | DOI: 10.2337/dc16-S008 – ASSESSMENT OF GLYCEMIC CONTROL Two primary techniques are available for health providers and patients to assess the effectiveness of the management plan on glycemic control: patient self-monitoring of blood glucose (SMBG) and A1C. Continuous glucose monitoring (CGM) or in- terstitial glucose may be a useful adjunct to SMBG in selected patients. Recommendations When prescribed as part of a broader educational context, self-monitoring of c blood glucose (SMBG) results may help to guide treatment decisions and/or or non- B self-management for patients using less frequent insulin injections E insulin therapies. 5. GLYCEMIC TARGETS When prescribing SMBG, ensure that patients receive ongoing instruction and c regular evaluation of SMBG technique, SMBG results, and their ability to use SMBG data to adjust therapy. E c Most patients on intensive insulin regimens (multiple-dose insulin or insulin pump therapy) should consider SMBG prior to meals and snacks, occasionally postprandially, at bedtime, prior to exercise, when they suspect low blood glucose, after treating low blood glucose until they are normoglycemic, and B prior to critical tasks such as driving. When used properly, continuous glucose monitoring (CGM) in conjunction c with intensive insulin regimens is a useful tool to lower A1C in selected adults (aged A 25 years) with type 1 diabetes. $ Although the evidence for A1C lowering is less strong in children, teens, and c younger adults, CGM may be helpful in these groups. Success correlates with adherence to ongoing use of the device. B c CGM may be a supplemental tool to SMBG in those with hypoglycemia un- C awareness and/or frequent hypoglycemic episodes. Given variable adherence to CGM, assess individual readiness for continuing c CGM use prior to prescribing. E When prescribing CGM, robust diabetes education, training, and support are c E required for optimal CGM implementation and ongoing use. People who have been successfully using CGM should have continued access c after they turn 65 years of age. E Self-monitoring of Blood Glucose Major clinical trials of insulin-treated patients have included SMBG as part of the t of intensive glycemic con- fi multifactorial interventions to demonstrate the bene trol on diabetes complications. SMBG is thus an integral component of effective therapy (1). SMBG allows patients to evaluate their individual response to therapy and assess whether glycemic targets are being achieved. Integrating SMBG results into diabetes management can be a useful tool for guiding medical nutrition therapy and physical activity, preventing hypoglycemia, and adjusting medications (particularly prandial insulin doses). Among patients with type 1 diabetes, there is a correlation fi c needs and s speci between greater SMBG frequency and lower A1C (2). The patient ’ goals should dictate SMBG frequency and timing. Suggested citation: American Diabetes Associa- tion. Glycemic targets. Sec. 5. In Standards of Optimization . Diabetes Care 2016 Medical Care in Diabetes d SMBG accuracy is dependent on the instrument and user, so it is important to – S46 2016;39(Suppl. 1):S39 evaluate each patient ’ s monitoring technique, both initially and at regular intervals © 2016 by the American Diabetes Association. thereafter. Optimal use of SMBG requires proper review and interpretation of the Readers may use this article as long as the work data, by both the patient and the provider. Among patients who check their blood is properly cited, the use is educational and not fi t, and the work is not altered. for pro glucose at least once daily, many report taking no action when results are high or

47 Volume 39, Supplement 1, January 2016 Diabetes Care S40 Glycemic Targets ̈ low. In a yearlong study of insulin-na ı ve suggested that SMBG reduced A1C by automatic low glucose suspend feature patients with suboptimal initial glycemic 0.25% at 6 months (13), but the effect was has been approved by the FDA. The Auto- control, a group trained in structured attenuated at 12 months (14). A key con- mation to Simulate Pancreatic Insulin Re- SMBG (a paper tool was used at least sideration is that performing SMBG alone sponse (ASPIRE) trial of 247 patients quarterly to collect and interpret 7-point does not lower blood glucose levels. To be showed that sensor-augmented insulin fi les taken on 3 consecutive SMBG pro useful, the information must be integrated pump therapy with a low glucose sus- days) reduced their A1C by 0.3 percent- f-management plans. into clinical and sel cantly reduced nocturnal hy- pend signi fi age points more than the control group poglycemia, without increasing A1C (3). Patients should be taught how to use levels for those over 16 years of age Continuous Glucose Monitoring SMBG data to adjust food intake, exer- (23). These devices may offer the oppor- Real-time CGM measures interstitial cise, or pharmacological therapy to tunity to reduce severe hypoglycemia for glucose (which correlates well with plasma glucose) and includes sophisti- fi achieve speci c goals. The ongoing need those with a history of nocturnal hypo- for and frequency of SMBG should be glycemia. Due to variable adherence, op- catedalarms for hypo- and hyperglycemic reevaluated at each routine visit to avoid timal CGM use requires an assessment of excursions, but the U.S. Food and Drug 6). SMBG is especially impor- overuse (4 – individual readiness for the technology Administration (FDA) has not approved tant for insulin-treated patients to monitor as well as initial and ongoing education these devices as a sole agent to monitor for and prevent asymptomatic hypoglyce- and support (16,24). Additionally, providers glucose. CGMs require calibration with mia and hyperglycemia. need to provide robust diabetes education, SMBG, with the latter still required for training, and support for optimal CGM making acute treatment decisions. For Patients on Intensive Insulin Regimens implementation and ongoing use. As A 26-week randomized trial of 322 pa- Most patients on intensive insulin regimens people with type 1 or type 2 diabetes tients with type 1 diabetes showed that (multiple-dose insulin or insulin pump ther- are living longer healthier lives, individu- 25 years using intensive in- $ adults aged apy) should consider SMBG prior to meals sulintherapyandCGMexperienceda0.5% als who have been successfully using and snacks, occasionally postprandially, at CGM should have continued access after reduction in A1C (from 7.6% to 7.1% ; bedtime, prior to exercise, when they sus- they turn 65 years of age. 60 mmol/mol to 54 mmol/mol]), com- [ ; pect low blood glucose, after treating low pared with those using intensive insulin blood glucose until they are normoglyce- A1C TESTING therapy with SMBG (15). Sensor use in mic, and prior to critical tasks such as driv- those aged , 25 years (children, teens, Recommendations ing. For many patients, this will require and adults) did not result in signi fi cant two Perform the A1C test c at least 10 (or more) times daily, al- – testing 6 A1C lowering, and there was no signi fi cant timesayearinpatientswhoare though individual needs may vary. A data- difference in hypoglycemia in any group. meeting treatment goals (and who base study of almost 27,000 children and The greatest predictor of A1C lowering E have stable glycemic control). adolescents with type 1 diabetes showed for all age-groups was frequency of sensor Perform the A1C test quarterly in c that, after adjustment for multiple con- 25 $ use, which was highest in those aged patients whose therapy has changed founders, increased daily frequency of years and lower in younger age-groups. or who are not meeting glycemic fi cantly associated with SMBG was signi A registry study of 17,317 participants goals. E 2 0.2% per additional test per lower A1C ( rmed that more frequent CGM use is fi con c Point-of-care testing for A1C pro- day) and with fewer acute complications. associated with lower A1C (16), whereas vides the opportunity for more another study showed that children with For Patients Using Basal Insulin or Oral E timely treatment changes. Agents . 70% sensor use missed fewer school fi cient regarding The evidence is insuf fl A1C re ects average glycemia over days (17). Small randomized controlled when to prescribe SMBG and how often several months and has strong predic- trials in adults and children with baseline testing is needed for patients who do tive value for diabetes complications 58 mmol/mol) have – 7.5% (53 – A1C 7.0 not use an intensive insulin regimen, (25,26). Thus, A1C testing should be fi rmed favorable outcomes (A1C and con such as those with type 2 diabetes using performed routinely in all patients with hypoglycemia occurrence) in groups us- oral agents or on basal insulin. For patients diabetes d at initial assessment and as ing CGM, suggesting that CGM may pro- on basal insulin, lowering of A1C has been part of continuing care. Measurement t for individuals with fi vide further bene demonstrated for those who adjust their approximately every 3 months deter- type 1 diabetes who already have tight dose to attain a fasting glucose within a glycemic targets mines whether patients ’ control (18,19). targeted range (7,8). have been reached and maintained. The A meta-analysis suggests that, com- For individuals with type 2 diabetes on frequency of A1C testing should depend paredwithSMBG,CGMisassociated less intensive insulin therapy, more fre- on the clinical situation, the treatment 0.26% ; with short-term A1C lowering of quent SMBG (e.g., fasting, before/after s judgment. Pa- ’ regimen, and the clinician (20). The long-term effectiveness of CGM meals) may be helpful, as increased fre- tients with type 2 diabetes with stable needs to be determined. This technology quency has been shown to be inversely glycemia well within target may do well maybeparticularlyusefulinthosewith with testing only twice per year. Unstable or correlated with glycemic control (9). hypoglycemia unawareness and/or fre- highly intensively managed patients (e.g., Several randomized trials have called quent hypoglycemic episodes, although pregnant women with type 1 diabetes) into question the clinical utility and cost- studies have not shown consistent re- may require testing more frequently than effectiveness of routine SMBG in noninsulin- – ductions in severe hypoglycemia (20 every 3 months (27). 12). A meta-analysis – treated patients (10 22). A CGM device equipped with an

48 Glycemic Targets S41 care.diabetesjournals.org — Mean glucose levels for speci fi ed A1C levels (24,28) Table 5.1 Mean plasma glucose* Mean fasting glucose Mean premeal glucose Mean postmeal glucose Mean bedtime glucose A1C mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL % (mmol/mol) mg/dL mmol/L mmol/L 126 7.0 6 (42) 118 6.5 (48) 122 6.8 6.5 , 144 8.0 136 7.5 7.9 6.5 6.99 (48 – 53) 142 – 139 7.7 164 9.1 153 8.5 8.6 7 (53) 154 – 9.8 177 9.8 176 8.4 152 8.4 152 58) . 7.49 (53 – 7.0 8.6 7.5 7.99 (58 – 64) 167 9.3 155 – 189 10.5 175 9.7 8 (64) 183 10.2 – . 8.0 69) 8.5 (64 – 178 9.9 179 9.9 206 11.4 222 12.3 9 (75) 212 11.8 10 (86) 240 13.4 11 (97) 269 14.9 12 (108) 298 16.5 A calculator for converting A1C results into eAG, in either mg/dL or mmol/L, is available at http://professional.diabetes.org/eAG. *These estimates are based on ADAG data of ; 2,700 glucose measurements over 3 months per A1C measurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C and average glucose was 0.92 (28). A1C Limitations A1C GOALS type 2, and no diabetes (28), and an em- The A1C test is subject to certain limita- pirical study of the average blood glucose For glycemic goals in children, please refer tions. Conditions that affect red blood levels at premeal, postmeal, and bedtime ” Children and Adolescents. “ to Section 11 cell turnover (hemolysis, blood loss) associated with speci fi ed A1C levels using For glycemic goals in pregnant women, and hemoglobin variants must be consid- data from the ADAG trial (24). The Amer- “ Management please refer to Section 12 ered, particularly when the A1C result does ican Diabetes Association (ADA) and the of Diabetes in Pregnancy. ” sbloodglu- ’ not correlate with the patient American Association for Clinical Chemis- Recommendations cose levels. For patients in whom A1C/ try have determined that the correlation A reasonable A1C goal for many c estimated average glucose (eAG) and ( r 5 0.92) in the ADAG trial is strong 7% (53 , nonpregnant adults is measured blood glucose appear discrep- enough to justify reporting both the A1C mmol/mol). A ant, clinicians should consider the possi- result and the eAG result when a clinician Providers might reasonably sug- c bilities of hemoglobinopathy or altered orders the A1C test. Clinicians should gest more stringent A1C goals red blood cell turnover and the options note that the mean plasma glucose num- , 6.5% [48 mmol/mol]) (such as of more frequent and/or different timing bers in the table are based on ; 2,800 for selected individual patients if of SMBG or CGM use. Other measures of readings per A1C in the ADAG trial. this can be achieved without signif- chronic glycemia such as fructosamine are A1C Differences in Ethnic Populations and icant hypoglycemia or other adverse available, but their linkage to average glu- Children effects of treatment. Appropriate cance are fi cose and their prognostic signi In the ADAG study, there were no signif- patients might include those with not as clear as for A1C (see Section 2 Clas- “ icant differences among racial and ethnic short duration of diabetes, type 2 fi cation and Diagnosis of Diabetes ” si ). groups in the regression lines between diabetes treated with lifestyle or A1C does not provide a measure of gly- A1C and mean glucose, although there metformin only, long life expec- cemic variability or hypoglycemia. For was a trend toward a difference between cant cardiovascu- fi tancy, or no signi patients prone to glycemic variability, es- the African/African American and non- C lar disease. pecially patients with type 1 diabetes or Hispanic white cohorts. A small study Less stringent A1C goals (such as c - fi type 2 diabetes with severe insulin de comparing A1C to CGM data in children 8% [64 mmol/mol]) may be ap- , ciency, glycemic control is best evaluated with type 1 diabetes found a highly sta- propriate for patients with a his- by the combination of results from SMBG fi tistically signi cant correlation between tory of severe hypoglycemia, and A1C. A1C may also con fi rm the accu- A1C and mean blood glucose, although limited life expectancy, advanced ’ racy of the patient s ’ s meter (or the patient 5 r the correlation ( 0.7) was signifi- microvascular or macrovascular reported SMBG results) and the adequacy cantly lower than in the ADAG trial (29). complications, extensive comor- of the SMBG testing schedule. Whether there are signi fi cant differences bid conditions, or long-standing A1C and Mean Glucose in how A1C relates to average glucose in diabetes in whom the general shows the correlation between Table 5.1 children or in different ethnicities is an fi goal is dif cult to attain despite A1C levels and mean glucose levels based area for further study (30,31). For the diabetes self-management educa- on two studies: the international A1C- time being, the question has not led to tion, appropriate glucose monitor- Derived Average Glucose (ADAG) trial, different recommendations about testing ing, and effective doses of multiple which based the correlation with A1C on A1C or to different interpretations of the glucose-lowering agents including frequent SMBG and CGM in 507 adults clinical meaning of given levels of A1C in insulin. B (83% non-Hispanic whites) with type 1, those populations.

49 Volume 39, Supplement 1, January 2016 Diabetes Care S42 Glycemic Targets A1C and Microvascular Complications events (combined fatal or nonfatal MI poor control to fair/good control. These Type 1 Diabetes and sudden death) in the intensive glyce- analyses also suggest that further lower- mic control arm that did not reach statis- ing of A1C from 7% to 6% [53 mmol/mol nes diabetes, and Hyperglycemia de fi cance ( 5 0.052), and there tical signi P fi to 42 mmol/mol] is associated with fur- glycemic control is fundamental to dia- fi t on other was no suggestion of bene ther reduction in the risk of microvascular betes management. The Diabetes Con- CVD outcomes (e.g., stroke). However, af- complications, although the absolute risk trol and Complications Trial (DCCT) (1), a ter 10 years of follow-up, those originally reductions become much smaller. Given prospective randomized controlled trial randomly assigned to intensive glycemic the substantially increased risk of hypo- of intensive versus standard glycemic cant long-term reduc- control had signi fi glycemia in type 1 diabetes trials and control in patients with relatively recently tions in MI (15% with sulfonylurea or in- with polypharmacy in type 2 diabetes, fi diagnosed type 1 diabetes, showed de n- sulin as initial pharmacotherapy, 33% the risks of lower glyce mic targets outweigh itively that improved glycemic control is with metformin as initial pharmacother- ts on microvascular fi the potential bene associated with signi fi cantly decreased apy) and in all-cause mortality (13% and complications. rates of microvascular (retinopathy [32] 27%, respectively) (37). The concerning mortality ndings in fi and diabetic kidney disease) and neuro- The ACCORD, ADVANCE, and VADT the ACCORD trial (42), discussed below, pathic complications. Follow-up of the suggested no signi cant reduction in fi and the relatively intense efforts required DCCT cohorts in the Epidemiology of CVD outcomes with intensive glycemic to achieve near-euglycemia should also DiabetesInterventionsandComplications control in participants followed for be considered when setting glycemic tar- (EDIC) study (33) demonstrated persis- 5.6 years who had more advanced 2 3.5 gets. However, on the basis of physician ts in fi tence of these microvascular bene type 2 diabetes than UKPDS partici- judgment and patient preferences, select previously intensively treated subjects, pants. All three trials were conducted patients, especially those with little co- even though their glycemic control ap- in participants with more long-standing morbidity and long life expectancy, may proximated that of previous standard 11 years) – diabetes (mean duration 8 bene t from adopting more intensive gly- fi arm subjects during follow-up. and either known CVD or multiple car- , cemic targets (e.g., A1C target 6.5% Type 2 Diabetes diovascular risk factors. The target cant hy- fi [48 mmol/mol]) as long as signi The Kumamoto Study (34) and UK Pro- A1C among intensive control subjects poglycemia does not become a barrier. spective Diabetes Study (UKPDS) (35,36) was , 6% (42 mmol/mol) in ACCORD, rmed that intensive glycemic control con fi A1C and Cardiovascular Disease , 6.5% (48 mmol/mol) in ADVANCE, was associated with signi fi cantly de- Outcomes and a 1.5% reduction in A1C compared creased rates of microvascular and neu- Cardiovascular Disease and Type 1 with control subjects in VADT, with ropathic complications in patients with Diabetes achieved A1C of 6.4% versus 7.5% type 2 diabetes. Long-term follow-up of Cardiovascular disease (CVD) is a more (46 mmol/mol vs. 58 mmol/mol) in the UKPDS cohorts showed enduring ef- common cause of death than microvas- ACCORD, 6.5% versus 7.3% (48 mmol/mol fects of early glycemic control on most cular complications in populations with vs. 56 mmol/mol) in ADVANCE, and microvascular complications (37). diabetes. There is evidence for a cardio- 6.9% versus 8.4% (52 mmol/mol vs. 68 Therefore, achieving glycemic control fi t of intensive glycemic vascular bene mmol/mol) in VADT. Details of these , 7% (53 mmol/mol) of A1C targets of control after long-term follow-up of studies are reviewed extensively in the has been shown to reduce microvascular study cohorts treated early in the course Intensive Glyce- “ ADA position statement complications of diabetes and, in patients of type 1 and type 2 diabetes. In the mic Control and the Prevention of Cardio- with type 1 diabetes, mortality. If imple- DCCT, there was a trend toward lower vascular Events: Implications of the mented soon after the diagnosis of diabetes, risk of CVD events with intensive control. In ACCORD, ADVANCE, and VA Diabetes this target is associated with long-term the 9-year post-DCCT follow-up of the EDIC Trials: A Position Statement of the Amer- reduction in macrovascular disease. cohort, participants previously randomly ican Diabetes Association and a Scienti c fi assigned to the intensive arm had a signif- Statement of the American College of ACCORD, ADVANCE, and VADT icant 57% reduction in the risk of nonfatal Three landmark trials (Action to Control Cardiology Foundation and the American myocardial infarction (MI), stroke, or CVD Cardiovascular Risk in Diabetes [ACCORD], (46). Heart Association ” h those previously in death compared wit Action in Diabetes and Vascular Disease: The glycemic control comparison in fi thestandardarm(43).Thebene tofin- Preterax and Diamicron MR Controlled ACCORD was halted early due to an in- tensive glycemic control in this cohort with Evaluation [ADVANCE], and Veterans Af- creased mortality rate in the intensive type 1 diabetes has been shown to persist fairs Diabetes Trial [VADT]) showed that compared with the standard arm for several decades (44) and to be associ- lower A1C levels were associated with (1.41% vs. 1.14% per year; hazard ratio ated with a modest re duction in all-cause 1.22 [95% CI 1.01 1.46]), with a similar – reduced onset or progression of micro- mortality (45). increase in cardiovascular deaths. Anal- vascular complications (38 – 40). ysis of the ACCORD data did not identify a Epidemiological analyses of the DCCT Cardiovascular Disease and Type 2 clear explanation for the excess mortality Diabetes (1) and UKPDS (41) demonstrate a cur- In type 2 diabetes, there is evidence that vilinear relationship between A1C and in the intensive arm (42). more intensive treatment of glycemia in microvascular complications. Such analyses Longer-term follow-up has shown no suggest that, on a population level, the tor evidence of cardiovascular bene fi newly diagnosed patients may reduce greatest number of complications will be harm in the ADVANCE trial (47), which is long-term CVD rates. During the UKPDS averted by taking patients from very perhapsnot unexpectedgiven the narrow trial, there was a 16% reduction in CVD

50 Glycemic Targets S43 care.diabetesjournals.org separation in A1C between groups. The Table 5.2 — Summary of glycemic recommendations for nonpregnant adults with end-stage renal disease rate was lower diabetes in the intensive group over follow-up. , 7.0% (53 mmol/mol)* A1C However, 10-year follow-up of the VADT – Preprandial capillary plasma glucose 80 – 130 mg/dL* (4.4 7.2 mmol/L) cohort (48) showed a reduction in the risk † , 180 mg/dL* (10.0 mmol/L) Peak postprandial capillary plasma glucose of cardiovascular events (52.7 [control *More or less stringent glycemic goals may be appropriate for individual patients. Goals should group] vs. 44.1 [intervention group] be individualized based on duration of diabetes, age/life expectancy, comorbid conditions, events per 1,000 person-years) with no known CVD or advanced microvascular complications, hypoglycemia unawareness, and individual patient considerations. t in cardiovascular or overall mor- fi bene Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial † tality. Heterogeneity of mortality effects glucose goals. Postprandial glucose measurements should be made 1 – 2 h after the beginning of across studies was noted, which may re- the meal, generally peak levels in patients with diabetes. ect differences in glycemic targets, ther- fl apeutic approaches, and population characteristics (49). , of 7% (53 mmol/mol). The issue of pre- and landmark glycemic control trials fi Mortality ndings in ACCORD (42) and prandial versus postprandial SMBG targets such as the DCCT and UKPDS relied subgroup analyses of VADT (50) suggest is complex (54). Elevated postchallenge (2-h overwhelmingly on preprandial SMBG. that the potential risks of intensive glyce- oral glucose tolerance test) glucose values Additionally, a randomized controlled ts in fi mic control may outweigh its bene have been associated with increased cardio- trial in patients with known CVD found higher-risk patients. In all three trials, se- vascular risk independent of fasting plasma t of insulin regimens tar- no CVD bene fi fi vere hypoglycemia was signi cantly more glucose in some epidemiological studies. In geting postprandial glucose compared likely in participants who were randomly subjects with diabetes, surrogate measures with those targeting preprandial glucose assigned to the intensive glycemic control of vascular pathology, such as endothelial (55). Therefore, it is reasonable for post- arm. Those patients with long duration of dysfunction, are negatively affected by prandial testing to be recommended for diabetes, a known history of severe hypo- postprandial hyperglycemia. It is clear that individualswhohavepremealglucose val- glycemia, advanced atherosclerosis, or postprandial hyperglycemia, like prepran- ues within target but have A1C values fi advanced age/frailty may bene t from dial hyperglycemia, co ntributes to elevated above target. Taking postprandial plasma less aggressive targets (51,52). A1C levels, with its relative contribution be- 2 h after the glucose measurements 1 – Providers should be vigilant in pre- ing greater at A1C levels that are closer to start of a meal and using treatments aimed venting severe hypoglycemia in patients 7% (53 mmol/mol). However, outcome at reducing postprandial plasma glucose with advanced disease and should not studies have clearly shown A1C to be values to , 180mg/dL(10.0mmol/L) aggressively attempt to achieve near- the primary predictor of complications, may help to lower A1C. normal A1C levels in patients in whom such targets cannot be safely and rea- sonably achieved. Severe or frequent hypoglycemia is an absolute indication cation of treatment regi- fi for the modi mens, including setting higher glycemic goals. Many factors, including patient preferences, should be taken into ac- count when developing a patient ’ sindi- vidualized goals ( Table 5.2 ). A1C and Glycemic Targets Numerous aspects must be considered when setting glycemic targets. The ADA proposes optimal targets, but each target must be individualized to the needs of each patient and his or her disease factors. When possible, such decisions should fl be made with the patient, re ecting his or her preferences, needs, and values. Figure 5.1 is not designed to be applied rigidly but to be used as a broad con- struct to guide clinical decision making (53), both in type 1 and type 2 diabetes. Recommended glycemic targets for many nonpregnant adults are shown in Table 5.2 . The recommendations in- — Figure 5.1 Depicted are patient and disease factors used to determine optimal A1C targets. clude blood glucose levels that appear Characteristics and predicaments toward the left justify more stringent efforts to lower A1C; those toward the right suggest less stringent efforts. Adapted with permission from Inzucchi et al. (53). to correlate with achievement of an A1C

51 Volume 39, Supplement 1, January 2016 Diabetes Care S44 Glycemic Targets An analysis of data from 470 partici- (e.g., bedtime snack to prevent overnight c Ongoing assessment of cognitive pants of the ADAG study (237 with hypoglycemia), exercise management, function is suggested with in- type 1 diabetes and 147 with type 2 dia- medication adjustment, glucose monitor- creased vigilance for hypoglyce- betes) found that actual average glucose ing, and routine clinical surveillance may mia by the clinician, patient, and levels associated with conventional A1C improve patient outcomes (61). Docu- caregivers if low cognition or de- targets were higher than older DCCT and mented symptomatic hypoglycemia and B clining cognition is found. fi nd- Table 5.1 ADA targets ( ) (24,28). These fi asymptomatic hypoglycemia are de ned ings support that premeal glucose targets as occurring at a plasma glucose concen- Hypoglycemia is the major limiting fac- may be relaxed without undermining over- 70 mg/dL (3.9 mmol/L) (61). # tration of tor in the glycemic management of type all glycemic control as measured by A1C. This level remains a general threshold for 1 and insulin-treated type 2 diabetes. These data have prompted a revision in de fi ning hypoglycemia. Mild hypoglycemia may be inconve- the ADA-recommended premeal target In 2014, the ADA changed its glycemic nient or frightening to patients with 7.2 mmol/L). to 80 – – 130 mg/dL (4.4 to 80 – 130 mg/dL(4.4 – 7.2 mmol/L). target fi ned diabetes. Severe hypoglycemia is de ects the results of the fl This change re as hypoglycemia requiring assistance HYPOGLYCEMIA ADAG study, which demonstrated that from another person. It is characterized higher glycemic targets corresponded to Recommendations by cognitive impairment that may be rec- A1C goals (24). An additional goal of rais- c Individuals at risk for hypogly- ognized or unrecognized and can prog- tar- ingthelower range of the glycemic cemia should be asked about ress to loss of consciousness, seizure, was to limit overtreatment and get symptomatic and asymptomatic coma, or death, and it is reversed by ad- provide a safety margin in patients ti- hypoglycemia at each encoun- ministration of rapid-acting glucose. Se- trating glucose-lowering drugs such as C ter. vere hypoglycemia can cause acute insulin to glycemic targets. 20 g) is the preferred – Glucose (15 c harm to the person with diabetes or Hypoglycemia Treatment treatment for the conscious in- others, especially if it causes falls, motor Hypoglycemia treat ment requires in- dividual with hypoglycemia, al- vehicle accidents, or other injury. A large gestion of glucose- or carbohydrate- though any form of carbohydrate cohort study suggested that among older containing foods. The acute glycemic that contains glucose may be adults with type 2 diabetes, a history of response correlates better with the glu- used. Fifteen minutes after treat- severe hypoglycemia was associated with cose content of food than with the car- ment, if SMBG shows continued greater risk of dementia (56). Conversely, bohydrate content of food. Pure glucose hypoglycemia, the treatment in a substudy of the ACCORD trial, cogni- is the preferred treatment, but any form should be repeated. Once SMBG tive impairment at baseline or decline in of carbohydrate that contains glucose returns to normal, the individual cognitive function during the trial was sig- will raise blood glucose. Added fat may should consume a meal or snack fi ni cantly associated with subsequent ep- retard and then prolong the acute gly- to prevent recurrence of hypogly- isodes of severe hypoglycemia (57). cemic response. Ongoing insulin activity cemia. E Evidence from DCCT/EDIC, which in- or insulin secretagogues may lead to re- c Glucagon should be prescribed for volved younger adults and adolescents current hypoglycemia unless further all individuals at increased risk of with type 1 diabetes, found no associa- food is ingested after recovery. ned as fi severe hypoglycemia, de tion between frequency of severe hypo- hypoglycemia requiring assis- Glucagon glycemia and cognitive decline (58), as tance, and caregivers, school per- Those in close contact with, or having “ Children and discussed in Section 11 sonnel, or family members of these custodial care of, people with hypoglyce- Adolescents. ” individuals should be instructed in mia-prone diabetes (family members, Severe hypoglycemia was associated its administration. Glucagon admin- roommates, school personnel, child care with mortality in participants in both the istrationisnotlimitedtohealth providers, correctional institution staff, or standard and the intensive glycemia E care professionals. coworkers) should be instructed on the use arms of the ACCORD trial, but the relation- Hypoglycemia unawareness or c of glucagon kits. An individual does not ships between hypoglycemia, achieved one or more episodes of severe need to be a health care professional to A1C, and treatment intensity were not hypoglycemia should trigger re- safely administer glucagon. Care should straightforward. An association of severe evaluation of the treatment regi- betakentoensurethatglucagonkitsare hypoglycemia with mortality was also E men. not expired. found in the ADVANCE trial (59). An asso- c Insulin-treated patients with hy- ciation between self-reported severe hy- Hypoglycemia Prevention poglycemia unawareness or an ep- poglycemia and 5-year mortality has also Hypoglycemia prevention is a critical isode of severe hypoglycemia been reported in clinical practice (60). component of diabetes management. should be advised to raise their Young children with type 1 diabetes SMBG and, for some patients, CGM are glycemic targets to strictly avoid and the elderly are noted as particularly essential tools to assess therapy and de- further hypoglycemia for at least vulnerable to severe hypoglycemia be- tect incipient hypoglycemia. Patients several weeks in order to partially cause of their reducedabilityto recognize should understand situations that in- reverse hypoglycemia unaware- hypoglycemic symptoms and effectively crease their risk of hypoglycemia, such ness and reduce risk of future ep- communicate their needs. Individualized as fasting for tests or procedures, during isodes. A or after intense exercise, and during patient education, dietary intervention

52 Glycemic Targets S45 care.diabetesjournals.org – HbA1c by 0.25%. Ann Intern Med 2012;156:JC6 sleep. Hypoglycemia may increase the hyperglycemic nonketotic hyperosmo- JC12 risk of harm to self or others, such as lar state, please refer to the ADA con- 14. Malanda UL, Welschen LM, Riphagen II, with driving. Teaching people with diabetes sensus report Hyperglycemic Crises in “ Dekker JM, Nijpels G, Bot SD. Self-monitoring to balance insulin use and carbohydrate in- Adult Patients With Diabetes (63). ” of blood glucose in patients with type 2 diabetes take and exercise are necessary, but these mellitus who are not using insulin. Cochrane Database Syst Rev 2012;1:CD005060 fi strategies are not always suf cient for References 15. Tamborlane WV, Beck RW, Bode BW, et al.; prevention. 1. The Diabetes Control and Complications Trial Juvenile Diabetes Research Foundation Contin- Research Group. The effect of intensive treatment In type 1 diabetes and severely insulin- uous Glucose Monitoring Study Group. Contin- of diabetes on the development and progression de cient type 2 diabetes, hypoglycemia fi uous glucose monitoring and intensive treatment of long-term complications in insulin-dependent unawareness (or hypoglycemia-associated of type 1 diabetes. N Engl J Med 2008;359: diabetes mellitus. N Engl J Med 1993;329:977 – 986 1476 – 1464 autonomic failure) can severely compro- 2. Miller KM, Beck RW, Bergenstal RM, et al.; 16. Wong JC, Foster NC, Maahs DM, et al.; T1D mise stringent diabetes control and quality T1D Exchange Clinic Network. Evidence of a Exchange Clinic Network. Real-time continuous strong association between frequency of self- of life. This syndrome is characterized by glucose monitoring among participants in the monitoring of blood glucose and hemoglobin fi cient counterregulatory hormone re- de T1D Exchange clinic registry. Diabetes Care A1c levels in T1D Exchange clinic registry partic- lease, especially in older adults, and a di- 2709 – 2014;37:2702 ipants. Diabetes Care 2013;36:2009 – 2014 17. Hommel E, Olsen B, Battelino T, et al.; minished autonomi c response, which 3. Polonsky WH, Fisher L, Schikman CH, et al. SWITCH Study Group. Impact of continuous glu- both are risk factors for, and caused by, Structured self-monitoring of blood glucose sig- cose monitoring on quality of life, treatment cantly reduces A1C levels in poorly con- fi ni hypoglycemia. A corollary to this vicious “ satisfaction, and use of medical care resources: trolled, noninsulin-treated type 2 diabetes: cycle is that several weeks of avoidance ” analyses from the SWITCH study. Acta Diabetol results from the Structured Testing Program of hypoglycemia has been demonstrated 2014;51:845 – 851 267 study. Diabetes Care 2011;34:262 – 18. Battelino T, Phillip M, Bratina N, Nimri R, to improve counterregulation and aware- 4. Gellad WF, Zhao X, Thorpe CT, Mor MK, Good Oskarsson P, Bolinder J. Effect of continuous CB,FineMJ.DualuseofDepartmentofVet- ness to some extent in many patients (62). glucose monitoring on hypoglycemia in type 1 ts and use of erans Affairs and Medicare bene fi Hence, patients with one or more episodes diabetes. Diabetes Care 2011;34:795 – 800 test strips in veterans with type 2 diabetes mel- tfrom of severe hypoglycemia may bene fi 19. Beck RW, Hirsch IB, Laffel L, et al.; Juvenile litus. JAMA Intern Med 2015;175:26 – 34 at least short-term relaxation of glycemic Diabetes Research Foundation Continuous Glu- 5. Grant RW, Huang ES, Wexler DJ, et al. Pa- cose Monitoring Study Group. The effect of con- targets. tients who self-monitor blood glucose and their tinuous glucose monitoring in well-controlled unused testing results. Am J Manag Care 2015; – type 1 diabetes. Diabetes Care 2009;32:1378 – e129 21:e119 INTERCURRENT ILLNESS 1383 6. Endocrine Society. Choosing wisely [Internet], For further information on management 20. Yeh H-C, Brown TT, Maruthur N, et al. Com- 2013. Available from http://www.choosingwisely of patients with hyperglycemia in the parative effectiveness and safety of methods of .org/societies/endocrine-society/. Accessed 18 insulin delivery and glucose monitoring for di- hospital, please refer to Section 13 August 2015 abetes mellitus: a systematic review and meta- 7. Rosenstock J, Davies M, Home PD, Larsen J, ” Diabetes Care in the Hospital. “ 347 analysis. Ann Intern Med 2012;157:336 – Koenen C, Schernthaner G. A randomised, Stressful events (e.g., illness, trauma, 21. Choudhary P, Ramasamy S, Green L, et al. 52-week, treat-to-target trial comparing insulin surgery, etc.) frequently aggravate glycemic Real-time continuous glucose monitoring signif- detemir with insulin glargine when adminis- control and may precipitate diabetic keto- icantly reduces severe hypoglycemia in hypogly- tered as add-on to glucose-lowering drugs in cemia-unaware patients with type 1 diabetes. acidosis or nonketotic hyperosmolar state, insulin-naive people with type 2 diabetes. Dia- – 4162 Diabetes Care 2013;36:4160 betologia 2008;51:408 – 416 life-threatening conditions that require im- 22. Choudhary P, Rickels MR, Senior PA, et al. 8. Garber AJ. Treat-to-target trials: uses, inter- mediate medical care to prevent complica- Evidence-informed clinical practice recommen- pretation and review of concepts. Diabetes tions and death. Any condition leading to dations for treatment of type 1 diabetes com- Obes Metab 2014;16:193 205 – deterioration in glycemic control necessi- plicated by problematic hypoglycemia. Diabetes ́ 9. Elgart JF, Gonz alez L, Prestes M, Rucci E, 1029 – Care 2015;38:1016 Gagliardino JJ. Frequency of self-monitoring tates more frequent monitoring of blood 23. Bergenstal RM, Klonoff DC, Garg SK, et al.; blood glucose and attainment of HbA1c target glucose; ketosis-prone patients also require ASPIRE In-Home Study Group. Threshold-based values. Acta Diabetol. 5 April 2015 [Epub ahead urine or blood ketone monitoring. If accom- insulin-pump interruption for reduction of hy- of print] panied by ketosis, vomiting, or alteration in – poglycemia. N Engl J Med 2013;369:224 232 10. Farmer A, Wade A, Goyder E, et al. Impact the level of consciousness, marked hyper- 24. Wei N, Zheng H, Nathan DM. Empirically of self monitoring of blood glucose in the man- establishing blood glucose targets to achieve agement of patients with non-insulin treated porary adjustment of glycemia requires tem – HbA1c goals. Diabetes Care 2014;37:1048 diabetes: open parallel group randomised trial. the treatment regimen and immediate in- 1051 BMJ 2007;335:132 teraction with the diabetes care team. The 25. Albers JW, Herman WH, Pop-Busui R, et al.; Kane MJ, Bunting B, Copeland M, Coates ’ 11. O patient treated with noninsulin therapies mplications Trial/ Diabetes Control and Co VE; ESMON Study Group. Ef fi cacy of self moni- or medical nutrition therapy alone may Epidemiology of Diabetes Interventions and toring of blood glucose in patients with newly Complications Research Group. Effect of prior diagnosed type 2 diabetes (ESMON study): temporarily require insulin. Adequate intensive insulin treatment during the Diabetes randomised controlled trial. BMJ 2008;336: fl uid and caloric intake must be ensured. Control and Complications Trial (DCCT) on pe- – 1177 1174 Infection or dehydration is more likely to ripheral neuropathy in type 1 diabetes during 12. Simon J, Gray A, Clarke P, Wade A, Neil A, necessitate hospitalization of the person the Epidemiology of Diabetes Interventions Farmer A; Diabetes Glycaemic Education and and Complications (EDIC) Study. Diabetes Care with diabetes than the person without Monitoring Trial Group. Cost effectiveness of 1096 – 2010;33:1090 self monitoring of blood glucose in patients diabetes. with non-insulin treated type 2 diabetes: eco- 26. Stratton IM, Adler AI, Neil HAW, et al. As- A physician with expertise in diabetes sociation of glycaemia with macrovascular and nomic evaluation of data from the DiGEM trial. management should treat the hospital- microvascular complications of type 2 diabetes BMJ 2008;336:1177 – 1180 ized patient. For further information on (UKPDS 35): prospective observational study. 13. Willett LR. Meta-analysis: self-monitoring BMJ 2000;321:405 – 412 in non-insulin-treated type 2 diabetes improved diabetic ketoacidosis management or

53 Volume 39, Supplement 1, January 2016 Diabetes Care S46 Glycemic Targets ˇ c L, Savas H, Mehta M, Trujillo A, 27. Jovanovi glucose control and vascular outcomes in patients 50. Duckworth WC, Abraira C, Moritz TE, et al.; Pettitt DJ. Frequent monitoring of A1C during – with type 2 diabetes. N Engl J Med 2008;358:2560 Investigators of the VADT. The duration of di- pregnancy as a treatment tool to guide therapy. 2572 abetes affects the response to intensive glucose – 54 Diabetes Care 2011;34:53 40. Ismail-Beigi F, Craven T, Banerji MA, et al.; control in type 2 subjects: the VA Diabetes Trial. J Diabetes Complications 2011;25:355 – 361 28. Nathan DM, Kuenen J, Borg R, Zheng H, ACCORDTrialGroup.Effectofintensivetreatment 51. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, Schoenfeld D, Heine RJ; A1c-Derived Average of hyperglycaemia on microvascular out- Steinman MA. Potential overtreatment of diabetes Glucose Study Group. Translating the A1C assay comesintype2diabetes:ananalysisofthe mellitus in older adults with tight glycemic control. into estimated average glucose values. Diabetes ACCORD randomised trial. Lancet 2010;376: – JAMA Intern Med 2015;175:356 362 Care 2008;31:1473 – 1478 – 419 430 52. Vijan S, Sussman JB, Yudkin JS, Hayward RA. 29. Wilson DM, Kollman; Diabetes Research in 41. Adler AI, Stratton IM, Neil HAW, et al. As- ’ risks and preferences on Effect of patients Children Network (DirecNet) Study Group. Re- sociation of systolic blood pressure with macro- health gains with plasma glucose level lowering lationship of A1C to glucose concentrations in vascular and microvascular complications of in type 2 diabetes mellitus. JAMA Intern Med children with type 1 diabetes: assessments by type 2 diabetes (UKPDS 36): prospective obser- 2014;174:1227 – 1234 high-frequency glucose determinations by sen- 419 – vational study. BMJ 2000;321:412 53. Inzucchi SE, Bergenstal RM, Buse JB, et al. – 385 sors. Diabetes Care 2008;31:381 42. Gerstein HC, Miller ME, Byington RP, et al.; Management of hyperglycemia in type 2 diabe- 30. Buse JB, Kaufman FR, Linder B, Hirst K, El Action to Control Cardiovascular Risk in Diabe- tes, 2015: a patient-centered approach. Update Ghormli L, Willi S; HEALTHY Study Group. Dia- tes Study Group. Effects of intensive glucose to a position statement of the American Diabe- betes screening with hemoglobin A(1c) versus lowering in type 2 diabetes. N Engl J Med tes Association and the European Association fasting plasma glucose in a multiethnic middle- – 2559 2008;358:2545 for the Study of Diabetes. Diabetes Care 2015; – school cohort. Diabetes Care 2013;36:429 435 43. Nathan DM, Cleary PA, Backlund J-YC, et al.; 149 – 38:140 31. Kamps JL, Hempe JM, Chalew SA. Racial dis- mplications Trial/ Diabetes Control and Co 54. American Diabetes Association. Postpran- parity in A1C independent of mean blood glu- Epidemiology of Diabetes Interventions and dial blood glucose. Diabetes Care 2001;24: cose in children with type 1 diabetes. Diabetes Complications (DCCT/EDIC) Study Research – 778 775 – 1027 Care 2010;33:1025 Group. Intensive diabetes treatment and cardio- 55. Raz I, Wilson PWF, Strojek K, et al. Effects of 32. Lachin JM, White NH, Hainsworth DP, Sun W, vascular disease in patients with type 1 diabetes. prandial versus fasting glycemia on cardiovas- Cleary PA, Nathan DM; Diabetes Control and – N Engl J Med 2005;353:2643 2653 cular outcomes in type 2 diabetes: the HEART2D Complications Trial (DCCT)/Epidemiology of Dia- 44. Nathan DM, Zinman B, Cleary PA, et al.; – 386 trial. Diabetes Care 2009;32:381 betes Interventions and Complications (EDIC) Re- mplications Trial/ Diabetes Control and Co 56. Whitmer RA, Karter AJ, Yaffe K, Quesenberry search Group. Effect of intensive diabetes therapy Epidemiology of Diabetes Interventions and CP Jr, Selby JV. Hypoglycemic episodes and risk of on the progression of diabetic retinopathy in pa- Complications (DCCT/EDIC) Research Group. dementia in older patients with type 2 diabetes tients with type 1 diabetes: 18 years of follow-up Modern-day clinical course of type 1 diabetes mellitus. JAMA 2009;301:1565 – 1572 642 in the DCCT/EDIC. Diabetes 2015;64:631 – mellitus after 30 years ’ duration: the Diabetes 57. Punthakee Z, Miller ME, Launer LJ, et al.; 33. Diabetes Control and Complications Trial/ Control and Complications Trial/Epidemiology ACCORD Group of Investigators; ACCORD- Epidemiology of Diabetes Interventions and of Diabetes Interventions and Complications MIND Investigators. Poor cognitive function Complications Research Group. Retinopathy and Pittsburgh Epidemiology of Diabetes Com- and risk of severe hypoglycemia in type 2 and nephropathy in patients with type 1 diabetes plications experience (1983-2005). Arch Intern diabetes: post hoc epidemiologic analysis of the four years after a trial of intensive therapy. N Engl – 1316 Med 2009;169:1307 ACCORD trial. Diabetes Care 2012;35:787 – 793 J Med 2000;342:381 389 – 45. Orchard TJ, Nathan DM, Zinman B, et al.; 58. Jacobson AM, Musen G, Ryan CM, et al.; 34. Ohkubo Y, Kishikawa H, Araki E, et al. Inten- Writing Group for the DCCT/EDIC Research Diabetes Control and Co mplications Trial/ sive insulin therapy prevents the progression of Group. Association between 7 years of intensive Epidemiology of Diabetes Interventions and diabetic microvascular complications in Japa- treatment of type 1 diabetes and long-term Complications Study Research Group. Long- nese patients with non-insulin-dependent dia- – 53 mortality. JAMA 2015;313:45 term effect of diabetes and its treatment on betes mellitus: a randomized prospective 6-year 46. Skyler JS, Bergenstal R, Bonow RO, et al.; cognitive function. N Engl J Med 2007;356: study. Diabetes Res Clin Pract 1995;28:103 117 – American Diabetes Association; American Col- 1842 1852 – 35. UK Prospective Diabetes Study (UKPDS) lege of Cardiology Foundation; American Heart 59. Zoungas S, Patel A, Chalmers J, et al.; Group. Effect of intensive blood-glucose control Association. Intensive glycemic control and the ADVANCE Collaborative Group. Severe hypogly- with metformin on complications in overweight ular events: implica- prevention of cardiovasc cemia and risks of vascular events and death. N patients with type 2 diabetes (UKPDS 34). Lan- tions of the ACCORD, ADVANCE, and VA Diabe- – 1418 Engl J Med 2010;363:1410 865 cet 1998;352:854 – tes Trials: a position statement of the American 60. McCoy RG, Van Houten HK, Ziegenfuss JY, 36. UK Prospective Diabetes Study (UKPDS) Diabetes Association and a scienti fi c statement ShahND,WermersRA,SmithSA.Increased Group. Intensive blood-glucose control with sul- of the American College of Cardiology Founda- mortality of patients with diabetes reporting phonylureas or insulin compared with conven- tion and the American Heart Association. severe hypoglycemia. Diabetes Care 2012;35: tional treatment and risk of complications in Diabetes Care 2009;32:187 – 192 1901 – 1897 patients with type 2 diabetes (UKPDS 33). Lan- 47. Zoungas S, Chalmers J, Neal B, et al.; 61. Seaquist ER, Anderson J, Childs B, et al. Hy- 853 cet 1998;352:837 – ADVANCE-ON Collaborative Group. Follow-up of poglycemia and diabetes: a report of a work- 37. Holman RR, Paul SK, Bethel MA, Matthews blood-pressure lowering and glucose control in group of the American Diabetes Association DR, Neil HAW. 10-year follow-up of intensive type 2 diabetes. N Engl J Med 2014;371:1392 – 1406 and the Endocrine Society. Diabetes Care glucose control in type 2 diabetes. N Engl 48. Hayward RA, Reaven PD, Wiitala WL, et al.; 1395 – 2013;36:1384 J Med 2008;359:1577 – 1589 VADT Investigators. Follow-up of glycemic con- 62. Cryer PE. Diverse causes of hypoglycemia- 38. Duckworth W, Abraira C, Moritz T, et al.; trol and cardiovascular outcomes in type 2 associated autonomic failure in diabetes. N Engl VADT Investigators. Glucose control and vascu- diabetes. N Engl J Med 2015;372:2197 – 2206 – 2279 J Med 2004;350:2272 larcomplications in veterans with type 2 diabetes. 49. Turnbull FM, Abraira C, Anderson RJ, et al. 63. Kitabchi AE, Umpierrez GE, Miles JM, Fisher 139 – N Engl J Med 2009;360:129 Intensive glucose control and macrovascular JN. Hyperglycemic crises in adult patients with 39. Patel A, MacMahon S, Chalmers J, et al.; outcomes in type 2 diabetes. Diabetologia diabetes. Diabetes Care 2009;32:1335 – 1343 ADVANCE Collaborative Group. Intensive blood – 2298 2009;52:2288

54 Diabetes Care Volume 39, Supplement 1, January 2016 S47 American Diabetes Association 6. Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care 2016;39(Suppl. 1):S47 – S51 | DOI: 10.2337/dc16-S009 There is strong and consistent evidence that obesity management can delay pro- fi cial in the gression from prediabetes to type 2 diabetes (1,2) and may be bene treatment of type 2 diabetes. In overweight and obese patients with type 2 diabetes, modest and sustained weight loss has been shown to improve glycemic control and 5). Small studies have dem- to reduce the need for glucose-lowering medications (3 – 6. OBESITY MANAGEMENT IN TYPE 2 DIABETES onstrated that in obese patients with type 2 diabetes more extreme dietary energy 6.5% (48 mmol/mol) and , restriction with very low-calorie diets can reduce A1C to , 126 mg/dL (7.0 mmol/L) in the absence of pharmacological fasting glucose to induced improvements in glycemia – therapy or ongoing procedures (6,7). Weight loss are most likely to occur early in the natural history of type 2 diabetes when obesity- -cell dysfunction but insulin b associated insulin resistance has caused reversible secretory capacity remains relatively preserved (5,8). Although the Action for Health in Diabetes (Look AHEAD) trial did not show that an intensive lifestyle intervention reduced cardiovascular events in overweight or obese adults with type 2 diabetes (9), it did show the feasibility of achieving and maintaining long-term weight loss in patients with type 2 diabetes. LOOK AHEAD In the Look AHEAD intensive lifestyle intervention group, mean weight loss was 4.7% (SE 0.2) at 8 years (10). Approximately 50% of intensive lifestyle intervention par- ticipants lost 10% of their initial body weight at 8 years (10). $ $ 5% and 27% lost Participants randomly assigned to the intensive lifestyle group achieved equivalent risk factor control but required fewer glucose-, blood pressure – , and lipid-lowering medications than those randomly assigned to standard care. Secondary analyses of the Look AHEAD trial and other large cardiovascular outcome studies document other bene fi ts of weight loss in patients with type 2 diabetes, including improve- ments in mobility, physical and sexual functioning, and health-related quality of life (11). The goal of this section is to provide evidence-based recommendations for dietary, pharmacological, and surgical interventions for obesity management as treatments for hyperglycemia in type 2 diabetes. ASSESSMENT Recommendation At each patient encounter, BMI should be calculated and documented in the c medical record. B At each routine patient encounter, BMI should be calculated from the height and ed to determine the presence of overweight or obesity, weight. BMI should be classi fi ). In Asian Table 6.1 discussedwiththepatient,anddocumentedinthepatientrecord( ne overweight and obesity are lower: normal Americans, the BMI cutoff points to de fi 2 2 2 ), obese (27.5 27.4 kg/m 37.4 kg/m ), and extremely – ), overweight (23.0 – , 23 kg/m ( Suggested citation: American Diabetes Associa- 2 tion. Obesity management for the treatment of ) (12). Providers should advise overweight and obese patients that 37.5 kg/m obese ( $ Standards of Medical type 2 diabetes. Sec. 6. In r disease and all-cause mortality. Providers higherBMIsincreasetheriskofcardiovascula 2016 Care in Diabetes d . Diabetes Care 2016; should assess each patient ’ s readiness to achieve weigh t loss and jointly determine 39(Suppl. 1):S47 – S51 . Strategies include diet, physical activity, weight loss goals and intervention strategies © 2016 by the American Diabetes Association. Table 6.1 behavioral therapy, pharmacological therapy, and bariatric surgery ( ). The latter Readers may use this article as long as the work ly selected patients as adjuncts to diet, two strategies may be prescribed for careful is properly cited, the use is educational and not physical activity, and behavioral therapy. for pro fi t, and the work is not altered.

55 Volume 39, Supplement 1, January 2016 Diabetes Care S48 Obesity Management for the Treatment of Type 2 Diabetes DIET, PHYSICAL ACTIVITY, AND control, and/or other obesity-related consumption of a reduced calorie diet, BEHAVIORAL THERAPY medical conditions, lifestyle changes and participation in high levels of phys- that result in modest and sustained ical activity (200 – 300 min/week). Some Recommendations weight loss produce clinically meaning- commercial and proprietary weight loss Diet, physical activity, and behavioral c ful reductions in blood glucose, A1C, and programs have shown promising weight therapy designed to achieve 5% triglycerides (3 – 5). Greater weight loss loss results (18). weight loss should be prescribed ts, including fi produces even greater bene When provided by trained practi- for overweight and obese patients reductions in blood pressure, improve- tioners in medical care settings with with type 2 diabetes ready to ments in LDL and HDL cholesterol, and close medical monitoring, short-term achieve weight loss. A reductions in the need for medications (3-month) high-intensity lifestyle inter- c Such interventions should be high in- to control blood glucose, blood pressure, ventions that use very low-calorie diets 16 sessions in 6 months) $ tensity ( and lipids (9,10). ned as (de 800 kcal/day) and total # fi and focus on diet, physical activity, meal replacements may achieve greater and behavioral strategies to achieve 15%) than short-term weight loss (10 – a 500 – 750 kcal/day energy de fi cit. A Lifestyle Interventions lifestyle interven- intensive behavioral Weight loss can be attained with life- Diets that provide the same caloric c tions that typically achieve 5% weight – style programs that achieve a 500 750 restriction but differ in protein, loss. Weight regain fol lowing the cessation kcal/day energy de cit or provide ap- fi carbohydrate, and fat content are of high-intensity lifestyle interventions is – proximately 1,200 1,500 kcal/day for equally effective in achieving greater than following intensive behavioral women and 1,500 – 1,800 kcal/day for A weight loss. lifestyle interventions unless a long-term men, adjusted for the individual s base- ’ For patients who achieve short- c comprehensive weight loss maintenance line body weight. Although bene fi ts may term weight loss goals, long-term program is provided (19,20). be seen with as little as 5% weight loss, ( $ 1-year) comprehensive weight PHARMACOTHERAPY sustained weight loss of 7% is optimal. $ maintenance programs should be These diets may differ in the types of prescribed. Such programs should Recommendations foods they restrict (such as high-fat or provide at least monthly contact When choosing glucose-lowering c high-carbohydrate foods) but are effec- and encourage ongoing monitoring medications for overweight or tive if they create the necessary energy of body weight (weekly or more fre- obese patientswithtype2diabetes, 16). The diet choice should – cit (13 de fi quently), continued consumption consider their effect on weight. E be based on the patient ’ shealthstatus of a reduced calorie diet, and par- c Whenever possible, minimize the and preferences. ticipation in high levels of physical medications for comorbid condi- Intensive behavioral lifestyle inter- A activity (200 – 300 min/week). tions that are associated with weight ventions should include 16 sessions $ To achieve weight loss of 5%, c . gain. E in 6 months and focus on diet, physical short-term (3-month) high-intensity Weight loss medications may be c oral strategies to activity, and behavi lifestyle interventions that use effective as adjuncts to diet, physical 750 kcal/day energy – achieve an 500 ; 800 # very low-calorie diets ( activity, and behavioral counseling de fi cit. Interventions should be pro- kcal/day) and total meal replace- forselectedpatientswithtype2di- vided by trained interventionists in ei- ments may be prescribed for 2 .Potential $ abetes and BMI 27 kg/m ther individual or group sessions (17). carefully selected patients by ts must be weighed against the fi bene Overweight and obese patients with trained practitioners in medical A potential risks of the medications. type 2 diabetes who have lost weight care settings with close medical s response to weight loss ’ If a patient c during the 6-month intensive behavioral monitoring. To maintain weight 5% after 3 months , medications is lifestyle intervention should be enrolled loss, such programs must incorpo- or if there are any safety or tolerabil- 1-year) comprehensive $ in long-term ( rate long-term comprehensive ity issues at any time, the medication weight loss maintenance programs B weight maintenance counseling. should be discontinued and alterna- that provide at least monthly contact tive medications or treatment ap- or obese patients Among overweight with a trained interventionist and focus proaches should be considered. A with type 2 diabetes and inadequate on ongoing monitoring of body weight glycemic, blood pressure and lipid (weekly or more frequently), continued When considering pharmacological treat- ments for overweight or obese patients with type 2 diabetes, providers should Treatment for overweight and obesity in type 2 diabetes — Table 6.1 rst consider their choice of glucose- fi 2 ) BMI category (kg/m lowering medications. Whenever possi- – 39.9 – 35.0 34.9 30.0 27.0 40 $ 23.0* or 25.0 – 26.9 29.9 – Treatment ble, medications should be chosen to Diet, physical activity, and promote weight loss or to be weight neu- behavioral therapy ┼┼┼┼┼ tral. Agents associated with weight loss Pharmacotherapy ┼┼┼┼ -glucosidase inhibi- a include metformin, ┼┼ Bariatric surgery tors, glucagon-like peptide 1 agonists, ┼ Treatment may be indicated for selected motivated patients. glucose – amylin mimetics, and sodium *Cutoff points for Asian American individuals. cotransporter 2 inhibitors. Dipeptidyl

56 Obesity Management for the Treatment of Type 2 Diabetes S49 care.diabetesjournals.org peptidase 4 inhibitors appear to be In general, pharmacological treatment education, lifestyle counseling, and weight neutral. Unlike these agents, insu- of obesity has been limited by low adher- encouragement to participate in Weight lin secretagogues, thiazolidinediones, and fi ence, modest ef cacy, adverse effects, 6% # Watchers) in achieving a target A1C insulin have often been associated with and weight regain after medication cessa- (42 mmol/mol) at 3 years among obese weight gain (see Section 7 Approaches “ tion (21). patients with uncontrolled type 2 diabe- to Glycemic Treatment ). ” tes (mean A1C 9.3% [78 mmol/mol]). This BARIATRIC SURGERY , A1C target was achieved by 38% ( P Concomitant Medications 0.001) in the gastric bypass group, 24% Recommendations Providers should carefully review the ( P 5 0.01) in the sleeve gastrectomy Bariatric surgery may be considered c patient ’ s concomitant medications 2 group, and 5% in the group that received and 35 kg/m . for adults with BMI and, whenever possible, minimize or only medical therapy (26). Diabetes re- type 2 diabetes, especially if diabe- provide alternatives for medications mission rates tend to be higher with pro- tes or associated comorbidities are that promote weight gain. The latter in- cedures that bypass portions of the small dif fi cult to control with lifestyle and clude atypical antipsychotics (clozapine, intestine and lower with procedures that B pharmacological therapy. olanzapine, risperidone, etc.) and an- only restrict the stomach. Patients with type 2 diabetes who c tidepressants (tricyclic antidepressants, Younger age, shorter duration of have undergone bariatric surgery selective serotonin reuptake inhibitors, type 2 diabetes, lower A1C, higher need lifelong lifestyle support and monoamine oxidase inhibitors), serum insulin levels, and nonuse of and annual medical monitoring, glucocorticoids, oral contraceptives insulin have all been associated with at a minimum. B that contain progestins, anticonvulsants higher remission rates after bariatric Although small trials have shown a c including gabapentin, and a number of surgery (27). tofbariatricsur- glycemic bene fi antihistamines and anticholinergics. Although bariatric surgery has been gery in patients with type 2 dia- 2 fi shown to improve the metabolic pro les , betes and BMI 30 35 kg/m – Approved Medications of morbidly obese patients with type 1 cient evi- fi there is currently insuf The U.S. Food and Drug Administration diabetes, the role of bariatric surgery in dence to generally recommend (FDA) has approved ve weight loss fi such patients will require larger and surgeryinpatientswithBMI medications (or combination medica- 2 longer studies (28). . E 35 kg/m # tions) for long-term use by patients 2 with one or more 27 kg/m $ with BMI Disadvantages Bariatric and metabolic surgeries, either obesity-associated comorbid conditions 2 Bariatric surgery is costly and has asso- gastric bandingor procedures that involve 30 kg/m and by patients with BMI $ ciated risks. Morbidity and mortality resecting, bypassing, or transposing sec- who are motivated to lose weight (21 – rates directly related to the surgery tions of the stomach and small intestine, 23). Medications approved for long-term have decreased considerably in recent can be effective weight loss treatments weight loss and weight loss mainte- years, with 30-day mortality rates for severe obesity when performed as nance and their advantages and disad- now 0.2% for laparoscopic procedures, part of a comprehensive weight manage- . vantages are summarized in Table 6.2 similar to those for laparoscopic cholecys- ment program with lifelong lifestyle sup- The rationale for weight loss medica- tectomy, and 2.1% for open procedures port and medical monitoring. In one tions is to help patients to more consis- (29,30). Outcomes vary depending on meta-analysis, gastric banding resulted tently adhere to low-calorie diets and to the procedure and the experience of in less weight loss than sleeve gastrec- reinforce lifestyle changes including phys- the surgeon and center. Longer-term tomy and Roux-en-Y gastric bypass ical activity. Providers should be knowl- concerns include dumping syndrome ; 33% vs. (1-year excess weight loss edgeable about the product label and (nausea, colic, diarrhea), vitamin and ; 70%) (24). National guidelines sup- ts of fi should balance the potential bene fi mineral de ciencies, osteoporosis, and, port consideration of bariatric surgery successful weight loss against the poten- rarely, severe hypoglycemia from insulin for people with type 2 diabetes with tial risks of the medication for each pa- 2 hypersecretion. More recent studies also . BMI . 35 kg/m tient. All medications are FDA pregnancy suggest that patients who undergo bari- category X. These medications are con- atric surgery may be at increased risk for Advantages traindicated in women who are or may Treatment with bariatric surgery has substance use, including drug and alcohol become pregnant. Women in their repro- been shown to achieve near or complete use and cigarette smoking (31). Cohort ductive years must be cautioned to use a normalization of glycemia 2 years follow- studies attempting to match surgical reliable method of contraception. ing surgery in 72% of patients (compared and nonsurgical subjects suggest that with 16% in a matched control group the procedure may reduce longer-term Assessing Ef fi cacy and Safety cacy and safety should be assessed at Ef fi treated with lifestyle and pharmacologi- mortality (25). least monthly for the fi rst 3 months of treat- cal interventions) (25). A study evaluated – In contrast, a propensity score s response is deemed in- ’ ment. If a patient the effectiveness of surgical intervention adjusted analysis of older, severely obese fi 5%) or if there are , cient (weight loss suf (Roux-en-Y gastric bypass or sleeve gas- patients in Veterans Affairs Medical Cen- any safety or tolerability issues at any time, trectomy) and medical therapy compared ters found that bariatric surgery was not the medication should be discontinued and with medical therapy alone (quarterly associated with decreased mortality com- alternative medications or treatment ap- visits, pharmacological therapy, self- pared with usual care (mean follow-up proaches should be considered. monitoring of blood glucose, diabetes 6.7 years) (32). Retrospective analyses

57 Volume 39, Supplement 1, January 2016 Diabetes Care S50 Obesity Management for the Treatment of Type 2 Diabetes 854. – 2diabetes. ndications. 7 2.4%), , Serious 12 – 2,6 Serotonin syndrome or Pancreatitis, thyroid C-cell Topiramate is teratogenic and of MTC or MEN2, acute renal failure of mania Depression, precipitation with personal/family history cleft lip/palate has been associated with contraindicated in patients tumors in rodents, valve disorder ( NMS-like reactions, heart bradycardia nephropathy Liver failure and oxalate Adverse effects 7 thout type 2 diabetes); 13% had type ive years must be cautioned to use a reliable method Common 2 diabetes); 13% had type 2 diabetes. ion were also observed. ie-diet-induced weight loss: the SCALE Maintenance ptic malignant syndrome; s.c., subcutaneous; tabs, tablets. ns (i.e., patients with or without type 2 diabetes), but the n GLP-1 analog, liraglutide. Int J Obes (Lond) 2012;36:843 Paresthesia, xerostomia, constipation, Nausea, constipation, headache, Hypoglycemia, nausea, vomiting, vomiting diarrhea, constipation, headache headache Hypoglycemia, headache, fatigue vitamins (A, D, E, K) and medications (e.g., cyclosporine, thyroid hormone replacement, or anticonvulsants), potentiation of the effects of warfarin spotting/stool, fecal urgency, malabsorption of fat-soluble Abdominal pain/discomfort, oily abetes). Percentage of patients with type 2 diabetes was not reported. 5% $ 5 – 2 70% 57% 73% 48% 73% – – – – – opulations (i.e., patients with or wi weight 45 38 36 51 35 loss of baseline % Patients with 86. – 4.1 kg 5.9 kg – – 5.8 2.0 3.2 kg 1-Year weight change status (32 mg/360 mg) 2.5 kg (60 mg) 3.4 kg (120 mg) relative to placebo Average weight loss 8.9 kg (15 mg/92 mg) 6.7 kg (7.5 mg/46 mg) 1 $1,282 $263 82 (60 mg) – $615 (120 mg) $41 price (per month) Average wholesale $239 (maximum dose) highest strength) dose using the $239 (maximum ve double-blind, placebo-controlled clinical trials in mixed-type study p fi 10 mg b.i.d. 1451. – 5%) and serious adverse effects are noted. Refer to the medication package inserts for full information about adverse effects, cautions, and contrai Adult dosing frequency . (during or up to 1 h after a low-fat meal) 60 mg or 120 mg t.i.d. q.d. for 14 days, then increase to 7.5 mg/46 mg q.d. Maintenance dose: 3 mg s.c. q.d. 32 mg/bupropion 360 mg b.i.d. for a total daily dosage of naltrexone Maximum dose: two tablets of Contrave Maximum dose: 15 mg/92 mg q.d. Recommended dose: 3.75 mg/23 mg receptor agonist 2C ned as an incidence of fi Medications approved by the FDA for the long-term treatment of obesity lled pen Desk Reference. PDR Network, LLC (electronic version). Truven Health Analytics, Greenwood Village, CO. fi ’ — Data of common adverse effects for Contrave were derived from Data of common adverse effects for Saxenda were derived from clinical trials in mixed-type study populations (i.e., patients with or without type 2 di Data of common adverse effects for Qsymia were derived from four clinical trials in mixed-type study populations (i.e., patients with or without type Data of common adverse effects for Belviq were derived from placebo-controlled clinical trials in patients with type 2 diabetes. Data of common adverse effects for Xenical were derived from seven double-blind, placebo-controlled clinical trials in mixed-type study populatio Astrup A, Carraro R, Finer N, et al.; NN8022-1807 Investigators. Safety, tolerability and sustained weight loss over 2 years with the once-daily huma Physicians DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA 2014;311:74 Selective common (de RED BOOK Online. Micromedex 2.0 (electronic version). Truven Health Analytics, Greenwood Village, CO. Wadden TA, Hollander P, Klein S, et al.; NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calor 9 Acylated human glucagon-like peptide 1 receptor agonist Liraglutide (Saxenda) 6 mg/mL pre Opioid antagonist/aminoketone antidepressant combination Naltrexone/bupropion (Contrave) 8 mg/90 mg tabs 7.5 mg/46 mg caps, 15 mg/92 mg caps 11.25 mg/69 mg caps, Sympathomimetic amine anorectic/antiepileptic combination 3.75 mg/23 mg caps, Phentermine/topiramate ER (Qsymia) randomized study. Int J Obes (Lond) 2013;37:1443 percentage of patients with type 2 diabetes was not reported. In clinical trials in obese patients with diabetes, hypoglycemia and abdominal distens orlistat (Xenical) 120 mg caps of contraception. Caps, capsules; ER, extended release; MEN2, multiple endocrine neoplasia type 2; MTC, medullary thyroid carcinoma; NMS, neurole Table 6.2 All medications are FDA pregnancy category X; these medications are contraindicated in women who are or may become pregnant. Women in their reproduct Generic drug name, (proprietary name[s]) and Selective serotonin (5-HT) 5-HT dosage strength and form Lipase inhibitor Orlistat (Alli) 60 mg caps or Lorcaserin (Belviq) 10 mg tabs 4 8 6 2 3 7 1 11 12 10 5

58 Obesity Management for the Treatment of Type 2 Diabetes S51 care.diabetesjournals.org intervention: the Look AHEAD study. Obesity 23. Pi-Sunyer X, Astrup A, Fujioka K, et al.; and modeling studies suggest that bariat- (Silver Spring) 2014;22:5 13 – SCALE Obesity and Prediabetes NN8022-1839 ric surgery may be cost-effective or even 11. Wilding JPH. The importance of weight Study Group. A randomized, controlled trial of cost-saving for patients with type 2 di- management in type 2 diabetes mellitus. Int J 3.0 mg of liraglutide in weight management. abetes, but the results are largely de- Clin Pract 2014;68:682 – 691 – 22 N Engl J Med 2015;373:11 pendent on assumptions about the 12. WHO Expert Consultation. Appropriate 24. Chang S-H, Stoll CRT, Song J, Varela JE, body-mass index for Asian populations and its Eagon CJ, Colditz GA. The effectiveness and risks long-term effectiveness and safety of implications for policy and intervention strate- of bariatric surgery: an updated systematic re- the procedures (33,34). Understanding – gies. Lancet 2004;363:157 163 view and meta-analysis, 2003-2012. JAMA Surg ts and risks of bari- the long-term bene fi 13. Sacks FM, Bray GA, Carey VJ, et al. Compar- 287 2014;149:275 – atric surgery in individuals with type 2 ̈ ̈ om L, Peltonen M, Jacobson P, et al. ison of weight-loss diets with different compo- 25. Sj ostr Association of bariatric surgery with long-term diabetes, especially those who are not sitions of fat, protein, and carbohydrates. N Engl remission of type 2 diabetes and with microvas- J Med 2009;360:859 – 873 severely obese, will require well-de- cular and macrovascular complications. JAMA 14. de Souza RJ, Bray GA, Carey VJ, et al. Effects signed clinical trials, with optimal med- 2304 – 2014;311:2297 of 4 weight-loss diets differing in fat, protein, ical therapy as the comparator (35). 26. Schauer PR, Bhatt DL, Kirwan JP, et al.; and carbohydrate on fat mass, lean mass, vis- Unfortunately, such studies may not STAMPEDE Investigators. Bariatric surgery ceral adipose tissue, and hepatic fat: results versus intensive medical therapy for diabetes d from the POUNDS LOST trial. Am J Clin Nutr be feasible (36). – 3-year outcomes. N Engl J Med 2014;370:2002 2012;95:614 625 – 2013 15. Johnston BC, Kanters S, Bandayrel K, et al. References 27. Still CD, Wood GC, Benotti P, et al. Preop- Comparison of weight loss among named diet ̈ om J, Eriksson JG, et al.; 1. Tuomilehto J, Lindstr erative prediction of type 2 diabetes remission programs in overweight and obese adults: a Finnish Diabetes Prevention Study Group. Pre- after Roux-en-Y gastric bypass surgery: a retro- meta-analysis. JAMA 2014;312:923 – 933 vention of type 2 diabetes mellitus by changes spective cohort study. Lancet Diabetes Endocri- 16. Jensen MD, Ryan DH, Apovian CM, et al.; in lifestyle among subjects with impaired glu- 45 – nol 2014;2:38 American College of Cardiology/American Heart – cose tolerance. N Engl J Med 2001;344:1343 28. Brethauer SA, Aminian A, Rosenthal RJ, Association Task Force on Practice Guidelines; 1350 Kirwan JP, Kashyap SR, Schauer PR. Bariatric sur- Obesity Society. 2013 AHA/ACC/TOS guideline 2. Knowler WC, Barrett-Connor E, Fowler SE, gery improves the metabolic pro le of morbidly fi for the management of overweight and obesity et al.; Diabetes Prevention Program Research obese patients with type 1 diabetes. Diabetes in adults: a report of the American College of Group. Reduction in the incidence of type 2 Care 2014;37:e51 – e52 Cardiology/American Heart Association Task Force diabetes with lifestyle intervention or metfor- 29. Buchwald H, Estok R, Fahrbach K, Banel D, on Practice Guidelines and The Obesity Society. J 403 – min. N Engl J Med 2002;346:393 Sledge I. Trends in mortality in bariatric surgery: Am Coll Cardiol 2014;63(25 Pt B):2985 – 3023 3. UK Prospective Diabetes Study 7. UK Pro- a systematic review and meta-analysis. Surgery 17. Selph S, Dana T, Bougatsos C, Blazina I, Patel spective Diabetes Study 7: response of fasting 2007;142:621 – 632 H, Chou R. Screening for abnormal glucose and plasma glucose to diet therapy in newly pre- 30. The Longitudinal Assessment of Bariatric type 2 diabetes mellitus: a systematic review to senting type II diabetic patients, UKPDS Group. Surgery (LABS) Consortium. Peri-operative update the 2008 U.S. Preventive Services Task Metabolism 1990;39:905 912 – safety in the longitudinal assessment of bari- Force Recommendation [Internet], 2015. 4. Goldstein DJ. Bene cial health effects of fi atric surgery. N Engl J Med 2009;361:445 – Rockville, MD, Agency for Healthcare Research modest weight loss. Int J Obes Relat Metab Dis- 454 and Quality (Report No.: 13-05190-EF-1. U.S. 415 ord 1992;16:397 – 31. Conason A, Teixeira J, Hsu C-H, Puma L, Preventive Services Task Force Evidence Syn- 5. Pastors JG, Warshaw H, Daly A, Franz M, Knafo D, Geliebter A. Substance use following tic Evidence Reviews) theses, formerly Systema Kulkarni K. The evidence for the effectiveness bariatric weight loss surgery. JAMA Surg 2013; 18. Gudzune KA, Doshi RS, Mehta AK, et al. Ef- of medical nutrition therapy in diabetes man- 148:145 – 150 fi cacy of commercial weight-loss programs: an – agement. Diabetes Care 2002;25:608 613 32. Maciejewski ML, Livingston EH, Smith VA, updated systematic review. Ann Intern Med 6. Lim EL, Hollingsworth KG, Aribisala BS, Chen gh-risk patients after et al. Survival among hi 2015;162:501 – 512 MJ,MathersJC,TaylorR.Reversaloftype2 2426 – bariatric surgery. JAMA 2011;305:2419 19. Tsai AG, Wadden TA. The evolution of diabetes: normalisation of beta cell function in 33. Hoerger TJ, Zhang P, Segel JE, Kahn HS, very-low-calorie diets: an update and meta- association with decreased pancreas and liver tri- Barker LE, Couper S. Cost-effectiveness of analysis. Obesity (Silver Spring) 2006;14: – 2514 acylglycerol. Diabetologia 2011;54:2506 bariatric surgery for severely obese adults 1293 – 1283 7. Jackness C, Karmally W, Febres G, et al. Very with diabetes. Diabetes Care 2010;33:1933 – 20. Johansson K, Neovius M, Hemmingsson E. low-calorie diet mimics the early bene fi cial ef- 1939 Effects of anti-obesity drugs, diet, and exercise fect of Roux-en-Y gastric bypass on insulin sen- 34. Keating CL, Dixon JB, Moodie ML, Peeters on weight-loss maintenance after a very- -cell function in type 2 diabetic b sitivity and fi ’ Brien PE. Cost-ef cacy of sur- A, Playfair J, O low-calorie diet or low-calorie diet: a systematic – patients. Diabetes 2013;62:3027 3032 t loss for the manage- gically induced weigh review and meta-analysis of randomized con- 8. Rothberg AE, McEwen LN, Kraftson AT, ment of type 2 diabetes: a randomized – trolled trials. Am J Clin Nutr 2014;99:14 23 Fowler CE, Herman WH. Very-low-energy diet – controlled trial. Diabetes Care 2009;32:580 21. Yanovski SZ, Yanovski JA. Long-term drug for type 2 diabetes: an underutilized therapy? 584 treatment for obesity: a systematic and clinical – J Diabetes Complications 2014;28:506 510 35. Wolfe BM, Belle SH. Long-term risks and 86 review. JAMA 2014;311:74 – 9. Wing RR, Bolin P, Brancati FL, et al.; Look bene ts of bariatric surgery: a research chal- fi 22. Greenway FL, Fujioka K, Plodkowski RA, AHEAD Research Group. Cardiovascular effects 1793 – lenge. JAMA 2014;312:1792 et al.; COR-I Study Group. Effect of naltrexone of intensive lifestyle intervention in type 2 36. Courcoulas AP, Goodpaster BH, Eagleton JK, plus bupropion on weight loss in overweight – 154 diabetes. N Engl J Med 2013;369:145 et al. Surgical vs medical treatments for type 2 and obese adults (COR-I): a multicentre, rando- 10. Look AHEAD Research Group. Eight-year diabetes mellitus: a randomized clinical trial. mised, double-blind, placebo-controlled, phase weight losses with an intensive lifestyle JAMA Surg 2014;149:707 – 715 605 3 trial. Lancet 2010;376:595 –

59 S52 Diabetes Care Volume 39, Supplement 1, January 2016 American Diabetes Association 7. Approaches to Glycemic Treatment DOI: 10.2337/dc16-S010 | S59 – Diabetes Care 2016;39(Suppl. 1):S52 PHARMACOLOGICAL THERAPY FOR TYPE 1 DIABETES Recommendations c Most people with type 1 diabetes should be treated with multiple-dose insulin injections (three to four injections per day of basal and prandial insulin) or A continuous subcutaneous insulin infusion. c Consider educating individuals with type 1 diabetes on matching prandial insulin E dose to carbohydrate intake, premeal blood glucose, and anticipated activity. Most individuals with type 1 diabetes should use insulin analogs to reduce c hypoglycemia risk. A c Individuals who have been successfully using continuous subcutaneous insulin E infusion should have continued access after they turn 65 years of age. Insulin Therapy Insulin is the mainstay of therapy for individuals with type 1 diabetes. There are n and management of insulin therapy to excellent reviews to guide the initiatio achieve desired glycemic goals (1). Although most studies of multiple-dose insulin versus pump therapy have been small and of short duration, a systematic review and 7. APPROACHES TO GLYCEMIC TREATMENT meta-analysis concluded that there are minimal differences between the two forms bined mean between-group difference of intensive insulin therapy in A1C (com 0.30% [95% CI favoring insulin pump therapy 2 2 0.58 to 0.02]) and severe hypo- 2 glycemia rates in children and adults (2). A large randomized trial in patients with type 1 diabetes with nocturnal hypoglycemia reported that sensor-augmented in- sulin pump therapy with the threshold suspend feature reduced nocturnal hypo- ed hemoglobin values (3). Intensive glycemia, without increasing glycat management through pump therapy/continuous glucose monitoring and active 6). Selected – patient/family participation should be strongly encouraged (4 individuals who have mastered carbohydrate counting should be educated that fat increases glucose concentrations and insulin requirements (7). The Diabetes Control and Complications Trial (DCCT) clearly showed that in- tensive insulin therapy (three or more injections per day of insulin) or continuous subcutaneous insulin infusion (CSII) (i nsulin pump therapy) was a key part of improved glycemia and better outcomes (8,9). The study was carried out with short-acting and intermediate-acting human insulins. Despite better microvascular, macrovascular, and all-cause mortality outcomes, intensive insulin therapy was as- sociated with a high rate of severe hypoglycemia (62 episodes per 100 patient-years of therapy). Since the DCCT, a number of rapid-acting and long-acting insulin analogs have been developed. These analogs are associated with less hypoglycemia in type 1 diabetes, while matching the A1C lowering of human insulins (10,11). Rapid-acting inhaled insulin used before meals in type 1 diabetes leads to inferior A1C lowering when compared with aspart insulin, with less hypoglycemia across all Suggested citation: American Diabetes Associa- A1C target categories (12). tion. Approaches to glycemic treatment. Sec. 7. Postprandial glucose excursions can be better controlled by adjusting the timing In Standards of Medical Care in Diabetes d 2016 . of prandial (bolus) insulin dose administration. The optimal time to inject prandial – S59 Diabetes Care 2016;39(Suppl. 1):S52 insulin varies, based on the type of insulin injected (regular, rapid-acting analog, © 2016 by the American Diabetes Association. inhaled, etc.), the measured blood glucose level, timing of meals, and carbohydrate Readers may use this article as long as the work consumption. Recommendations for prandial insulin dose administration should is properly cited, the use is educational and not therefore be individualized. for pro fi t, and the work is not altered.

60 Approaches to Glycemic Treatment S53 care.diabetesjournals.org Recommended therapy for type 1 di- , P insulin requirements (6.6 units/day, c A patient-centered approach abetes consists of the following: 0.001) and led to small reductions in should be used to guide the choice weight and total and LDL cholesterol but of pharmacological agents. Con- 1. Multiple-dose insulin injections (three not to improved glycemic control (abso- siderations include ef fi cacy, cost, to four injections per day of basal and lute A1C reduction 0.11%, 0.42) (14). 5 P potential side effects, weight, co- prandial insulin) or CSII therapy. Incretin-Based Therapies morbidities, hypoglycemia risk, 2. Match prandial insulin to carbohy- Therapies approved for the treatment of and patient preferences. E drate intake, premeal blood glucose, type 2 diabetes are currently being eval- c For patients with type 2 diabetes and anticipated physical activity. uated in type 1 diabetes. Glucagon-like who are not achieving glycemic 3. For most patients (especially those at peptide 1 (GLP-1) agonists and dipep- goals, insulin therapy should not elevated risk of hypoglycemia), use tidyl peptidase 4 (DPP-4) inhibitors are B be delayed. insulin analogs. not currently FDA approved for those 4. For patients with frequent nocturnal with type 1 diabetes but are being stud- An American Diabetes Association/ hypoglycemia, recurrent severe hy- ied in this population. European Association for the Study of poglycemia, and/or hypoglycemia Diabetes position statement (17) evalu- Glucose Cotransporter 2 Sodium – unawareness, a sensor-augmented ated the data and developed recom- Inhibitors low glucose threshold suspend pump mendations, including advantages and Sodium glucose cotransporter 2 (SGLT2) – may be considered. disadvantages, for antihyperglycemic inhibitors provide insulin-independent agents for patients with type 2 diabetes. Pramlintide glucose lowering by blocking glucose re- A patient-centered approach is stressed, Pramlintide, an amylin analog, is an absorption in the proximal renal tubule including patient preferences, cost, and agent that delays gastric emptying, by inhibiting SGLT2. These agents potential side effects of each class, effects blunts pancreatic secretion of glucagon, provide modest weight loss and blood on body weight, and hypoglycemia risk. and enhances satiety. It is a U.S. Food pressure reduction. There are three cations that improve fi Lifestyle modi and Drug Administration (FDA)-approved FDA-approved agents for use in patients health (see Section 3 Foundations of “ therapy for use in adults with type 1 di- with type 2 diabetes, but there are in- Care and Comprehensive Medical Eval- abetes. It has been shown to induce suf cient data to recommend treatment fi ” ) should be emphasized along uation weight loss and lower insulin dose. Con- in type 1 diabetes (15). The FDA recently with any pharmacological therapy. current reduction of prandial insulin issued a warning about the risk of keto- dosing is required to reduce the risk of acidosis with SGLT2 inhibitors in individ- Initial Therapy severe hypoglycemia. uals with type 1 or type 2 diabetes. Most patients should begin with life- Symptoms of ketoacidosis include nau- style changes, which may include life- Pancreas and Islet Cell Transplantation sea, vomiting, abdominal pain, tiredness, style counseling, setting a physical Pancreas and islet cell transplantation and dyspnea. Urinary tract infections activity goal of 150 min/week minimum, have been shown to normalize glucose leading to urosepsis and pyelonephritis and weight loss counseling to lose a min- levels but require lifelong immunosup- may also occur with SGLT2 inhibitors. Pa- imum of 7% of body weight (for details pression to prevent graft rejection and tients should stop taking their SGLT2 in- Obe- on lifestyle therapy, see Section 6 “ recurrence of autoimmune islet destruc- hibitor and seek medical attention sity Management for the Treatment of tion. Given the potential adverse effects immediately if they have symptoms of Type 2 Diabetes ” ). When lifestyle efforts of immunosuppressive therapy, pan- ketoacidosis (16). alone do not achieve or maintain glyce- creas transplantation should be reserved mic goals, metformin monotherapy PHARMACOLOGICAL THERAPY for patients with type 1 diabetes under- FOR TYPE 2 DIABETES should be added at, or soon after, diag- going simultaneous renal transplanta- nosis, unless there are contraindications tion, following renal transplantation, Recommendations or intolerance. Metformin has a long- or for those with recurrent ketoacidosis c Metformin, if not contraindicated cacy and fi standing evidence base for ef or severe hypoglycemia despite aggres- and if tolerated, is the preferred safety, is inexpensive, and may reduce sive glycemic management (13). Islet initial pharmacological agent for risk of cardiovascular events and death cell transplantation remains investiga- A type 2 diabetes. (18). Accumulating observational data tional. Autoislet tr ansplantation may Consider initiating insulin therapy c suggest that metformin may be safely be considered for patients requiring to- (with or without additional agents) fi continued down to glomerular ltration tal pancreatectomy who meet eligibility in patients with newly diagnosed 2 or even rate(GFR)of45mL/min/1.73m criteria. type2diabetesand markedlysymp- 2 (19). If metformin is 30 mL/min/1.73 m tomatic and/or elevated blood glu- Investigational Agents used in the lower GFR range, the dose E cose levels or A1C. Metformin should be reduced and patients should c If noninsulin monotherapy at max- Adding metformin to insulin therapy may beadvisedtostopthemedicationfornau- imum tolerated dose does not reduce insulin requirements and improve sea, vomiting, and dehydration. In patients achieve or maintain the A1C target metabolic control in overweight/obese with metformin intolerance or contraindi- over 3 months, then add a second patients with poorly controlled type 1 di- cations, consider an in itial drug from other oral agent, a glucagon-like peptide abetes. In a meta-analysis, metformin in under classes depicted in Fig. 7.1 “ Dual 1 receptor agonist, or basal insulin. A type 1 diabetes was found to reduce therapy ” and proceed accordingly.

61 Volume 39, Supplement 1, January 2016 S54 Approaches to Glycemic Treatment Diabetes Care — Antihyperglycemic therapy in type 2 diabetes: general recommendations (17). The order in the chart was determined by historical Figure 7.1 fi availability and the route of administration, with injectables to the right; it is not meant to denote any speci c preference. Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, with the usual transition moving vertically from top to bottom (although - horizontal movement within therapy stages is also possible, depending on the circumstances). DPP-4-i, DPP-4 inhibitor; fxs, fractures; GI, gastro rea; intestinal; GLP-1-RA, GLP-1 receptor agonist; GU, genitourinary; HF, heart failure; Hypo, hypoglycemia; SGLT2-i, SGLT2 inhibitor; SU, sulfonylu 9% (75 mmol/mol). Consider starting at this stage when A1C is † cacy categorization. fi $ TZD, thiazolidinedione. *See ref. 17 for description of ef – 108 mmol/mol), especially 12% (86 – 10 $ 19.4 mmol/L) and/or A1C is – 350 mg/dL (16.7 – 300 $ Consider starting at this stage when blood glucose is ‡ 1 mealtime insulin is the preferred initial regimen. §Usually a basal if symptomatic or catabolic features are present, in which case basal insulin insulin (NPH, glargine, detemir, degludec). Adapted with permission from Inzucchi et al. (17). Combination Therapy medical, psychosocial, and health eco- may be low-value based on high cost and Although there are numerous trials nomic outcomes (21). moderate glycemic effect (24). comparing dual therapy with metformin If the A1C target is not achieved after Rapid-acting secretagogues (megliti- alone, few directly compare drugs as approximately 3 months, consider a com- nides) may be used instead of sulfonyl- add-on therapy. A comparative effec- bination of metformin and one of these six ureas in patients with irregular meal tiveness meta-analysis (20) suggests treatment options: sulfonylurea, thiazolidi- schedules or those who develop late that overall each new class of noninsulin nedione, DPP-4 inhibitors (22), SGLT2 in- postprandial hypoglycemia on a sulfo- agents added to initial therapy lowers hibitors, GLP-1 receptor agonists, or basal nylurea. Other drugs not shown in the A1C around 0.9 – 1.1%. A comprehensive insulin ( Fig. 7.1 ). Drug choice is based on a fi gure (e.g., -glucosidase inhibitors, co- listing, including the cost, is available in patient preferences (23), as well as various lesevelam, bromocriptine, pramlintide) The ongoing Glycemia Reduc- Table 7.1. rug characteristics, patient, disease, and d fi c situations, but may be tried in speci tion Approaches in Diabetes: A Compar- with the goal of reducing blood glucose are generally not favored due to modest ative Effectiveness Study (GRADE) will levels while minimizing side effects, espe- fi cacy, the frequency of administra- ef compare the effect of four major drug emphasizes cially hypoglycemia. Figure 7.1 tion, and/or side effects. classes (sulfonylurea, DPP-4 inhibitor, drugs commonly used in the U.S. and/or For all patients, consider initiating GLP-1 analog, and basal insulin) over Europe. Cost-effectiveness models have therapy with a dual combination when 4 years on glycemic control and other suggested that some of the newer agents A1C is $ 9% (75 mmol/mol) to more

62 Approaches to Glycemic Treatment S55 care.diabetesjournals.org Low Low Low High High High Cost* Low to moderate Moderate tes (17) Continued on p. S56 cacy cacy cacy fi fi fi ciency fi de 12 Disadvantages absorption of other ↓ Heart failure hospitalizations MI (meta-analyses, atulence, diarrhea) Triglycerides Weight Weight LDL-C (rosiglitazone) Weight ↑ ↑ fl immune-mediated dermatological May Vitamin B ↑ Constipation Hypoglycemia Generally modest A1C ef Fatigue ? ? Acute pancreatitis ↑ Contraindications: CKD, acidosis, effects Rhinitis Angioedema/urticaria and other Frequent dosing schedule hypoxia, dehydration, etc. Lactic acidosis risk (rare) ( Gastrointestinal side effects Generally modest A1C ef Nausea Dizziness/syncope ? Generally modest A1C ef ↑ Bone fractures Hypoglycemia (diarrhea, abdominal cramping) Edema/heart failure Gastrointestinal side effects medications ↑ ↑ Frequent dosing schedule rosiglitazone) c c c c c c c c c c c c c c c c c c c c c c c c c c c c c exibility fl Advantages CVD events CVD events (STOP- CVD events (Cycloset HDL-C Microvascular risk CVD events (UKPDS) Postprandial glucose Triglycerides LDL-C Postprandial glucose ↓ ↓ ↓ No hypoglycemia ↓ Durability ↓ (UKPDS) Well tolerated ↑ No hypoglycemia excursions Extensive experience No hypoglycemia ↓ No hypoglycemia (pioglitazone) ↓ Nonsystemic Safety Trial) ? ? Dosing No hypoglycemia ? excursions ↓ ↓ Extensive experience No hypoglycemia NIDDM) (PROactive, pioglitazone) c c c c c c c c c c c c c c c c c c c c c c Hepatic glucose production Incretin levels Insulin secretion (glucose Insulin sensitivity Glucagon secretion (glucose Hepatic glucose production Insulin secretion Insulin secretion Insulin sensitivity ↑ ↓ ↑ digestion/absorption ? Slows intestinal carbohydrate dependent) ↑ ↑ regulation of metabolism dependent) Modulates hypothalamic ↓ ↑ ? ↑ ↓ Primary physiological action(s) c c c c c c c c c c c g -cell -cell b b -glucosidase a channels on channels on ATP ATP Cellular mechanism(s) Closes K Closes K Inhibits DPP-4 activity, increasing Binds bile acids in intestinal tract, Inhibits intestinal Activates AMP-kinase (? other) Activates the nuclear postprandial active incretin (GLP-1, GIP) concentrations increasing hepatic bile acid Activates dopaminergic receptors production transcription factor PPAR- plasma membranes plasma membranes ‡ † † Compound(s) Colesevelam Rosiglitazone§ Glyburide/ Gliclazide Bromocriptine (quick release)§ Glipizide Metformin Pioglitazone Acarbose Linagliptin Saxagliptin Nateglinide Sitagliptin Glimepiride Miglitol Repaglinide glibenclamide Vildagliptin Alogliptin c c c c c c c c c c c c c c c c c c 2nd Generation Properties of available glucose-lowering agents in the U.S. and Europe that may guide individualized treatment choices in patients with type 2 diabe — -Glucosidase inhibitors Biguanides Class Table 7.1 Bile acid sequestrants Meglitinides (glinides) DPP-4 inhibitors Sulfonylureas Dopamine-2 agonists TZDs a

63 Volume 39, Supplement 1, January 2016 Diabetes Care S56 Approaches to Glycemic Treatment High High High high# Cost* Moderate to cacy fi ; PROactive, Prospective g Disadvantages activated receptor – LDL-C Creatinine (transient) Heart rate Hypoglycemia unless insulin dose is Polyuria (nausea/vomiting) Gastrointestinal side effects ? Mitogenic effects Injectable (except inhaled insulin) Weight gain dizziness Training requirements Generally modest A1C ef ↑ ↑ Training requirements Hypoglycemia Injectable Pulmonary toxicity (inhaled insulin) ↑ Training requirements DKA, urinary tract infections leading to urosepsis, pyelonephritis thyroid tumors in animals C-cell hyperplasia/medullary Genitourinary infections Patient reluctance ? Acute pancreatitis Frequent dosing schedule Injectable Gastrointestinal side effects (nausea/vomiting/diarrhea) simultaneously reduced Volume depletion/hypotension/ c c c c c c c c c c c c c c c c c c c c c c c c c olidinedione; UKPDS, UK Prospective Diabetes Study (34,35). Initial concerns regarding bladder cancer risk are decreasing after ‡ Advantages , peroxisome proliferator g cacy fi Weight Weight Microvascular risk Postprandial glucose Blood pressure Postprandial glucose Weight Some cardiovascular ozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (31); mortality in patients OUTCOME) ↓ with CVD (EMPA-REG ↓ CVD event rate and excursions Associated with lower No hypoglycemia (UKPDS) ↓ ↓ excursions type 2 diabetes Effective at all stages of Nearly universal ↓ risk factors ↓ ↓ No hypoglycemia ef Theoretically unlimited response ↓ fl c c c c c c c c c c c c c c human insulins) and dosage. Adapted with permission from Inzucchi et al. (17). Not licensed in the U.S. † . Satiety Glucagon secretion (glucose Satiety Glucose disposal Insulin secretion (glucose Hepatic glucose production Glucagon secretion ↓ dependent) dependent) ↑ ↑ Slows gastric emptying ↓ ↑ Slows gastric emptying ↑ ↓ Suppresses ketogenesis glucosuria the kidney, increasing Blocks glucose reabsorption by Primary physiological action(s) c c c c c c c c c c c Cellular mechanism(s) Activates GLP-1 receptors Activates amylin receptors nephron Inhibits SGLT2 in the proximal ‡ † † ozin ozin ozin fl fl fl Compound(s) - Glulisine - Lispro - Human Regular - Inhaled insulin - Detemir - Degludec - Aspart - Human NPH - Glargine Exenatide extended release Pramlintide§ Lixisenatide Dapagli Rapid-acting analogs Activates insulin receptors Basal insulin analogs Empagli Exenatide Dulaglutide Intermediate-acting Short-acting Liraglutide Canagli Premixed (several types) Albiglutide c c c c c c c c c c c c c c c Continued — Table 7.1 SGLT2 inhibitors Class GIP, glucose-dependent insulinotropic peptide; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; MI, myocardial infarction; PPAR- Pioglitazone Clinical Trial in Macrovascular Events (32); STOP-NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (33); TZD, thiaz subsequent study. §Not licensed in Europe for type 2 diabetes. #Cost is highly dependent on type/brand (analogs CKD, chronic kidney disease; CVD, cardiovascular disease; DKA, diabetic ketoacidosis; EMPA-REG OUTCOME, BI 10773 (Empagli Cycloset trial of quick-release bromocriptine (36). *Cost is based on lowest-priced member of the class (see ref. 17). Amylin mimetics GLP-1 receptor agonists Insulins

64 Approaches to Glycemic Treatment S57 care.diabetesjournals.org Approach to starting and adjusting insulin in type 2 diabetes (17). FBG, fasting blood glucose; GLP-1-RA, GLP-1 receptor agonist; hypo, — Figure 7.2 hypoglycemia; mod., moderate; PPG, postprandial glucose; #, number. Adapted with permission from Inzucchi et al. (17). expeditiously achieve the target A1C elevated blood glucose levels or A1C. control in patients with type 2 diabetes level. Insulin has the advantage of being Many patients with type 2 diabetes initiating insulin (25). effective where other agents may not be eventually require and bene fi tfromin- Basal Insulin and should be considered as part of any sulin therapy. Providers may wish to Basal insulin alone is the most conve- combination regimen when hyperglyce- exibility when de fl consider regimen nient initial insulin regimen, beginning mia is severe, especially if symptoms are vising a plan for the initiation and ad- 0.2 units/kg, depend- at 10 units or 0.1 – present or any catabolic features (weight justment of insulin therapy in people ing on the degree of hyperglycemia. loss, ketosis) are present. Consider ini- with type 2 diabetes ( ). The pro- Fig. 7.2 Basal insulin is usually prescribed in con- tiating combination insulin injectable gressive nature of type 2 diabetes and junction with metformin and possibly $ 300 – therapy when blood glucose is its therapies should be regularly and ob- one additional noninsulin agent. While 350 mg/dL (16.7 – 19.4 mmol/L) and/or jectively explained to patients. For pa- there is evidence for reduced risk of hy- 12% (86 A1C is $ 10 – – 108 mmol/mol). As tients with type 2 diabetes who are not poglycemia with newer, longer-acting, s glucose toxicity resolves, the ’ the patient ls, providers should achieving glycemic goa basal insulin analogs, people with type regimen may, potentially, be simpli ed. fi promptly initiate insulin therapy. 2 diabetes without history of hypogly- Providers should avoid using insulin cemia or severe hypoglycemia may use asathreatordescribingitasafailureor Insulin Therapy NPH safely at much lower cost (24,26). Consider initiating insulin therapy (with punishment. Equipping patients with an Concentrated preparation of basal in- or without additional agents) in patients algorithm for self-titration of insulin ve times fi sulinsuchasU-500regularis with newly diagnosed type 2 diabetes doses based on self-monitoring of blood and markedly symptomatic and/or as potent per volume of insulin (i.e., glucose (SMBG) improves glycemic

65 Volume 39, Supplement 1, January 2016 Diabetes Care S58 Approaches to Glycemic Treatment – of hypoglycemia. N Engl J Med 2013;369:224 0.01 mL 5 units of U-100 regular) and ; current insulin dose and then providing 232 has a delayed onset and longer one-half of this amount as basal and 4. Wood JR, Miller KM, Maahs DM, et al.; T1D duration of action than U-100 regular. one-half as mealtime insulin, the latter Exchange Clinic Network. Most youth with U-300 glargine and U-200 degludec are split evenly between three meals. It is crit- type 1 diabetes in the T1D Exchange clinic reg- three and two times, respectively, as istry do not meet American Diabetes Associa- ical that individuals who have been suc- tion or International Society for Pediatric and potent per volume, have a longer dura- cessfully using CSII should have continued Adolescent Diabetes clinical guidelines. Diabe- tion of action, and may allow higher access after they turn 65 years of age (30). tes Care 2013;36:2035 – 2037 doses of insulin administration in 5. Kmietowicz Z. Insulin pumps improve control Inhaled Insulin smaller volumes. These concentrated and reduce complications in children with Inhaled insulin is now available for pran- type 1 diabetes. BMJ 2013;347:f5154 preparationsmaybemorecomfortable dial use with a more limited dosing 6. Phillip M, Battelino T, Atlas E, et al. Nocturnal for the patient and allow better absorp- range and may require serial lung func- glucose control with an arti cial pancreas at a dia- fi tion. However, they are more expen- tion testing prior to and after starting 833 betes camp. N Engl J Med 2013;368:824 – sive, and accurate dosing may be more 7. Wolpert HA, Atakov-Castillo A, Smith SA, therapy. complicated. Steil GM. Dietary fat acutely increases glucose Treatment Strategies concentrations and insulin requirements in If basal insulin has been titrated to an focuses solely on sequential Figure 7.2 patients with type 1 diabetes: implications for acceptable fasting blood glucose level, carbohydrate-based bolus dose calculation and insulin strategies, describing the num- but A1C remains above target, consider intensive diabetes management. Diabetes Care ber of injections and the relative com- advancing to combination injectable 2013;36:810 816 – exibility of each stage. Once fl plexity and therapy ( Fig. 7.2 ) to cover postprandial 8. The Diabetes Control and Complications Trial an insulin regimen is initiated, dose ti- Research Group. The effect of intensive treat- glucose excursions. Options include tration is important, with adjustments ment of diabetes on the development and adding a GLP-1 receptor agonist (27) or progression of long-term complications in insulin- made in both mealtime and basal insu- mealtime insulin, consisting of one to dependent diabetes mellitus. N Engl J Med 1993; lins based on the prevailing blood glu- three injections of rapid-acting insulin 329:977 – 986 cose levels and an understanding of the analog (lispro, aspart, or glulisine) ad- 9. Nathan DM, Cleary PA, Backlund J-YC, et al.; le of each for- pharmacodynamic pro fi Diabetes Control and Complications Trial/ ministered just before eating. A less mulation (pattern control). Epidemiology of Diabetes Interventions and studied alternative, transitioning from Complications (DCCT/EDIC) Study Research Noninsulin agents may be continued, basal insulin to twice-daily premixed Group. Intensive diabetes treatment and car- although sulfonylureas, DPP-4 inhibi- (or biphasic) insulin analogs (70/30 as- diovascular disease in patients with type 1 di- tors, and GLP-1 receptor agonists are part mix, 75/25 or 50/50 lispro mix), 2653 – abetes. N Engl J Med 2005;353:2643 typically stopped once more complex in- 10. DeWitt DE, Hirsch IB. Outpatient insulin could also be considered; pharmacody- sulin regimens beyond basal are used. In therapy in type 1 and type 2 diabetes mellitus: namic pro les make them suboptimal to fi c review. JAMA 2003;289:2254 fi scienti 2264 – patients with suboptimal blood glucose cover postprandial glucose excursions. 11. Rosenstock J, Dailey G, Massi-Benedetti M, control, especially those requiring in- Fritsche A, Lin Z, Salzman A. Reduced hypoglyce- Bolus Insulin creasing insulin doses, adjunctive use mia risk withinsulin glargine: a meta-analysis com- Some individuals with type 2 diabetes of thiazolidinediones (usually pioglita- paring insulin glargine with human NPH insulin in may require bolus insulin dosing in ad- zone) or SGLT2 inhibitors may be helpful 955 – type 2 diabetes. Diabetes Care 2005;28:950 dition to basal insulin. Rapid-acting an- ng Document: fi 12. MannKind Corporation. Brie in improving control and reducing the alogs are preferred due to their prompt Endocrinologic and Metabolic Drug Advisory amount of insulin needed. Comprehen- Committee. AFREZZA (insulin human [rDNA origin]) onset of action after dosing. The FDA sive education regarding SMBG, diet, ex- inhalation powder. An ultra-rapid acting insulin recently approved a more concentrated ercise, and the avoidance of and response treatment to improve glycemic control in adult formulation of rapid-acting insulin ana- to hypoglycemia are critically important patients with diabetes mellitus [Internet], 2014. log, U-200 (200 units/mL), dosed 15 min Available from http://www.fda.gov/downloads/ in any patient using insulin. AdvisoryCommittees/Commit teesMeetingMaterials/ or immediately prior to a meal. BARIATRIC SURGERY Drugs/EndocrinologicandMetabolicDrugsAdvisory Regular human insulin and human Committee/UCM390865.pdf. Accessed 6 November Bariatric surgery also improves glycemic NPH-Regular premixed formulations 2015 control in type 2 diabetes. Its effects are (70/30) are less costly alternatives to 13. American Diabetes Association. Pancreas Obesity Man- discussed in Section 6 “ rapid-acting insulin analogs and pre- and islet transplantation in type 1 diabetes. Di- agement for the Treatment of Type 2 abetes Care 2006;29:935 mixed insulin analogs, respectively, 14. Vella S, Buetow L, Royle P, Livingstone S, ” Diabetes. but their pharmacodynamic pro fi les Colhoun HM, Petrie JR. The use of metformin make them suboptimal to cover post- fi - in type 1 diabetes: a systematic review of ef References prandial glucose excursions. cacy. Diabetologia 2010;53:809 – 820 1. Wallia A, Molitch ME. Insulin therapy for 15. Chiang JL, Kirkman MS, Laffel LM, Peters AL; Continuous Subcutaneous Insulin Infusion type 2 diabetes mellitus. JAMA 2014;311: Type 1 Diabetes Sourcebook Authors. Type 1 di- A less commonly used and more costly 2325 – 2315 abetes through the life span: a position state- 2. Yeh H-C, Brown TT, Maruthur N, et al. Com- therapy basal – ” alternative to “ bolus ment of the American Diabetes Association. parative effectiveness and safety of methods of with multiple daily injections is CSII (in- Diabetes Care 2014;37:2034 2054 – insulin delivery and glucose monitoring for di- 16. U.S. Food and Drug Administration. SGLT2 sulin pump) (28,29). In addition to the abetes mellitus: a systematic review and meta- inhibitors: drug safety communication – labels suggestions provided for determining 347 – analysis. Ann Intern Med 2012;157:336 to include warnings about too much acid the starting dose of mealtime insulin 3. Bergenstal RM, Klono ff DC, Garg SK, et al.; in the blood and serious urinary tract infec- – bolus regimen, another under a basal ASPIRE In-Home Study Group. Threshold- tions [Internet], 4 December 2015. Available from http://www.fda.gov/safety/medwatch/ method consists of adding up the total based insulin-pump interruption for reduction

66 Approaches to Glycemic Treatment S59 care.diabetesjournals.org safetyinformation/safetyalertsforhumanmedical 24. Institute for Clinical and Economic Review. infusion versus multiple daily injections in older products/ucm475553.htm. Accessed 7 Decem- Controversies in the management of patients adults with type 2 diabetes. Diabetes Care 2005; ber 2015 with type 2 diabetes [Internet], 2014. Available 28:1568 – 1573 17. Inzucchi SE, Bergenstal RM, Buse JB, et al. from http://cepac.icer-review.org/wp-content/ 31. Zinman B, Wanner C, Lachin JM, et al.; Management of hyperglycemia intype2diabetes, uploads/2014/08/CEPAC-T2D-Final-Report- EMPA-REG OUTCOME Investigators. Empagli- 2015: a patient-centered approach. Update to a December-22.pdf. Accessed 6 November 2015 fl ozin, cardiovascular outcomes, and mortality position statement of the American Diabetes As- 25. Blonde L, Merilainen M, Karwe V, Raskin P; in type 2 diabetes. N Engl J Med. 17 September sociation and the European Association for the TITRATE Study Group. Patient-directed titration 2015 [Epub ahead of print]. DOI: 10.1056/ – Study of Diabetes. Diabetes Care 2015;38:140 for achieving glycaemic goals using a once-daily NEJMoa1504720 149 basal insulin analogue: an assessment of two 32. Dormandy JA, Charbonnel B, Eckland DJA, et al.; 18. Holman RR, Paul SK, Bethel MA, Matthews the different fasting plasma glucose targets d PROactive Investigators. Secondary prevention DR, Neil HA. 10-year follow-up of intensive glu- TITRATE study. Diabetes Obes Metab 2009;11: of macrovascular events in patients with type 2 cose control in type 2 diabetes. N Engl J Med – 631 623 diabetes in the PROactive Study (PROspective – 2008;359:1577 1589 26. Tricco AC, Ashoor HM, Soobiah C, et al. pioglitAzone Clinical Trial In macroVascular Events): 19. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, Safety, effectiveness, and cost of long-acting a randomised controlled trial. Lancet 2005;366: McGuire DK. Metformin in patients with versus intermediate-acting insulin for type 1 di- 1279 – 1289 type 2 diabetes and kidney disease: a systematic abetes: protocol for a systematic review and 33. Chiasson J-L, Josse RG, Gomis R, Hanefeld 2675 – review. JAMA 2014;312:2668 network meta-analysis. Syst Rev 2013;2:73 M, Karasik A, Laakso M; STOP-NIDDM Trial Re- 20. Bennett WL, Maruthur NM, Singh S, et al. 27. Eng C, Kramer CK, Zinman B, Retnakaran R. search Group. Acarbose for prevention of type 2 Comparative effectiveness and safety of medi- Glucagon-like peptide-1 receptor agonist and diabetes mellitus: the STOP-NIDDM randomised cations for type 2 diabetes: an update including basal insulin combination treatment for the 2077 – trial. Lancet 2002;359:2072 new drugs and 2-drug combinations. Ann Intern management of type 2 diabetes: a systematic 34. UK Prospective Diabetes Study (UKPDS) Group. Med 2011;154:602 – 613 review and meta-analysis. Lancet 2014;384: Intensive blood-glucose control with sulphonylureas 21. Nathan DM, Buse JB, Kahn SE, et al.; GRADE 2234 2228 – or insulin compared with conventional treatment Study Research Group. Rationale and design of 28. Reznik Y, Cohen O, Aronson R, et al.; OpT2mise and risk of complications in patients with type 2 di- the glycemia reduction approaches in diabetes: Study Group. Insulin pump treatment compared – 853 abetes (UKPDS 33). Lancet 1998;352:837 a comparative effectiveness study (GRADE). with multiple daily injections for treatment of 35. UK Prospective Diabetes Study (UKPDS) Diabetes Care 2013;36:2254 – 2261 type 2 diabetes (OpT2mise): a randomised Group. Effect of intensive blood-glucose control 22. Green JB, Bethel MA, Armstrong PW, et al.; open-label controlled trial. Lancet 2014;384: with metformin on complications in overweight TECOS Study Group. Effect of sitagliptin on car- 1265 1272 – patients with type 2 diabetes (UKPDS 34). Lan- diovascular outcomes in type 2 diabetes. N Engl 29. Johnson SL, McEwen LN, Newton CA, et al. The – 865 cet 1998;352:854 242 J Med 2015;373:232 – impact of continuous subcutaneous insulin infusion 36. Gaziano JM, Cincotta AH, O ’ Connor CM, 23. Vijan S, Sussman JB, Yudkin JS, Hayward RA. and multiple daily injections of insulin on glucose et al. Randomized clinical trial of quick- risks and preferences on Effect of patients ’ variability in older adults with type 2 diabetes. release bromocriptine among patients with health gains with plasma glucose level lowering – J Diabetes Complications 2011;25:211 215 type 2 diabetes on overall safety and cardio- in type 2 diabetes mellitus. JAMA Intern Med 30. Herman WH, Ilag LL, Johnson SL, et al. A vascular outcomes. Diabetes Care 2010;33: 1234 2014;174:1227 – clinical trial of continuous subcutaneous insulin – 1508 1503

67 S60 Diabetes Care Volume 39, Supplement 1, January 2016 American Diabetes Association 8. Cardiovascular Disease and Risk Management DOI: 10.2337/dc16-S011 | S71 – Diabetes Care 2016;39(Suppl. 1):S60 For prevention and management of diabetes complications in children and adolescents, please refer to Section 11 ” “ Children and Adolescents. ar risk factors should be systematically as- In all patients with diabetes, cardiovascul sessed at least annually. These risk factors inc lude dyslipidemia, hypertension, smoking, a family history of premature coronary diseas e, and the presence of albuminuria. Abnor- cribed elsewhere in these guidelines. mal risk factors should be treated as des de fi Atherosclerotic cardiovascular disease (ASCVD) d ned as acute coronary al infarction (MI), stable or unstable syndromes (ACSs), a history of myocardi ularization, stroke, transient ischemic angina, coronary or other arterial revasc is attack, or peripheral arterial disease presumed to be of atherosclerotic origin d the leading cause of morbidity and mortality for individuals with diabetes and is the largest contributor to the direct and indirect costs of diabetes. The common con- ditions coexisting with type 2 diabetes (e .g., hypertension and dyslipidemia) are itself confers independent risk. Numerous clearriskfactorsforASCVD,anddiabetes studieshaveshowntheef fi cacy of controlling individual cardiovascular risk factors ts are seen in preventing or slowing ASCVD in people with diabetes. Large bene fi when multiple risk factors are addressed simultaneously. There is evidence that measures of 10-year coronary heart dis ease (CHD) risk among U.S. adults with cantly over the past decade (1) and that ASCVD diabetes have improved signi fi 4). morbidity and mortality have decreased (2 – HYPERTENSION/BLOOD PRESSURE CONTROL 8. CARDIOVASCULAR DISEASE AND RISK MANAGEMENT Recommendations Screening and Diagnosis Blood pressure should be measured at every routine visit. Patients found to have c elevated blood pressure should have blood pressure con fi B rmed on a separate day. Goals Systolic Targets People with diabetes and hypertension should be treated to a systolic blood c , 140 mmHg. A pressure goal of c Lower systolic targets, such as , 130 mmHg, may be appropriate for certain indi- viduals with diabetes, such as younger patients, those with albuminuria, and/or those with hypertension and one or more additional atherosclerotic cardiovascular disease risk factors, if they can be achieved without undue treatment burden. C Diastolic Targets c Individuals with diabetes should be treated to a diastolic blood pressure goal A 90 mmHg. , of 80 mmHg, may be appropriate for certain indi- , c Lower diastolic targets, such as viduals with diabetes, such as younger patients, those with albuminuria, and/or those with hypertension and one or more additional atherosclerotic cardiovascular B disease risk factors, if they can be achieved without undue treatment burden. Suggested citation: American Diabetes Associa- tion. Cardiovascular disease and risk manage- Treatment Standards of Medical Care in ment. Sec. 8. In Patients with blood pressure . 120/80 mmHg should be advised on lifestyle c Diabetes d 2016 . Diabetes Care 2016;39(Suppl. 1): changes to reduce blood pressure. B – S60 S71 . ce-based blood pressure fi fi c 140/90 mmHg should, Patients with con rmed of © 2016 by the American Diabetes Association. in addition to lifestyle therapy, have prompt initiation and timely subsequent Readers may use this article as long as the work is properly cited, the use is educational and not A titration of pharmacological therapy to achieve blood pressure goals. for pro fi t, and the work is not altered.

68 Cardiovascular Disease and Risk Management S61 care.diabetesjournals.org Diabetes and Vascular Disease: Preterax arm supported at heart level, after 5 min In older adults, pharmacological ther- c and Diamicron MR Controlled Evalua- ofrest.Cuff size should beappropriate for apy to achieve treatment goals of the upper-arm circumference. Elevated tion – Blood Pressure (ADVANCE-BP), ex- , 130/70 mmHg is not recom- amined the bene fi t of tighter blood rmed on a separate fi values should be con mended; treating to systolic blood day. Postural changes in blood pressure pressure control in patients with type 2 pressure 130 mmHg has not been , and pulse may be evidence of autonomic diabetes. shown to improve cardiovascular out- neuropathy and therefore require adjust- ACCORD. The ACCORD trial examined comes and treating to diastolic blood ment of blood pressure targets. , 120 mmHg in whether a lower SBP of 70 mmHg has been asso- , pressure Home blood pressure self-monitoring patients with type 2 diabetes at high risk ciated with higher mortality. C and 24-h ambulatory blood pressure for ASCVD provided greater cardiovascular Lifestyle therapy for elevated blood c monitoring may provide evidence of 140 mmHg protection than an SBP of 130 – pressure consists of weight loss, if white-coat hypertension, masked hyper- (10). The study did not fi nd a bene fi tin overweight or obese; a Dietary Ap- tension, or other discrepancies between primary end point (nonfatal MI, nonfatal proaches to Stop Hypertension blood pressure. Studies ” of fi ce and true “ stroke, and cardiovascular death) compar- (DASH)-style dietary pattern includ- in individuals without diabetes found ing intensive blood pressure treatment ing reducing sodium and increasing that home measurements may better 120 mmHg, average blood pres- , (goal potassium intake; moderation of al- correlate with ASCVD risk than of ce fi sure achieved 5 119/64 mmHg on 3.4 cohol intake; and increased physical measurements (5,6). However, most of medications) with standard treatment activity. B the evidence of bene fi ts of hyperten- (average blood pressure achieved 5 Pharmacological therapy for patients c sion treatment in people with diabetes 143/70 mmHg on 2.1 medications). In with diabetes and hypertension isbasedonof ce measurements. fi ACCORD, there was no bene fi tofag- should comprise a regimen that in- gressive blood pressure lowering, de- cludes either an ACE inhibitor or an Treatment Goals spite the extra cost and efforts. angiotensin receptor blocker but not Epidemiological analyses show that If one class is not tolerated, both. B blood pressure . 115/75 mmHg is asso- In ADVANCE, the active blood ADVANCE. the other should be substituted. C ciated with increased cardiovascular pressure intervention arm (a single-pill, c Multiple-drug therapy (including a event rates and mortality in individuals fi xed-dose combination of perindopril thiazide diuretic and ACE inhibitor/ with diabetes and that systolic blood and indapamide) showed a signi fi cant angiotensin receptor blocker, at pressure (SBP) . 120 mmHg predicts reductionintheriskoftheprimarycom- maximal doses) is generally required long-term end-stage renal disease. posite end point (major macrovascular to achieve blood pressure targets. B Randomized clinical trials have dem- fi cant or microvascular event) and signi If ACE inhibitors, angiotensin recep- c onstrated the bene fi t (reduction of reductions in the risk of death from any tor blockers, or diuretics are used, CHD events, stroke, and diabetic kidney cause and of death from cardiovascular serum creatinine/estimated glomer- disease) of lowering blood pressure to causes (11). The baseline blood pres- fi ular ltration rate and serum potas- , 140 mmHg systolic and , 90 mmHg sure among the study subjects was sium levels should be monitored. E diastolic in individuals with diabetes 145/81 mmHg. Compared with the pla- In pregnant patients with diabetes c (7). There is limited prespeci fi ed clinical cebo group, the patients treated with a and chronic hypertension, blood ts of lower fi trial evidence for the bene fi xed-dose combination of single-pill, pressure targets of 110 – 129/65 – 79 SBP or diastolic blood pressure (DBP) perindopril and indapamide experienced mmHg are suggested in the interest targets (8). A meta-analysis of random- an average reduction of 5.6 mmHg in SBP of optimizing long-term maternal ized trials of adults with type 2 diabetes and 2.2 mmHg in DBP. The fi nal blood health and minimizing impaired fetal comparing intensive blood pressure pressure in the treated group was growth. E targets (upper limit of 130 mmHg systolic 136/73 mmHg, not quite the intensive and 80 mmHg diastolic) with standard or tight control achieved in ACCORD. Hypertension is a common diabetes comor- targets (upper limit of 140 160 mmHg – Recently published 6-year follow-up bidity that affects many patients, with the – 100 mmHg diastolic) systolic and 85 – of the ADVANCE Post-Trial Observational prevalence depending on type of diabetes, cant reduction in mortal- fi foundnosigni Study (ADVANCE-ON) reported that the age, BMI, and ethnicity. Hypertension is a ityornonfatalMI.There wasa statistically reductions in the risk of death from any major risk factor for both ASCVD and micro- fi cant 35% relative risk (RR) reduc- signi cause and of death from cardiovascular vascular complications. In type 1 diabetes, tion in stroke with intensive targets, but causes in the intervention group were hypertension is often the result of under- the absolute risk reduction was only 1%, attenuated, but remained signi cant(12). fi lying diabetic kidney disease, while in and intensive targets were associated Systolic Blood Pressure Interven- SPRINT. type 2 diabetes, it usually coexists with with an increased risk for adverse events tion Trial (SPRINT) was a multicenter, ran- other cardiometabolic risk factors. such as hypotension and syncope (9). domized controlled trial that compared ACCORD, ADVANCE, SPRINT, AND HOT two strategies for treating SBP with either Screening and Diagnosis Blood pressure measurement should be Given the epidemiological relationship be- the standard target of , 140 mmHg or an tween lower blood pressure and better done by a trained individual and should 120 mmHg; primary , intensive target of follow the guidelines established for the long-term clinical outcomes, two landmark outcomes were MI, ACS, stroke, heart trials, Action to Control Cardiovascular Risk general population: measurement in the failure, and death due to cardiovascular in Diabetes (ACCORD) and Action in disease. Of note, patients with diabetes oor and fl seated position, with feetonthe

69 Volume 39, Supplement 1, January 2016 Diabetes Care S62 Cardiovascular Disease and Risk Management antihypertensive agents, including ACE in- were excluded from participating in this additional ASCVD risk factors such as dysli- hibitors, angiotensin receptor blockers trial, so the results have no direct impli- pidemia, smoking, or obesity (14). The -blockers, diuretics, and calcium (ARBs), b cations for blood pressure management etes Association 2016 American Diab channel blockers, has been shown to be The National Insti- in this population. (ADA) Standards of Care recommendations effective in reducing cardiovascular tutes of Health halted this study early have been revised to re fl ect the higher- events. Several studies have suggested because intensive therapy with a target quality evidence that exists to support a that ACE inhibitors may be superior to SBP of 120 mmHg demonstrated a risk 90 mmHg, although lower , goal of DBP dihydropyridine calcium channel blockers reduction of cardiovascular events by targets may be appropriate for certain in- 20). – in reducing cardiovascular events (18 almost a third and the risk of death dividuals. These targets are in harmoniza- However, several studies have also shown by almost a quarter compared with a tion with a recent publication by the Eighth no speci fi c advantage to ACE inhibitors as target SBP of 140 mmHg (13). Joint National Committee that recom- an initial treatment of hypertension in the mended for individuals over 18 years of HOT. The results from the ACCORD and general hypertensive population, while age with diabetes a DBP threshold of Hypertension Optimal Treatment (HOT) showing an advantage of initial therapy 140 mmHg (8). , 90 mmHg and SBP , (14) trials support the recommendation with low-dose thiazide diuretics on car- to achieve blood pressure levels , 140/90 diovascular outcomes (17,21,22). Treatment Strategies mmHg and underscore the important Angiotensin Receptor Blockers. In people Lifestyle Modi fi cation clinical difference between patients who with diabetes, inhibitors of the renin- well-controlled Although there are no are able to easily achieve lower blood angiotensin system (RAS) may have studies of diet and exercise in the treat- pressure levels (e.g., as seen in observa- unique advantages for initial or early ment of elevated blood pressure or tional epidemiological studies) and pa- treatment of hypertension. In a trial of hypertension in individuals with diabe- tients who require intensive medical individuals at high risk for ASCVD, tes, the Dietary Approaches to Stop management to achieve lower blood including a large subset with diabetes, Hypertension (DASH) study evaluated pressure goals (e.g., the clinical trials). an ACE inhibitor reduced ASCVD out- the impact of healthy dietary patterns Systolic Blood Pressure comes (23). In patients with congestive in individuals withou t diabetes and has . There is strong evidence that SBP 140 heart failure, including subgroups with shown antihypertensive effects similar to mmHgisharmful,suggestingthat clinicians diabetes, ARBs have been shown to re- those of pharmacological monotherapy. should promptly initiate and titrate ther- – duce major ASCVD outcomes (24 27). Lifestyle therapy consists of reducing apy in an ongoing fashion to achieve and In patients with type 2 diabetes with excess body weight, restricting sodium 140 mmHg in most pa- , maintain SBP signi fi cant diabetic kidney disease, intake ( , 2,300 mg/day), increasing con- Older Adults tients (see Section 10 ” ). A “ ARBs were superior to calcium channel – 10 sumption of fruits and vegetables (8 recent systematic review and meta-anal- blockers for reducing heart failure (28). servings per day) and low-fat dairy ysis evaluating SBP lowering in adults with Although evidence fordistinct advantages – products (2 3 servings per day), avoiding type 2 diabetes showed that each 10-mmHg of RAS inhibitors on ASCVD outcomes in excessive alcohol consumption (no more reduction of SBP was associated with signif- fl icting (11,22), the diabetes remains con than 2 servings per day in men and no icantly lower risk of mortality, cardiovascular high ASCVD risks associated with diabetes more than 1 serving per day in women) events, CHD, stroke, albuminuria, and reti- and the high prevalence of undiagnosed (16), and increasing activity levels (17). nopathy. However, when trials were strati- ASCVD may still favor recommendations These lifestyle (nonpharmacological) $ 140 mmHg or fi ed by mean baseline SBP for their use as rst-line antihypertensive fi strategies may also positively affect lowering – , 140 mmHg, blood pressure therapy in people with diabetes (17). glycemia and lipid co ntrol and should be treatment was associatedwithlowerrisks However, the use of both ACE inhibitors encouraged in those with even mildly ele- of stroke and albuminuria, regardless of and ARBs in combination is not recom- vated blood pressure , although the impact initial SBP (15). Therefore, individuals in mended given the lack of added ASCVD of lifestyle therapy on cardiovascular events whomstroke risk is a concern may, aspart fi bene t and increased rate of adverse has not been established. Nonpharmaco- of shared decision making, have lower events namely, hyperkalemia, syncope, d logical therapy is reasonable in individuals systolic targets such as , 130 mmHg. (29) . and renal dysfunction with diabetes and mildly elevated blood This is especially true if lower blood pres- . pressure (SBP 120 mmHg or DBP . 80 Other Pharmacological Interventions sure can be achieved with few drugs and mmHg). If theblood pressure is con fi rmed The blood pressure arm of the ADVANCE without side effects of therapy. 90 140 mmHg systolic and/or $ to be $ trial demonstrated that routine adminis- mmHg diastolic, pharmacological therapy tration of a xed combination of the ACE fi Diastolic Blood Pressure along with nonpharma- should be initiated inhibitor perindopril and the diuretic Similarly, strong evidence from random- cological therapy (17). To enable long-term indapamide signi cantly reduced com- fi ized clinical trials supports DBP targets adherence, lifestyle therapy should be adap- bined microvascular and macrovascular 90 mmHg. Prior recommendations for of , ted to suit the needs of the patient and outcomes, as well as death from cardio- lower DBP targets ( , 80 mmHg) were based discussed as part of diabetes management. vascular causes and total mortality. primarily on a post hoc analysis of the HOT The improved outcomes could also , 80 mmHg may still be trial (14). A DBP of have been due to lower achieved blood appropriate for patients with long life expec- Pharmacological Interventions Lowering of blood pres- ACE Inhibitors. pressure in the perindopril – indapamide tancy, those with chronic kidney disease, sure with regimens based on a variety of arm(11).Another trialshowedadecrease elevated urinary albumin excretion, and

70 Cardiovascular Disease and Risk Management S63 care.diabetesjournals.org in morbidityandmortality in those receiv- drugs known to be effective and safe in c For patients with diabetes aged ing benazepril and amlodipine versus be- pregnancy include methyldopa, labetalol, 40 – 75 years with additional ath- nazepril and hydrochlorothiazide (HCTZ) diltiazem, clonidine, and prazosin. Chronic erosclerotic cardiovascular dis- fi ts of RAS in- (30). The compelling bene diuretic use during pregnancy is not rec- ease risk factors, consider using hibitors in patients with diabetes and al- ommended as it has been associated with high-intensity statin and lifestyle buminuria or renal insuf ciency provide fi restricted maternal plasma volume, which therapy. B additional rationale for the use of these may reduce uteroplacental perfusion (33). For patients with diabetes aged c agents (see Section 9 “ Microvascular 75 years without additional ath- . LIPID MANAGEMENT Complications and Foot Care ). If needed ” erosclerotic cardiovascular dis- to achieve blood pressure targets, amlo- Recommendations ease risk factors, consider using dipine, HCTZ, or chlorthalidone can be In adults not taking statins, it is c moderate-intensity statin therapy added. If estimated glomerular ltration fi reasonable to obtain a lipid pro fi le B and lifestyle therapy. 2 , a loop di- , 30 mL/min/1.73 m rate is at the time of diabetes diagnosis, at For patients with diabetes aged c uretic, rather than HCTZ or chlorthali- an initial medical evaluation, and . 75 years with additional athero- done, should be prescribed. Titration of every 5 years thereafter, or more sclerotic cardiovascular disease risk and/or addition of further blood pressure E frequently if indicated. factors, consider using moderate- medications should be made in a timely Obtain a lipid pro le at initiation fi c intensity or high-intensity statin fashion to overcome clinical inertia in of statin therapy and periodically B therapy and lifestyle therapy. achieving blood pressure targets. thereafter as it may help to mon- c In clinical practice, providers may Bedtime Dosing itor the response to therapy and need to adjust intensity of statin Growing evidence suggests that there is inform adherence. E therapy based on individual patient an association between increase in sleep- cation focusing on fi Lifestyle modi c response to medication (e.g., side time blood pressure and incidence of weight loss (if indicated); the reduc- effects, tolerability, LDL cholesterol ASCVD events. A randomized controlled trans tion of saturated fat, fat, and levels). E trial of 448 participants with type 2 di- cholesterol intake; increase of c The addition of ezetimibe to abetes and hypertension demonstrated fi ber, omega-3 fatty acids, viscous moderate-intensity statin therapy reduced cardiovascular events and mor- and plant stanols/sterols intake; and has been shown to provide additional tality with median follow-up of 5.4 years increased physical activity should be cardiovascular bene fi tcompared if at least one antihypertensive medica- recommended to improve the lipid with moderate-intensity statin ther- tion was given at bedtime (31). Consider A pro le in patients with diabetes. fi apy alone and may be considered administering one or more antihyper- c Intensify lifestyle therapy and opti- for patients with a recent acute cor- tensive medications at bedtime (32). mize glycemic control for patients onary syndrome with LDL cholesterol with elevated triglyceride levels $ 50 mg/dL (1.3 mmol/L) or for those Other Considerations ( 150 mg/dL [1.7 mmol/L]) and/or $ patients who cannot tolerate high- An important caveat is that most patients low HDL cholesterol ( , 40 mg/dL intensity statin therapy. A with diabetes with hypertension require , 50 mg/dL [1.0 mmol/L] for men, brate) c Combination therapy (statin/ fi multiple-drug therapy to reach treatment [1.3 mmol/L] for women). C has not been shown to improve ath- goals (16). Identifying and addressing For patients with fasting triglyceride c erosclerotic cardiovascular disease barriers to medication adherence (such $ levels 500 mg/dL (5.7 mmol/L), outcomes and is generally not rec- as cost and side effects) should rou- evaluate for secondary causes of ommended. However, therapy A tinely be done. If blood pressure remains hypertriglyceridemia and consider with statin and feno brate may be fi rmed adher- fi uncontrolled despite con medical therapy to reduce the risk considered for men with both tri- ence to optimal doses of at least three C of pancreatitis. $ 204 mg/dL (2.3 glyceride level antihypertensive agents of different clas- For patients of all ages with diabetes c mmol/L) and HDL cholesterol ses, one of which should be a diuretic, and atherosclerotic cardiovascular dis- level # 34 mg/dL (0.9 mmol/L). B clinicians should consider an evaluation ease, high-intensity statin therapy Combination therapy (statin/niacin) c for secondary causes of hypertension. A should be added to lifestyle therapy. has not been shown to provide Pregnancy and Antihypertensive For patients with diabetes aged c t fi additional cardiovascular bene Medications 40 years with additional athero- , above statin therapy alone and In a pregnancy complicated by diabetes sclerotic cardiovascular disease risk may increase the risk of stroke and and chronic hypertension, target blood factors, consider using moderate- is not generally recommended. A – 129 mmHg pressure goals of SBP 110 intensity or high-intensity statin c Statin therapy is contraindicated – and DBP 65 79 mmHg are reasonable, and lifestyle therapy. C B in pregnancy. as they contribute to improved long- c For patients with diabetes aged term maternal health. Lower blood 75 years without additional 40 – pressure levels may be associated with Lifestyle Intervention atherosclerotic cardiovascular dis- Lifestyle intervention, including weight impaired fetal growth. During preg- ease risk factors, consider using loss, increased physical activity, and nancy, treatment with ACE inhibitors moderate-intensity statin and life- medical nutrition therapy, allows some and ARBs is contraindicated, as they style therapy. A may cause fetal damage. Antihypertensive patients to reduce ASCVD risk factors.

71 Volume 39, Supplement 1, January 2016 Diabetes Care S64 Cardiovascular Disease and Risk Management Nutrition interventio n should be tailored Recommendations for statin and combination treatment in people — Table 8.1 ’ according to each patient s age, diabe- with diabetes tes type, pharmacological treatment, Age Risk factors Recommended statin intensity* lipid levels, and medical conditions. , 40 years None None Recommendations should focus on re- Moderate or high ASCVD risk factor(s)** ducing saturated fat, cholesterol, and High ASCVD trans fat intake and increasing plant – 75 40 None Moderate stanols/sterols, omega-3 fatty acids, years High ASCVD risk factors and viscous ber (such as in oats, le- fi ASCVD High . 50 mg/dL (1.3 mmol/L) Moderate plus ezetimibe ACS and LDL cholesterol gumes, and citrus). Glycemic control in patients who cannot tolerate high-dose statins fi can also bene cially modify plasma lipid . 75 years None Moderate levels, particularly in patients with very ASCVD risk factors Moderate or high high triglycerides and poor glycemic High ASCVD control. 50mg/dL(1.3mmol/L) in Moderate plus ezetimibe ACS and LDL cholesterol . patients who cannot tolerate high-dose statins Statin Treatment *Inadditiontolifestyletherapy. Initiating Statin Therapy Based on Risk **ASCVD risk factors include LDL cholesterol $ 100 mg/dL (2.6 mmol/L), high blood pressure, Patients with type 2 diabetes have an smoking, overweight and obesity, and family history of premature ASCVD. increased prevalence of lipid abnormal- ities, contributing to their high risk of The Risk Calculator. Age > 75 Years The American College ASCVD. Multiple clinical trials have For adults with diabetes over 75 years of of Cardiology/American Heart Association demonstrated the bene fi cial effects of age, there are limited data regarding the ASCVD risk calculator may be a useful tool pharmacological (statin) therapy on bene fi ts and risks of statin therapy. to estimate 10-year ASCVD (http://my ASCVD outcomes in subjects with and Statin therapy should be individualized .Asdiabetesitself .americanheart.org) without CHD (34,35). Subgroup analy- based on risk pro fi le. High-intensity confers increased risk for ASCVD, the ses of patients with diabetes in larger statins, if well tolerated, are still appropri- risk calculator has limited use for 40) and trials in patients – trials (36 ate and recommended for older adults assessing cardiovascular risk in indi- with diabetes (41,42) showed signi fi - with ASCVD. High-intensity statin therapy viduals with diabetes. cant primary and secondary prevention may also be appropriate in adults with of ASCVD events and CHD death in 40 Years ‡ Age diabetes . 75 years of age with additional patients with diabetes. Meta-analyses, 40 In all patients with diabetes aged $ ASCVD risk factors. However, the risk – including data from over 18,000 patients years, moderate-intensity statin treat- le should be routinely evalu- tpro fi bene fi with diabetes from 14 randomized trials ment should be considered in addition ated in this population, with downward of statin therapy (mean follow-up 4.3 to lifestyle therapy. Clinical trials in high- titration (e.g., high to moderate intensity) years),demonstrate a 9%proportionalre- risk patients, such as those with ACS or performed as needed. See Section 10 duction in all-cause mortality and 13% re- 49), – previous cardiovascular events (47 “ Older Adults ” for more details on clinical duction in vascular mortality for each have demonstrated that more aggressive considerations for this population. mmol/L (39 mg/dL) reduction in LDL cho- therapy with high doses of statins led to a lesterol (43). 40 Years and/or Type 1 Diabetes Age < fi signi cant reduction in further events. As in those without diabetes, abso- Very little clinical trial evidence exists Therefore, high-dose statins are recom- lute reductions in ASCVD outcomes for patients with type 2 diabetes under mended in patients with increased car- (CHD death and nonfatal MI) are great- the age of 40 years or for patients with diovascular risk (e.g., LDL cholesterol est in people with high baseline ASCVD type 1 diabetes of any age. In the Heart 100 mg/dL [2.6 mmol/L], high blood $ risk (known ASCVD and/or very high LDL Protection Study (lower age limit pressure, smoking, albuminuria, and cholesterol levels), but the overall ben- 40 years), the subgroup of ; 600 patients family history of premature ASCVD) or fi e ts of statin therapy in people with di- with type 1 diabetes had a proportionately with ASCVD. abetes at moderate or even low risk for ASCVD are convincing (44,45). Statins are the drugs of choice for LDL choles- Table 8.2 High-intensity and moderate-intensity statin therapy* — terol lowering and cardioprotection. High-intensity statin therapy Moderate-intensity statin therapy Most trials of statins and ASCVD out- cdosesofstatins fi comes tested speci , Lowers LDL cholesterol by $ 50% 50% Lowers LDL cholesterol by 30% to 20 mg – Atorvastatin 40 Atorvastatin 10 – 80 mg against placebo or other statins rather – 10 mg Rosuvastatin 5 Rosuvastatin 20 – 40 mg fi than aiming for speci c LDL cholesterol 40 mg – Simvastatin 20 goals (46). In light of this fact, the 2016 Pravastatin 40 – 80 mg ADA Standards of Care position state- Lovastatin 40 mg ment was revised to recommend when Fluvastatin XL 80 mg to initiate and intensify statin therapy Pitavastatin 2 – 4mg (high vs. moderate intensity) based on *Once-daily dosing. risk pro fi le ( Table 8.1 Table 8.2 ). and

72 Cardiovascular Disease and Risk Management S65 care.diabetesjournals.org - similar, although not statistically signi fi levels, are the most prevalent pattern beconsideredin adults with heterozygous cant, reduction in risk as patients with of dyslipidemia in individuals with familial hypercholesterolemia who require type 2 diabetes (37). Even though the type 2 diabetes. However, the evidence additional lowering of LDL cholesterol. fi nitive, similar statin data are not de for the use of drugs that target these treatment approaches should be consid- lipid fractions is substantially less robust Combination Therapy for LDL ered for patients with type 1 or type 2 than that for statin therapy (57). In a Cholesterol Lowering diabetes, particularly in the presence of large trial in patients with diabetes, Statins and Ezetimibe other cardiovascular risk factors. Please fi brate failed to reduce overall feno The IMProved Reduction of Outcomes: “ Type 1 Diabetes Mellitus and refer to cardiovascular outcomes (58). Vytorin Ef fi cacy International Trial c Cardiovascular Disease: A Scienti fi (IMPROVE-IT) was a randomized con- Combination Therapy Statement From the American Heart As- trolled trial comparing the addition of Statin and Fibrate sociation and American Diabetes Associ- ezetimibe to simvastatin therapy versus Combination therapy (statin and fi brate) (50) for additional discussion. ” ation simvastatin alone. Individuals were is associated with an increased risk for High-intensity statin therapy is recom- $ 50 years of age who experienced an abnormal transaminase levels, myositis, mended for all patients with diabetes and ACS within the preceding 10 days and and rhabdomyolysis. The risk of rhabdo- ASCVD. Treatment with a moderate dose $ 50 mg/dL had an LDL cholesterol level myolysis is more common with higher of statin should be considered if the (1.3 mmol/L). In those with diabetes fi ciency doses of statins and renal insuf patient does not have ASCVD but has (27%), the combination of moderate- and appears to be higher when statins additional ASCVD risk factors. intensity simvastatin (40 mg) and ezetimibe fi are combined with gem brozil (59) (10 mg) showed a signi cant reduction fi fi (comparedwithfeno brate). Ongoing Therapy and Monitoring of major adverse cardiovascular events In the ACCORD study, in patients with With Lipid Panel with an absolute risk reduction of type 2 diabetes who were at high risk for In adults with diabetes, it is reasonable to 5% (40% vs. 45%) and RR reduction of brate fi ASCVD, the combination of feno fi obtain a lipid pro le (total cholesterol, 14% (RR 0.86 [95% CI 0.78 – 0.94]) over and simvastatin did not reduce the rate LDL cholesterol, HDL cholesterol, and moderate-intensity simvastatin (40 mg) of fatal cardiovascular events, nonfatal triglycerides) at the time of diagnosis, alone (53). Therefore, for people meeting MI, or nonfatal stroke as compared with at the initial medical evaluation, and at IMPROVE-IT eligibility criteria who can fi ed subgroup simvastatin alone. Prespeci least every 5 years thereafter. A lipid only tolerate a moderate-dose statin, the analyses suggested heterogeneity in panel should also be obtained immedi- addition of ezetimibe to statin therapy treatment effects with possible bene fi t ately before initiating statin therapy. should be considered. for men with both a triglyceride level Onceapatientistakingastatin,testing Statins and PCSK9 Inhibitors $ 204 mg/dL (2.3 mmol/L) and an HDL for LDL cholesterol may be considered Placebo-controlled trials evaluating the cholesterol level # 34 mg/dL (0.9 on an individual basis (e.g., to monitor addition of the novel PCSK9 inhibitors, mmol/L) (60). for adherence and ef cacy). In cases fi evolocumab and alirocumab, to maxi- Statin and Niacin where patients are adherent, but the mally tolerated doses of statin therapy The Atherothrombosis Intervention LDL cholesterol level is not responding, in participants who were at high risk for in Metabolic Syndrome With Low clinical judgment is recommended to de- ASCVD demonstrated an average reduc- HDL/High Triglycerides: Impact on termine the need for and timing of lipid tion in LDL cholesterol ranging from 36% Global Health Outcomes (AIM-HIGH) tri- panels. In individual patients, the highly to 59%. These agents may therefore al randomized over 3,000 patients lowering re- – variable LDL cholesterol be considered as adjunctive therapy (about one-third with diabetes) with es- sponse seen with statins is poorly under- for patients with diabetes at high risk for tablished ASCVD, low LDL cholesterol stood (51). When maximally tolerated ASCVD events who require additional low- 180 mg/dL [4.7 mmol/L]), low levels ( , doses of statins fail to substantially lower ering of LDL cholesterol or who require 40 mg/dL , HDL cholesterol levels (men , LDL cholesterol ( 30% reduction from but are intolerant to high-intensity statin [1.0 mmol/L] and women 50 mg/dL , the patient ’ s baseline), there is no strong therapy (54,55). It is important to note [1.3 mmol/L]), and triglyceride levels of evidence that combination therapy that the effects of this novel class of agents 400 mg/dL (1.7 – 150 – 4.5 mmol/L) to sta- should be used. Clinicians should attempt on ASCVD outcomes are unknown as tin therapy plus extended-release niacin fi to nd a dose or alternative statin that is phase 4 studies are currently under way. or placebo. The trial was halted early due tolerable, if side effects occur. There is to lack of ef fi cacy on the primary ASCVD evidence for bene fi tfromevenextremely Treatment of Other Lipoprotein fi outcome ( rst event of the composite low, less than daily, statin doses (52). Fractions or Targets Hypertriglyceridemia should be addressed of death from CHD, nonfatal MI, ische- Increased frequency of LDL cholesterol with dietary and lifestyle changes includ- mic stroke, hospitalization for an ACS, or monitoring should be considered for pa- ing abstinence from alcohol (56). Severe symptom-driven coronary or cerebral re- tients with new-onset ACS. A recent ran- . hypertriglyceridemia ( 1,000 mg/dL) vascularization) and a possible increase domized controlled trial evaluated the may warrant immediate pharmacological in ischemic stroke in those on combina- addition of ezetimibe to moderate- fi therapy ( fi bric acid derivatives and/or sh tion therapy (61). Therefore, combina- intensity statin therapy and demon- oil) to reduce the risk of acute pancreatitis. tion therapy with a statin and niacin is toverstatin fi strated ASCVD risk bene Low levels of HDL cholesterol, often not recommended given the lack of monotherapy (53). Increased frequency associated with elevated triglyceride ef fi cacy on major ASCVD outcomes, of LDL cholesterol monitoring may also

73 Volume 39, Supplement 1, January 2016 Diabetes Care S66 Cardiovascular Disease and Risk Management possibleincreaseinriskofischemic stroke. There was some evidence of a dif- disease prevention for adults with stroke, and side effects. ference in aspirin effect by sex: aspirin diabetes at low atherosclerotic fi signi cantly reduced ASCVD events in Diabetes With Statin Use cardiovascular disease risk (10- men, but not in women. Conversely, as- Several studies have reported an increased year atherosclerotic cardiovascu- pirin had no effect on stroke in men but risk of incident diabetes with statin use lar disease risk , 5%), such as in signi fi cantly reduced stroke in women. (62,63), which may be limited to those men or women with diabetes aged However, there was no heterogeneity of with diabetes risk factors. An analysis of 50yearswithnomajoradditional , effect by sex in the risk of serious vascular one of the initial studies suggested that atherosclerotic cardiovascular dis- 0.9). Sex differences in events ( 5 P although statins were linked to diabetes ease risk factors, as the potential ’ s effects have not been observed aspirin risk, the cardiovascular event rate reduc- adverse effects from bleeding likely in studies of secondary prevention (66). tion with statins far outweighed the risk of C ts. offset the potential bene fi In the six trials examined by the ATT incident diabetes even for patients at high- 50 years , c In patients with diabetes collaborators, the effects of aspirin on est risk for diabetes (64). The absolute risk of age with multiple other risk fac- major vascular events were similar for increase was small (over 5 years of follow- 10%), clin- – tors (e.g., 10-year risk 5 patients with or without diabetes: RR up, 1.2% of participants on placebo devel- ical judgment is required. E 0.88 (95% CI 0.67 – 1.15) and RR 0.87 5% on rosuvastatin oped diabetes and 1. 162 mg/day) c Use aspirin therapy (75 – 0.96), respectively. The con- – (95% CI 0.79 developed diabetes) (64). A meta-analysis as a secondary prevention strat- fi dence interval was wider for those with of 13 randomized statin trials with 91,140 egyinthosewithdiabetesanda diabetes because of smaller numbers. participants showed an odds ratio of 1.09 history of atherosclerotic cardio- Aspirin appears to have a modest effect for a new diagnosis of diabetes, so that A vascular disease. on ischemic vascular events with the (on average) treatment of 255 patients For patients with atherosclerotic c absolute decrease in events depending with statins for 4 years resulted in one cardiovascular disease and docu- on the underlying ASCVD risk. The main additional case of diabetes, while simul- mented aspirin allergy, clopidog- adverse effects appear to be an increased taneously preventing 5.4 vascular events rel (75 mg/day) should be used. B risk of gastrointestinal bleeding. The excess among those 255 patients (63). Dual antiplatelet therapy is reason- c – 5per1,000per risk may be as high as 1 able for up to a year after an acute Statins and Cognitive Function year in real-world settings. In adults with coronary syndrome. B A recent systematic review of the U.S. ASCVD risk 1% per year, the number of . Food and Drug Administration ’ s post- ASCVD events prevented will be similar to marketing surveillance databases, ran- orgreater than the number ofepisodes of Risk Reduction domized controlled trials, and cohort, bleeding induced, although these compli- Aspirin has been shown to be effective case-control, and cross-sectional stud- cations do not have equal effects on long- in reducing cardiovascular morbidity ies evaluating cognition in patients re- term health (72). and mortality in high-risk patients with ceiving statins found that published previous MI or stroke (secondary preven- Treatment Considerations data do not reveal an adverse effect of tion). Its netbene fi t in primary prevention In 2010, a position statement of the statins on cognition. Therefore, a con- among patients with no previous cardio- ADA, the American Heart Association, cern that statins might cause cognitive vascular events is more controversial, and the American College of Cardiology dysfunction or dementia should not both for patients with diabetes and for Foundation recommended that low-dose prohibit their use in individuals with patients without diabetes (66,67). Previ- 162 mg/day) aspirin for primary (75 – diabetes at high risk for ASCVD (65). ous randomized controlled trials of aspi- prevention is reasonable for adults rin speci fi cally in patients with diabetes with diabetes and no previous history ANTIPLATELET AGENTS failed to consistently show a signi fi cant of vascular disease who are at increased reduction in overall ASCVD end points, Recommendations ASCVD risk (10-year risk of ASCVD events fi raising questions about the ef cacy of 162 Consider aspirin therapy (75 c – over 10%) and who are not at increased aspirin for primary prevention in people mg/day) as a primary prevention risk for bleeding. This previous recom- with diabetes, although some sex differ- strategy in those with type 1 or mendation included most men over age 71). ences were suggested (68 – type 2 diabetes who are at increased 50 years and women over age 60 years (ATT) ’ The Antithrombotic Trialists cardiovascular risk (10-year risk who also have one or more of the follow- collaborators published an individual . 10%). This includes most men or ing major risk factors: smoking, hyperten- patient-level meta-analysis of the six women with diabetes aged 50 $ sion, dyslipidemia, family history of large trials of aspirin for primary preven- years who have at least one addi- premature ASCVD, and albuminuria (73). tion in the general population. These tri- tional major risk factor (family his- als collectively enrolled over 95,000 Sex Considerations tory of premature atherosclerotic Multiple recent well-conducted studies participants, including almost 4,000 cardiovascular disease, hyperten- and meta-analyses reported a risk of with diabetes. Overall, they found that sion, smoking, dyslipidemia, or al- heart disease and stroke that is equiva- aspirin reduced the risk of serious vascular buminuria) and are not at increased lent if not higher in women compared events by 12% (RR 0.88 [95% CI 0.82 – risk of bleeding. C with men with diabetes, including among 0.94]). The largest reduction was for non- c Aspirin should not be recommended nonelderly adults. Thus, the recommen- fatal MI, with little effect on CHD death for atherosclerotic cardiovascular dations for using aspirin as primary (RR 0.95 [95% CI 0.78 1.15]) or total –

74 Cardiovascular Disease and Risk Management S67 care.diabetesjournals.org Indications for P2Y12 Use prevention are now revised to include the initial test. In adults with diabetes A P2Y12 receptor antagonist in combi- $ both men and women aged 50 years 40 years of age, measurement of cor- $ nation with aspirin should be used for at with diabetes and one or more major onary artery calcium is also reasonable least 1 year in patients following an ACS. risk factors to re fl ect these more recent for cardiovascular risk assessment. Evidence supports use of either ticagrelor 77). Sex differences in the fi ndings (74 – Pharmacological stress echocardiography or clopidogrel if no percutaneous cor- antiplatelet effect of aspirin have been or nuclear imaging should be considered onary intervention was performed and suggested in the general population in individuals with diabetes in whom rest- clopidogrel, ticagrelor, or prasugrel if a (78); however, further studies are needed ing ECG abnormalities preclude exercise percutaneous coronary intervention to investigate the presence of such differ- stress testing (e.g., left bundle branch was performed (82). ences in individuals with diabetes. block or ST-T abnormalities). In addition, individuals who require stress testing and 50 Years of Age Aspirin Use in People < CORONARY HEART DISEASE are unable to exercise should undergo Aspirin is not recommended for those at pharmacological stress echocardiography Recommendations low risk of ASCVD (such as men and or nuclear imaging. women aged , 50 years with diabetes Screening with no other major ASCVD risk factors; In asymptomatic patients, routine c Screening Asymptomatic Patients 10-year ASCVD risk , 5%) as the low screening for coronary artery dis- The screening of asymptomatic patients fi bene t is likely to be outweighed by ease is not recommended as it with highASCVD riskisnot recommended the risks of signi fi cant bleeding. Clinical does not improve outcomes as (44), in part because these high-risk judgment should be used for those at long as atherosclerotic cardiovascu- patients should already be receiving intermediate risk (younger patients A lar disease risk factors are treated. d an approach intensive medical therapy with one or more risk factors or older Consider investigations for coro- c t as invasive fi that provides similar bene patients with no risk factors; those nary artery disease in the presence revascularization (83,84). There is also with 10-year ASCVD risk of 5 10%) until – of any of the following: atypical car- some evidence that silent MI may reverse further research is available. Aspirin use diac symptoms (e.g., unexplained over time, adding to the controversy con- 21 years is contrain- in patients aged , dyspnea, chest discomfort); signs cerning aggressive screening strategies dicated due to the associated risk of or symptoms of associated vascular (85). In prospective trials, coronary artery Reye syndrome. disease including carotid bruits, calcium has been established as an inde- transient ischemic attack, stroke, pendent predictor of future ASCVD Aspirin Dosing claudication, or peripheral arterial Average daily dosages used in most clini- events in patients with diabetes and disease; or electrocardiogram ab- cal trials involving patients with diabetes is superior to both the UK Prospective normalities (e.g., Q waves). E ranged from 50 mg to 650 mg but were Diabetes Study (UKPDS) risk engine 325 mg/day. – mostly in the range of 100 and the Framingham Risk Score in pre- Treatment There is little evidence to support any dicting risk in this population (86 – 88). In patients with known atheroscle- c c dose, but using the lowest fi speci However, a randomized observational rotic cardiovascular disease, use as- possible dose may help to reduce side t trial demonstrated no clinical bene fi pirin and statin therapy (if not effects (79). In the U.S., the most com- to routine screening of asymptomatic and consider contraindicated) A mon low-dose tablet is 81 mg. Although patients with type 2 diabetes and normal ACE inhibitor therapy C to reduce platelets from patients with diabetes ECGs (89). Despite abnormal myocardial the risk of cardiovascular events. have altered function, it is unclear what, perfusion imaging in more than one in In patients with prior myocardial in- c if any, effect that nding has on the fi ve patients, cardiac outcomes were fi farction, -blockers should be con- b required dose of aspirin for cardiopro- essentially equal (and very low) in tinued for at least 2 years after the tective effects in the patient with dia- screened versus unscreened patients. event. B betes. Many alternate pathways for Accordingly, indisc riminate screening In patients with symptomatic c platelet activation exist that are inde- is not considered cost -effective. Studies heart failure, thiazolidinedione and thus pendent of thromboxane A based have found that a risk factor – 2 A treatment should not be used. not sensitive to the effects of aspirin approach to the initial diagnostic eval- c In patients with type 2 diabetes with appears higher ” “ Aspirin resistance (80). uation and subsequent follow-up for stable congestive heart failure, met- in patients with diabetes when mea- ase fails to identify coronary artery dise formin may be used if renal function sured by a variety of ex vivo and in vitro which patients with type 2 diabetes will is normal but should be avoided in methods (platelet aggregometry, mea- have silent ischemia on screening tests unstable or hospitalized patients ) (78). A re- surement of thromboxane B (90,91). Any bene fi t of newer noninva- 2 B with congestive heart failure. cent trial suggested that more frequent sive coronary artery disease screening dosing regimens of aspirin may reduce methods, such as computed tomography Cardiac Testing Candidates for advanced or invasive platelet reactivity in individuals with dia- and computed tomography angiography, 1 )typ- cardiac testing include those with betes (81); however, these observations to identify patient subgroups for different ) ical or atypical cardiac symptoms and 2 fi cient to empirically rec- alone are insuf treatment strategies remains unproven. an abnormal resting electrocardiogram ommend that higher doses of aspirin be Although asymptomatic patients with di- (ECG). Exercise ECG testing without or used in this group at this time. It appears abetes with higher coronary disease bur- with echocardiography may be used as – that 75 162 mg/day is optimal. den have more future cardiac events

75 Volume 39, Supplement 1, January 2016 Diabetes Care S68 Cardiovascular Disease and Risk Management (86,92,93), the role of these tests beyond other glucose-lowering treatments in Cardiovascular Outcomes with Sitagliptin risk strati cation is not clear. Their routine fi patients with diabetes and congestive (TECOS), recent multicenter, randomized, use leads to radiation exposure and may heart failure, even in those with reduced double-blind, noninferiority trials, evalu- result in unnecessary invasive testing such left ventricular ejection fraction or con- ated heart failure and mortality outcomes as coronary angiography and revasculari- comitant chronic kidney disease; however, in patients with type 2 diabetes taking zation procedures. The ultimate balance of metformin should be avoided in hospi- different DPP-4 inhibitors, alogliptin bene fi t, cost, and risks of such an approach talized patients (105). and sitagliptin, respectively, compared in asymptomatic patients remains contro- with placebo. EXAMINE reported that References versial, particularly in the modern setting the hospital admission rate for heart fail- 1. Ali MK, Bullard KM, Saaddine JB, Cowie CC, of aggressive ASCVD risk factor control. ure was 3.1% for patients randomly as- Imperatore G, Gregg EW. Achievement of goals signed to alogliptin compared with 2.9% in U.S. diabetes care, 1999-2010. N Engl J Med Lifestyle and Pharmacological – 1624 2013;368:1613 for those randomly assigned to placebo Interventions 2. Buse JB, Ginsberg HN, Bakris GL, et al.; Amer- – 1.46]) (hazard ratio 1.07 [95% CI 0.79 Intensive lifestyle intervention focusing ican Heart Association; American Diabetes As- (102). Alogliptin had no effect on the sociation. Primary prevention of cardiovascular on weight loss through decreased calo- composite end point of cardiovascular diseases in people with diabetes mellitus: a sci- ric intake and increased physical activity death and hospital admission for heart enti fi c statement from the American Heart As- as performed in the Action for Health in sociation and the American Diabetes Association. failure in the post hoc analysis (hazard Diabetes (Look AHEAD) trial may be con- – 172 Diabetes Care 2007;30:162 1.21]) (102). ratio 1.00 [95% CI 0.82 – sidered for improving glucose control, 3. Gaede P, Lund-Andersen H, Parving H-H, TECOS showed a nonsigni cant difference fi Pedersen O. Effect of a multifactorial interven- fi tness, and some ASCVD risk factors. in the rate of heart failure hospitaliza- tion on mortality in type 2 diabetes. N Engl J Patients at increased ASCVD risk should tion for the sitagliptin group (3.1%; 1.07 Med 2008;358:580 – 591 receive aspirin and a statin and ACE in- 4. Centers for Disease Control and Prevention, per 100 person-years) compared with hibitor or ARB therapy if the patient has National Center for Health Statistics, Division of the placebo group (3.1%; 1.09 per 100 hypertension, unless there are contrain- Health Care Statistics. Crude and age-adjusted person-years) (103). hospital discharge rates for major cardiovascu- dications to a particular drug class. rst-listed diagnosis per 1,000 di- lar disease as fi While clear bene t exists for ACE inhib- fi EMPA-REG OUTCOME Study abetic population, United States, 1988 2006 – itorandARBtherapyinpatientswithne- [Internet]. Available from http://www.cdc fl ozin) Cardio- The BI 10773 (Empagli phropathy or hypertension, the bene ts fi g3.htm. .gov/diabetes/statistics/cvdhosp/cvd/ fi vascular Outcome Event Trial in in patients with ASCVD in the absence of Accessed 27 August 2015 Type 2 Diabetes Mellitus Patients ` es N, Vaur L, et al. Is isolated 5. Bobrie G, Gen “ these conditions are less clear, especially (EMPA-REG OUTCOME) was a random- ” “ home isolated hypertension as opposed to when LDL cholesterol is concomitantly ized, double-blind, placebo-controlled hypertension a sign of greater cardiovas- of fi ce ” controlled (94,95). In patients with prior cular risk? Arch Intern Med 2001;161:2205 – trial that assessed the effect of -blockers should be continued for at b MI, 2211 empagli fl ozin, a sodium – glucose co- least 2 years after the event (96). 6. Sega R, Facchetti R, Bombelli M, et al. Prog- transporter 2 inhibitor on cardiovascular nostic value of ambulatory and home blood outcomes (stroke, MI, amputation, or Diabetes and Heart Failure pressures compared with of fi ce blood pressure coronary, carotid, or peripheral artery Almost 50% of patients with type 2 di- in the general population: follow-up results from the Pressioni Arteriose Monitorate e obstruction) in patients with type 2 abetes will develop he art failure (97). Loro Associazioni (PAMELA) study. Circulation diabetes at high risk for cardiovascular Data on the effects of glucose-lowering 2005;111:1777 – 1783 disease. Study participants had a mean agents on heart failure outcomes have 7. Arguedas JA, Leiva V, Wright JM. Blood pres- age of 63 years, 57% had diabetes for demonstrated that thiazolidinediones sure targets for hypertension in people with di- more than 10 years, and 70% had a his- have a strong and consistent relationship abetes mellitus. Cochrane Database Syst Rev 2013;10:CD008277 tory of either stroke or MI. EMPA-REG with heart failure (98 100). Therefore, – 8. James PA, Oparil S, Carter BL, et al. 2014 OUTCOME showed that the therapy re- thiazolidinedione use should be avoided evidence-based guideline for the management duced the aggregate outcome of MI, in patients with sympto matic heart failure. of high blood pressure in adults: report from the stroke, and cardiovascular death by Recent studies have now examined panel members appointed to the Eighth Joint 14% (absolute rate 10.5% vs. 12.1% in National Committee (JNC 8). JAMA 2014;311: the relationship between dipeptidyl 507 – 520 the placebo group), due to a 38% reduc- peptidase 4 (DPP-4) inhibitors and 9. McBrien K, Rabi DM, Campbell N, et al. In- tion in cardiovascular death (absolute rate heart failure and have mixed results. tensive and standard blood pressure targets in fl 3.7% vs. 5.9%) (104). Empagli ozin is the The Saxagliptin Assessment of Vascular patients with type 2 diabetes mellitus: system- rst of the recently approved diabetes fi Outcomes Recorded in Patients with Di- atic review and meta-analysis. Arch Intern Med treatments associated with a lower risk 2012;172:1296 – 1303 – abetes Mellitus Thrombolysis in Myo- 10. Cushman WC, Evans GW, Byington RP, of cardiovascular disease. Whether empa- cardial Infarction 53 (SAVOR-TIMI 53) et al.; ACCORD Study Group. Effects of intensive – glucose cotrans- ozin or other sodium gli fl study showed that patients treated blood-pressure control in type 2 diabetes melli- porter 2 inhibitors will have a similar with saxagliptin (a DPP-4 inhibitor) were – tus. N Engl J Med 2010;362:1575 1585 effect in lower-risk patients with diabetes more likely to be hospitalized for heart 11. Patel A, MacMahon S, Chalmers J, et al.; xed fi ADVANCE Collaborative Group. Effects of a remains unknown. failure than were those given placebo combination of perindopril and indapamide on (3.5% vs. 2.8%, respectively) (101). How- macrovascular and microvascular outcomes in ever, Examination of Cardiovascular Metformin patients with type 2 diabetes mellitus (the A systematic review of 34,000 patients Outcomeswith Alogliptin versusStandard ADVANCE trial): a randomised controlled trial. showed that metformin is as safe as of Care (EXAMINE) and Trial Evaluating Lancet 2007;370:829 – 840

76 Cardiovascular Disease and Risk Management S69 care.diabetesjournals.org 12. Zoungas S, Chalmers J, Neal B, et al.; 38. Goldberg RB, Mellies MJ, Sacks FM, et al.; 25. McMurray JJV, Ostergren J, Swedberg K, ADVANCE-ON Collaborative Group. Follow-up The CARE Investigators. Cardiovascular events et al.; CHARM Investigators and Committees. of blood-pressure lowering and glucose control and their reduction with pravastatin in diabetic Effects of candesartan in patients with chronic in type 2 diabetes. N Engl J Med 2014;371: and glucose-intolerant myocardial infarction sur- heart failure and reduced left-ventricular systolic 1392 – 1406 vivors with average cholesterol levels: subgroup functiontakingangiotensin-converting-enzyme in- analyses in the Cholesterol And Recurrent Events hibitors: the CHARM-Added trial. Lancet 2003; 13. SPRINT Research Group. A randomized trial (CARE) trial. Circulation 1998;98:2513 – 2519 – 362:767 771 of intensive versus standard blood-pressure control. N Engl J Med. 9 November 2015 [Epub 39. Shepherd J, Barter P, Carmena R, et al. Effect 26. Pfeffer MA, Swedberg K, Granger CB, et al.; ahead of print]. DOI: 10.1056/NEJMoa1511939 of lowering LDL cholesterol substantially below CHARM Investigators and Committees. Effects currently recommended levels in patients with of candesartan on mortality and morbidity in 14. Cruickshank JM. Hypertension Optimal coronary heart disease and diabetes: the Treating patients with chronic heart failure: the – Treatment (HOT) trial. Lancet 1998;352:573 574 to New Targets (TNT) study. Diabetes Care 2006; CHARM-Overall programme. Lancet 2003;362: 15. Emdin CA, Rahimi K, Neal B, Callender T, 1226 – 29:1220 766 759 – Perkovic V, Patel A. Blood pressure lowering in ̈ ̈ 40.SeverPS,PoulterNR,Dahl of B, et al. of B, et al.; LIFE 27. Lindholm LH, Ibsen H, Dahl type 2 diabetes: a systematic review and meta- Reduction in cardiovascular events with ator- Study Group. Cardiovascular morbidity and – 615 analysis. JAMA 2015;313:603 vastatin in 2,532 patients with type 2 diabe- mortality in patients with diabetes in the Losar- 16. Sacks FM, Svetkey LP, Vollmer WM, et al.; tes: Anglo-Scandinavi an Cardiac Outcomes tan Intervention For Endpoint reduction in hy- DASH-Sodium Collaborative Research Group. Ef- – Trial lipid-lowering arm (ASCOT-LLA). Diabetes pertension study (LIFE): a randomised trial fectsonbloodpressureof reduceddietarysodium Care 2005;28:1151 – 1157 – against atenolol. Lancet 2002;359:1004 1010 and the Dietary Approaches to Stop Hypertension Emden M, Smilde JG, Pocock 41. Knopp RH, d ’ 28. Berl T, Hunsicker LG, Lewis JB, et al.; Irbe- (DASH) diet. N Engl J Med 2001;344:3 – 10 cacy and safety of atorvastatin in the pre- fi SJ. Ef sartan Diabetic Nephropathy Trial. Collabora- 17. Chobanian AV, Bakris GL, Black HR, et al.; vention of cardiovascular end points in subjects tive Study Group. Cardiovascular outcomes in National Heart, Lung, and Blood Institute Joint with type 2 diabetes: the Atorvastatin Study for the Irbesartan Diabetic Nephropathy Trial of pa- National Committee on Prevention, Detection, Prevention of Coronary Heart Disease End- tients with type 2 diabetes and overt nephrop- Evaluation, and Treatment of High Blood Pres- points in non-insulin-dependent diabetes melli- athy. Ann Intern Med 2003;138:542 – 549 sure; National High Blood Pressure Education 1485 tus (ASPEN). Diabetes Care 2006;29:1478 – 29. Yusuf S, Teo KK, Pogue J, et al.; ONTARGET Program Coordinating Committee. The Seventh 42. Colhoun HM, Betteridge DJ, Durrington PN, Investigators. Telmisartan, ramipril, or both in Report of the Joint National Committee on Pre- et al.; CARDS Investigators. Primary prevention patients at high risk for vascular events. N Engl J vention, Detection, Evaluation, and Treatment of cardiovascular disease with atorvastatin in – 1559 Med 2008;358:1547 of High Blood Pressure: the JNC 7 report. JAMA type 2 diabetes in the Collaborative Atorvasta- – 2572 2003;289:2560 30. Jamerson K, Weber MA, Bakris GL, et al.; tin Diabetes Study (CARDS): multicentre rando- ACCOMPLISH Trial Investigators. Benazepril 18. Tatti P, Pahor M, Byington RP, et al. Out- mised placebo-controlled trial. Lancet 2004; plus amlodipine or hydrochlorothiazide for hy- come results of the Fosinopril Versus Amlodi- 364:685 – 696 pertension in high-risk patients. N Engl J Med pine Cardiovascular Events Randomized Trial 43. Kearney PM, Blackwell L, Collins R, et al.; 2428 – 2008;359:2417 (FACET)inpatientswithhypertensionand (CTT) Collabo- ’ Cholesterol Treatment Trialists – NIDDM. Diabetes Care 1998;21:597 603 ́ ́ on A, Fern andez 31. Hermida RC, Ayala DE, Moj rators. Ef cacy of cholesterol-lowering therapy fi uence of time of day of blood pressure- fl JR. In 19.EstacioRO,JeffersBW,HiattWR, in 18,686 people with diabetes in 14 rando- lowering treatment on cardiovascular risk in hy- Biggerstaff SL, Gifford N, Schrier RW. The effect mised trials of statins: a meta-analysis. Lancet pertensivepatientswithtype 2 diabetes. Diabetes of nisoldipine as compared with enalapril on car- – 125 2008;371:117 Care 2011;34:1270 – 1276 diovascular outcomes in patients with non-insulin- 44. Taylor F, Huffman MD, Macedo AF, et al. dependent diabetes and hypertension. N Engl J 32. Zhao P, Xu P, Wan C, Wang Z. Evening ver- Statins for the primary prevention of cardiovas- Med 1998;338:645 652 – sus morning dosing regimen drug therapy for cular disease. Cochrane Database Syst Rev hypertension. Cochrane Database Syst Rev 20. Schrier RW, Estacio RO, Mehler PS, Hiatt 2013;1:CD004816 2011;10:CD004184 WR. Appropriate blood pressure control in hy- 45. Carter AA, Gomes T, Camacho X, Juurlink pertensive and normotensive type 2 diabetes 33. Sibai BM. Treatment of hypertension in DN, Shah BR, Mamdani MM. Risk of incident mellitus: a summary of the ABCD trial. Nat Clin pregnant women. N Engl J Med 1996;335:257 – diabetes among patients treated with statins: 438 Pract Nephrol 2007;3:428 – 265 population based study. BMJ 2013;346:f2610 34. Baigent C, Keech A, Kearney PM, et al.; Cho- cers and Coordinators for the fi 21. ALLHAT Of 46. Hayward RA, Hofer TP, Vijan S. Narrative lesterol Treatment Trialists ’ (CTT) Collaborators. ALLHAT Collaborative Research Group. Major review: lack of evidence for recommended cacy and safety of cholesterol-lowering fi Ef outcomes in high-risk hypertensive patients low-density lipoprotein treatment targets: a treatment: prospective meta-analysis of data randomized to angiotensin-converting enzyme solvable problem. Ann Intern Med 2006;145: from 90,056 participants in 14 randomised trials inhibitor or calcium channel blocker vs diuretic: – 530 520 1278 of statins. Lancet 2005;366:1267 – the Antihypertensive and Lipid-Lowering Treat- 47. Cannon CP, Braunwald E, McCabe CH, et al.; ment to Prevent Heart Attack Trial (ALLHAT). 35. Mihaylova B, Emberson J, Blackwell L, et al.; 2997 JAMA 2002;288:2981 – Pravastatin or Atorvastatin Evaluation and In- Cholesterol Treatment Trialists ’ (CTT) Collabo- fection Therapy-Thrombolysis in Myocardial In- 22.PsatyBM,SmithNL,SiscovickDS,etal. rators. The effects of lowering LDL cholesterol farction 22 Investigators. Intensive versus Health outcomes associated with antihyperten- with statin therapy in people at low risk of vas- moderate lipid lowering with statins after acute sive therapies used as rst-line agents. A sys- fi cular disease: meta-analysis of individual data coronary syndromes. N Engl J Med 2004;350: tematic review and meta-analysis. JAMA 1997; from 27 randomised trials. Lancet 2012;380: 1495 – 1504 745 – 277:739 581 – 590 48. de Lemos JA, Blazing MA, Wiviott SD, et al. ̈ ̆ ̈ 23. Heart Outcomes Prevention Evaluation a K, Pedersen TR, Kjekshus J, or al 36. Py Early intensive vs a delayed conservative sim- Study Investigators. Effects of ramipril on car- Faergeman O, Olsson AG, Thorgeirsson G. Cho- vastatin strategy in patients with acute coro- diovascular and microvascular outcomes in peo- lesterol lowering with simvastatin improves nary syndromes: phase Z of the A to Z trial. ple with diabetes mellitus: results of the HOPE prognosis of diabetic patients with coronary 1316 JAMA 2004;292:1307 – study and MICRO-HOPE substudy. Lancet 2000; heart disease. A subgroup analysis of the Scan- 355:253 – 259 dinavian Simvastatin Survival Study (4S). Diabe- 49. Nissen SE, Tuzcu EM, Schoenhagen P, et al.; 620 tes Care 1997;20:614 – REVERSAL Investigators. Effect of intensive 24. Granger CB, McMurray JJV, Yusuf S, et al.; compared with moderate lipid-lowering ther- 37. Collins R, Armitage J, Parish S, Sleigh P, Peto CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart apy on progression of coronary atherosclerosis: R; Heart Protection Study Collaborative Group. -ventricular systolic failure and reduced left a randomized controlled trial. JAMA 2004;291: MRC/BHF Heart Protection Study of cholesterol- function intolerant to angiotensin-converting- 1071 – 1080 lowering with simvastatin in 5963 people with enzyme inhibitors: the CHARM-Alternative trial. 50. de Ferranti SD, de Boer IH, Fonseca V, et al. diabetes: a randomised placebo-controlled trial. 776 Lancet 2003;362:772 – Type 1 diabetes mellitus and cardiovascular – Lancet 2003;361:2005 2016

77 Volume 39, Supplement 1, January 2016 Diabetes Care S70 Cardiovascular Disease and Risk Management disease: a scienti c statement from the Ameri- fi individuals and 12,539 strokes. Lancet 2014; vascular disease: collaborative meta-analysis of can Heart Association and American Diabetes 1980 – 383:1973 individual participant data from randomised tri- 1130 – Association. Circulation 2014;130:1110 1860 als. Lancet 2009;373:1849 – 78. Larsen SB, Grove EL, Neergaard-Petersen S, ̈ 51. Chasman DI, Posada D, Subrahmanyan L, urtz M, Hvas AM, Kristensen SD. Determi- W 67. Perk J, De Backer G, Gohlke H, et al.; Euro- Cook NR, Stanton VP Jr, Ridker PM. Pharmaco- nants of reduced antiplatelet effect of aspirin pean Association for Cardiovascular Prevention genetic study of statin therapy and cholesterol in patients with stable coronary artery disease. & Rehabilitation (EACPR); ESC Committee for – reduction. JAMA 2004;291:2821 2827 PLoS One 2015;10:e0126767 Practice Guidelines (CPG). European Guidelines on cardiovascular disease prevention in clinical 52. Meek C, Wierzbicki AS, Jewkes C, et al. Daily 79. Campbell CL, Smyth S, Montalescot G, practice (version 2012). The Fifth Joint Task and intermittent rosuvastatin 5 mg therapy in Steinhubl SR. Aspirin dose for the prevention Force of the European Society of Cardiology statin intolerant patients: an observational of cardiovascular disease: a systematic review. and Other Societies on Cardiovascular Disease 378 study. Curr Med Res Opin 2012;28:371 – JAMA 2007;297:2018 – 2024 Prevention in Clinical Practice (constituted by ` 53. Cannon CP, Blazing MA, Giugliano RP, et al.; G, Patrono C. Platelet activation and 80. Dav ı representatives of nine societies and by invited IMPROVE-IT Investigators. Ezetimibe added to atherothrombosis. N Engl J Med 2007;357: experts). Eur Heart J 2012;33:1635 – 1701 statin therapy after acute coronary syndromes. 2494 – 2482 68. 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Zhang X-L, Zhu Q-Q, Zhu L, et al. Safety and Taylor R, Prescott R, et al. The Prevention of and secondary prevention of cardiovascular cacy of anti-PCSK9 antibodies: a meta-analysis ef fi Progression of Arterial Disease and Diabetes disease: Antithrombotic Therapy and Preven- of 25 randomized, controlled trials. BMC Med (POPADAD) trial: factorial randomised placebo tion of Thrombosis, 9th ed: American College 2015;13:123 controlled trial of aspirin and antioxidants in of Chest Physicians Evidence-Based Clinical 56. Berglund L, Brunzell JD, Goldberg AC, et al.; patients with diabetes and asymptomatic pe- Practice Guidelines. Chest 2012;141(Suppl.): Endocrine Society. Evaluation and treatment of ripheral arterial disease. BMJ 2008;337:a1840 e637S e668S – hypertriglyceridemia: an Endocrine Society clin- 70. Zhang C, Sun A, Zhang P, et al. Aspirin for 83. Boden WE, O Rourke RA, Teo KK, et al.; ’ ical practice guideline. 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Wackers FJT, Chyun DA, Young LH, et al.; brate therapy on cardiovascular events in 9795 b4531 DetectionofIschemiainAsymptomaticDia- people with type 2 diabetes mellitus (the FIELD 72. Pignone M, Earnshaw S, Tice JA, Pletcher betics (DIAD) Investigators. Resolution of study): randomised controlled trial. Lancet MJ. Aspirin, statins, or both drugs for the pri- asymptomatic myocardial ischemia in patients 1861 2005;366:1849 – mary prevention of coronary heart disease with type 2 diabetes in the Detection of Ische- 59. Jones PH, Davidson MH. Reporting rate of events in men: a cost-utility analysis. Ann Intern mia in Asymptomatic Diabetics (DIAD) study. fi rhabdomyolysis with feno statin ver- 1 brate Med 2006;144:326 – 336 2898 Diabetes Care 2007;30:2892 – fi any statin. Am J Cardiol 2005; 1 brozil sus gem 73. Pignone M, Alberts MJ, Colwell JA, et al.; 86. Elkeles RS, Godsland IF, Feher MD, et al.; 95:120 – 122 American Diabetes Association; American Heart PREDICT Study Group. 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79 S72 Diabetes Care Volume 39, Supplement 1, January 2016 American Diabetes Association 9. Microvascular Complications and Foot Care DOI: 10.2337/dc16-S012 | S80 – Diabetes Care 2016;39(Suppl. 1):S72 DIABETIC KIDNEY DISEASE Recommendations Screening – At least once a year, assess urinary albumin (e.g., spot urinary albumin to c – fi creatinine ratio) and estimated glomerular ltration rate in patients with 5 years, in all patients with type 2 diabetes, $ type 1 diabetes with duration of and in all patients with comorbid hypertension. B Treatment Optimize glucose control to reduce the risk or slow the progression of diabetic c A kidney disease. , 140/90 mmHg) to reduce the risk or slow Optimize blood pressure control ( c A the progression of diabetic kidney disease. c For people with nondialysis-dependent diabetic kidney disease, dietary pro- tein intake should be 0.8 g/kg body weight per day (the recommended daily allowance). For patients on dialysis, higher levels of dietary protein intake A should be considered. c Either an ACE inhibitor or an angiotensin receptor blocker is recommended for the treatment of nonpregnant patients with diabetes and modestly elevated 299 mg/day) and is strongly recommended B urinary albumin excretion (30 – 300 mg/day and/or estimated for those with urinary albumin excretion $ 2 . A 60 mL/min/1.73 m , fi glomerular ltration rate 9. MICROVASCULAR COMPLICATIONS AND FOOT CARE Periodically monitor serum creatinine and potassium levels for the develop- c ment of increased creatinine or changes in potassium when ACE inhibitors, angiotensin receptor blockers, or diuretics are used. E c to – – creatinine ratio in patients with Continued monitoring of urinary albumin albuminuria treated with an ACE inhibitor or an angiotensin receptor blocker is reasonable to assess the response to treatment and progression of diabetic E kidney disease. An ACE inhibitor or an angiotensin receptor blocker is not recommended for c the primary prevention of diabetic kidney disease in patients with diabetes creatinine ratio to – who have normal blood pressure, normal urinary albumin – ( 30 mg/g), and normal estimated glomerular fi ltration rate. B , 2 60 mL/min/1.73 m c When estimated glomerular fi ltration rate is , evaluate , and manage potential complications of chronic kidney disease. E c Patients should be referred for evaluation for renal replacement treatment if 2 . A , ltration rate fi they have estimated glomerular 30 mL/min/1.73 m Promptly refer to a physician experienced in the care of kidney disease for c uncertainty about the etiology of kidney disease, dif fi cult management issues, and rapidly progressing kidney disease. B Suggested citation: American Diabetes Associ- ation. Microvascular complications and foot Assessment of Albuminuria and Renal Function Standards of Medical Care in care.Sec.9.In Diabetic kidney disease, or kidney disease attributed to diabetes, occurs in 20 – 40% . Diabetes Care 2016;39(Suppl. 1): Diabetes d 2016 of patients with diabetes and is the lead ing cause of end-stage renal disease S80 – S72 (ESRD) (1). © 2016 by the American Diabetes Association. Screening for kidney damage (albuminuria) can be most easily performed by Readers may use this article as long as the work to urinary albumin creatinine ratio (UACR) in a – random spot urine collection. – is properly cited, the use is educational and not t, and the work is not altered. fi for pro Timed or 24-h collections are more burdensome and add little to prediction or

80 Microvascular Complications and Foot Care S73 care.diabetesjournals.org accuracy (2,3). Measurement of a spot blood pressure control is a subject of – 10 notprogresstohigherlevelsover5 urine sample for albumin alone (whether debate. Continued surveillance can as- 11). Patients years of follow-up (5,9 – by immunoassay or by using a sensitive sess both response to therapy and dis- with persistent and severely increased dipstick test speci c for albuminuria) fi ease progression and may aid in assessing 300 mg/g Cr) levels of albuminuria $ ( without simultaneously measuring urine adherence to ACE inhibitor or ARB ther- are likely to develop ESRD (12,13). creatinine (Cr) is less expensive but sus- apy. Some suggest that reducing UACR to The presence of diabetic retinopathy ceptible to false-negative and false- , 30 mg/g Cr) or near normal normal ( in patients with UACR 300 mg/g Cr $ positive determinations as a result of may improve CKD and cardiovascular strongly suggests diabetic kidney dis- variation in urine concentration due to disease (CVD) prognosis, but this ap- ease, and its absence in those with re- hydration. proach has not been formally evaluated 300 mg/g Cr , duced eGFR and UACR fi , Normal UACR is de 30 mg/g ned as in prospective trials, and evidence suggests nondiabetic CKD. Other causes Cr, and increased urinary albumin excre- demonstrates spontaneous remission of CKD should be considered in patients ned as 30 mg/g Cr. Because tion is de $ fi of albuminuria in up to 40% of patients with diabetes and CKD but without di- of variability in urinary albumin excretion, with type 1 diabetes. abetic retinopathy and in those with an twoof three specimens ofUACR collected active urine sediment, with rapidly in- Progression of Diabetic Kidney Disease within a 3- to 6-month period should be creasing proteinuria or nephrotic syn- Conversely, patient s with increasing abnormal before considering a patient to drome with low or rapidly decreasing UACR, declining eGFR, retinopathy, in- have albuminuria. Exercise within 24 h, . 30% reduction in eGFR eGFR, with creasing blood pressure, macrovascular infection, fever, congestive heart failure, within 2 3 months of initiating ACE in- – disease, elevated lipids and/or uric acid marked hyperglycemia, menstruation, hibitor or ARB therapy, with refractory concentrations, or a family history of and marked hypertension may elevate hypertension, or with signs or symp- CKD are more likely to experience a pro- UACR independently of kidney damage. toms of other systemic diseases. gression of diabetic kidney disease (5). Complications of kidney disease cor- Estimated Glomerular Filtration Rate Interventions relate with level of kidney function. Serum Cr should be used to estimate Nutrition 2 , 60 mL/min/1.73 m When eGFR is , fi ltration rate (GFR). Esti- glomerular For people with nondialysis-dependent screening for complications of CKD is in- mated GFR (eGFR) is commonly report- diabetic kidney disease, dietary protein dicated ( Table 9.2 ). Early vaccination ed by laboratories or can be estimated intake should be 0.8 g/kg body weight against hepatitis B virus is indicated in using formulae such as the Modi fi cation per day (the recommended daily allow- patients likely to progress to ESRD. of Diet in Renal Disease (MDRD) study ance). Compared with higher levels of Identifying and monitoring diabetic equation (4) or the Chronic Kidney dietary protein intake, this level slowed kidney disease relies on assessments of Disease Epidemiology Collaboration GFR decline with evidence of a greater kidney damage (albuminuria) and kid- (CKD-EPI) equation. The latter is the pre- effect over time. Higher levels of dietary ney function (eGFR). Persistently in- ferred GFR estimating equation. GFR . 20% of daily calories protein intake ( creased UACR in the range of UACR calculators are available at http:// 1.3 g/kg/day) have from protein or . – 30 299 mg/g Cr is an early indicator of www.nkdep.nih.gov. been associated with increased albu- diabetic kidney disease in type 1 diabe- Abnormal urinary albumin excretion minuria, more rapid kidney function tes and a marker for development of di- and eGFR may be used to stage chronic loss, and CVD mortality and therefore abetic kidney disease in type 2 diabetes. kidney disease (CKD). The National Kid- should be avoided. Reducing the It is also a well-established marker of ) Table 9.1 cation ( fi ney Foundation classi amount of dietary protein below the increased CVD risk (6 8). – is based on both kidney damage (UACR recommended daily allowance of 0.8 Not all people with diabetes, kidney 30 mg/g Cr) and eGFR. $ g/kg/day is not recommended because disease, and reduced eGFR have albumin- it does not alter glycemic measures, car- uria. In addition, there is increasing evi- Surveillance diovascular risk measures, or the course dence that up to 40% of patients with The need for annual quantitative as- of GFR decline. type 1 diabetes and UACR levels 30 – 299 sessment of albumin excretion after di- Glycemia mg/g Cr have spontaneous remissions agnosis of albuminuria, institution of A number of interventions have been 40% remain with – and approximately 30 ACE inhibitor or angiotensin receptor demonstrated to reduce the risk and UACR levels of 30 299 mg/g Cr and do – blocker (ARB) therapy, and achieving slow the progression of diabetic kidney disease. Intensive diabetes manage- Stages of CKD — Table 9.1 ment with the goal of achieving near- 2 ) GFR (mL/min/1.73 m Description Stage normoglycemia has been shown in large prospective randomized studies to delay $ 1 Kidney damage* with normal or increased eGFR 90 the onset and progression of increased 2 – Kidney damage* with mildly decreased eGFR 60 89 urinary albumin excretion and reduced 59 – 30 3 Moderately decreased eGFR eGFR in patients with type 1 diabetes 4 Severely decreased eGFR 15 – 29 (13) and type 2 diabetes (1,14 – 17). 5 15 or dialysis Kidney failure , Despite prior concerns and published *Kidney damage is de fi ned as abnormalities on pathological, urine, blood, or imaging tests. case reports, current data indicate that Adapted from Levey et al. (3). the overall risk of metformin-associated

81 Volume 39, Supplement 1, January 2016 S74 Microvascular Complications and Foot Care Diabetes Care in hyperkalemic episodes in those on dual Table 9.2 — Management of CKD in diabetes therapy, and larger trials are needed be- 2 Recommended management ) GFR (mL/min/1.73 m fore recommending such therapy. Yearly measurement of Cr, UACR, potassium All patients Diuretics, calcium channel blockers, Referraltoanephrologistifpossibilityfornondiabetickidney – 45 60 and b -blockers can be used as add-on disease exists (duration of type 1 diabetes , 10 years, therapy to achieve blood pressure goals persistent albuminuria, abnormal ndings on renal fi in patients treated with maximum doses ultrasound, resistant hypertension, rapid fall in eGFR, or of ACE inhibitors or ARBs (26) or as alter- active urinary sediment on urine microscopic examination) nate therapy in the rare individual unable Consider the need for dose adjustment of medications Monitor eGFR every 6 months to tolerate ACE inhibitors and ARBs. Monitor electrolytes, bicarbonate, hemoglobin, calcium, Referral to a Nephrologist phosphorus, and parathyroid hormone at least yearly Consider referral to a physician experi- Assure vitamin D suf fi ciency enced in the care of kidney disease when Consider bone density testing Referral for dietary counseling there is uncertainty about the etiology of 30 44 Monitor eGFR every 3 months – kidney disease (absence of retinopathy, Monitor electrolytes, bicarbonate, calcium, phosphorus, heavy proteinuria, active urine sediment, parathyroid hormone, hemoglobin, albumin, and weight or rapid decline in GFR). Other triggers for 6 months – every 3 fi cult management referral may include dif Consider the need for dose adjustment of medications issues (anemia, secondary hyperparathy- Referral to a nephrologist , 30 roidism, metabolic bone disease, resistant hypertension, or electrolyte disturbances) or advanced kidney disease. The threshold lactic acidosis is low (1). GFR may be a 130 mmHg to avoid diastolic blood , for referral may vary depending on the more appropriate measure to assess 70 mmHg. – pressure levels below 60 frequency with which a provider en- continued metformin use than serum The UK Prospective Diabetes Study counters patients with diabetes and Cr, considering that the serum Cr level (UKPDS) provided strong evidence that kidney disease. Consultation with a ne- can translate into widely varying blood pressure control can reduce the de- phrologist when stage 4 CKD develops eGFR levels depending on age, ethnic- velopment of diabetic kidney disease (22). 2 ) has been (eGFR # 30 mL/min/1.73 m ity, and muscle mass (18). A review Interruption of the renin-angiotensin- found to reduce cost, improve quality of (19) proposed that metformin use aldosterone system with either ACE care, and delay dialysis (27). However, should be reevaluated at an eGFR inhibitors or ARBs contributes to reduc- other specialists and providers should 2 with a reduction 45 mL/min/1.73 m , tions of kidney disease events in hy- also educate their patients about the pro- in maximum dose to 1,000 mg/day. pertensive patients with diabetes and gressive nature of diabetic kidney disease, 2 and UACR Metformin should be discontinued eGFR , 60 mL/min/1.73 m fi ts of pro- the kidney preservation bene 2 ;in $ 300 mg/g Cr. when eGFR is 30 mL/min/1.73 m , active treatment of blood pressure and clinical situations in which there is an ACE inhibitors have been shown to re- blood glucose, and the potential need for increased risk of lactic acidosis, such duce major CVD events in patients with renal replacement therapy. as sepsis, hypotension, and hypoxia; or diabetes (23), thus further supporting the when there is a high risk of acute kidney use of these agents in patients with albu- DIABETIC RETINOPATHY injury resulting in a worsening of GFR, such minuria, a CVD risk factor. In those with as administration of radiocontrast dye in diabetic kidney disease, some evidence Recommendations 2 . those with eGFR , 60 mL/min/1.73 m suggests that ARBs compared with ACE Optimize glycemic control to re- c inhibitors are associated with a smaller Blood Pressure duce the risk or slow the progres- increase in serum potassium levels (24). There are no randomized controlled tri- sion of diabetic retinopathy. A Combination Therapy als of blood pressure levels in diabetes Optimize blood pressure and se- c Two clinical trials studied the combina- that have examined CKD events as out- rum lipid control to reduce the tions of ACE inhibitors and ARBs and comes. Blood pressure levels below risk or slow the progression of di- fi ts on CVD or diabetic found no bene 140/90 mmHg in diabetes are recom- abetic retinopathy. A kidney disease, and the drug combina- mended to reduce CVD mortality and Screening tion had higher adverse event rates (hy- slow CKD progression. In individuals c Adults with type 1 diabetes should perkalemia and/or acute kidney injury) with albuminuria, consider lower blood have an initial dilated and compre- (25). Therefore, the combined use of ACE pressure targets of , 130/80 mmHg hensive eye examination by an oph- inhibitors and ARBs should be avoided. (20,21). Of note, there is an adverse thalmologist or optometrist within Mineralocorticoid receptor blockers safety signal in clinical trials of diabetic B 5 years after the onset of diabetes. (spironolactone) in combination with ACE kidney disease when diastolic blood pres- c Patients with type 2 diabetes should inhibitors or ARBs remain an area of great sure is treated to below 70 mmHg and have an initial dilated and compre- interest and have been explored in several especially below 60 mmHg in older pop- hensive eye examination by an oph- short-term studies with a positive effect on ulations. As a result, clinical judgment thalmologist or optometrist at the albuminuria reduction in diabetic kidney should be used when attempting to time of the diabetes diagnosis. B disease. There was, however, an increase achieve systolic blood pressure targets

82 Microvascular Complications and Foot Care S75 care.diabetesjournals.org type 2 diabetes, with prevalence controlled type 2 diabetes, there was If there is no evidence of retinop- c strongly related to both the duration essentially no risk of development of athy for one or more annual eye of diabetes and the level of glycemic cant retinopathy with a 3-year in- fi signi exams, then exams every 2 years control. Diabetic retinopathy is the terval after a normal examination (35). may be considered. If any level of most frequent cause of new cases of Examinations will be required more fre- diabetic retinopathy is present, blindness among adults aged 20 – 74 quently by the ophthalmologist if reti- subsequent dilated retinal exami- years in developed countries. Glaucoma, nopathy is progressing. nations for patients with type 1 or cataracts, and other disorders of the eye Retinal photography, with remote type 2 diabetes should be re- occur earlier and more frequently in reading by experts, has great potential peated at least annually by an people with diabetes. to provide screening services in areas ophthalmologist or optometrist. In addition to diabetes duration, where quali fi ed eye care professionals If retinopathy is progressing or factors that increase the risk of, or are are not readily available (36).High-quality sight-threatenin g, then examina- associated with, retinopathy include fundus photographs can detect most tions will be required more fre- chronic hyperglycemia (28), nephropa- fi clinically signi cant diabetic retinopathy. B quently. Interpretation of the images should be thy (29), hypertension (30), and dys- c While retinal photography may performed by a trained eye care pro- lipidemia (31). Intensive diabetes serve as a screening tool for reti- vider. Retinal photography may also en- management with the goal of achieving nopathy, it is not a substitute for a ciency and reduce costs when hance ef fi near-normoglycemia has been shown in comprehensive eye exam, which the expertise of ophthalmologists can be large prospective randomized studies to should be performed at least ini- used for more complex examinations and prevent and/or delay the onset and pro- tially and at intervals thereafter as for therapy (37). In-person exams are still gression of diabetic retinopathy (15,32). recommended by an eye care pro- necessary when the retinal photos are un- Lowering blood pressure has been E fessional. acceptable and for follow-up if abnormal- shown to decrease retinopathy progres- c Eye examinations should occur be- ities are detected. Retinal photos are sion, although tight targets (systolic fore pregnancy or in the fi rst tri- not a substitute for a comprehensive 120 mmHg) do not impart additional , mester, and then patients should eye exam, which should be performed fi bene t (32). In patients with dyslipide- be monitored every trimester and at least initially and at intervals thereafter mia, retinopathy progression may be for 1 year postpartum as indicated as recommended by an eye care profes- slowed by the addition of feno fi brate, by the degree of retinopathy. B sional. Results ofeye examinations should particularly with very mild nonprolifer- Treatment be documented and transmitted to the ative diabetic retinopathy (NPDR) at c Promptly refer patients with any referring health care professional. baseline (31). Several case series and a level of macular edema, severe controlled prospective study suggest Type 1 Diabetes nonproliferative diabetic retinop- that pregnancy in patients with type 1 Because retinopathy is estimated to athy (a precursor of proliferative diabetes may aggravate retinopathy and take at least 5 years to develop after diabetic retinopathy), or any pro- threaten vision, especially when glyce- the onset of hyperglycemia, patients liferative diabetic retinopathy to mic control is poor at the time of con- with type 1 diabetes should have an ini- an ophthalmologist who is knowl- ception (33,34). Laser photocoagulation tial dilated and comprehensive eye ex- edgeable and experienced in the surgery can minimize the risk of vision amination within 5 years after the management and treatment of di- loss (34). diagnosis of diabetes (38). abetic retinopathy. A Type 2 Diabetes c Laser photocoagulation therapy is Screening Patients with type 2 diabetes who may indicatedtoreducethe risk ofvision The preventive effects of therapy and have had years of undiagnosed diabetes loss in patients with high-risk pro- the fact that patients with proliferative cant risk of prevalent fi and have a signi liferative diabetic retinopathy and, diabetic retinopathy (PDR) or macular diabetic retinopathy at the time of di- in some cases, severe nonprolifera- edema may be asymptomatic provide agnosis should have an initial dilated tive diabetic retinopathy. A strong support for screening to detect and comprehensive eye examination at ctions of antivas- Intravitreal inje c diabetic retinopathy. the time of diagnosis. cular endothelial growth factor An ophthalmologist or optometrist are indicated for center-involved who is knowledgeable and experienced Pregnancy diabetic macular edema, which oc- in diagnosing diabetic retinopathy Pregnancy is associated with a rapid curs beneath the foveal center and should perform the examinations. If di- progression of diabetic retinopathy may threaten reading vision. A abetic retinopathy is present, prompt (39,40). Women with preexisting type The presence of retinopathy is c referral to an ophthalmologist is recom- 1 or type 2 diabetes who are planning not a contraindication to aspirin pregnancy or who have become preg- mended. Subsequent examinations for therapy for cardioprotection, as nant should be counseled on the risk patients with type 1 or type 2 diabetes aspirin does not increase the risk are generally repeated annually for pa- of development and/or progression of A of retinal hemorrhage. diabetic retinopathy. In addition, rapid tients with minimal to no retinopathy. implementation of tight glycemic con- Exams every 2 years may be cost- trol in the setting of retinopathy is asso- effective after one or more normal eye c fi Diabetic retinopathy is a highly speci ciated with worsening of retinopathy vascular complication of both type 1 and exams, and in a population with well-

83 Volume 39, Supplement 1, January 2016 Diabetes Care S76 Microvascular Complications and Foot Care (34). Women who develop gestational di- 3. Up to 50% of diabetic peripheral replaced the need for laser photocoag- abetes mellitus do not require an eye neuropathy (DPN) may be asymp- ulationinthevastmajorityofpatients examination during pregnancy and do tomatic. If not recognized and if pre- with diabetic macular edema (47). not appear to be at increased risk of ventive foot care is not implemented, Most patients require near-monthly developing diabetic retinopathy during patients are at risk for injuries to their administration of intravitreal therapy pregnancy (41). insensate feet. rst with anti-VEGF agents during the fi 4. Recognition and treatment of auto- 12 months of treatment with fewer in- Treatment nomic neuropathy may improve jections needed in subsequent years to Two of the main motivations for screen- symptoms, reduce sequelae, and im- maintain remission from center-involved ing for diabetic retinopathy are to pre- prove quality of life. diabetic macular edema. Other emerging vent loss of vision and to intervene with therapies for retinopathy that may use treatment when vision loss can be pre- Speci fi c treatment for the underlying sustained intravitreal delivery of phar- vented or reversed. nerve damage, other than improved gly- macological agents are currently under Photocoagulation Surgery cemic control, is currently not available. investigation. Two large trials, the Diabetic Retinopathy Glycemic control can effectively prevent Study (DRS) in patients with PDR and the NEUROPATHY DPN and cardiac autonomic neuropathy Early Treatment Diabetic Retinopathy (CAN) in type 1 diabetes (48,49) and may Recommendations Study (ETDRS) in patients with macular modestly slow their progression in type 2 edema, provide the strongest support Screening diabetes (17) but does not reverse neuro- All patients should be assessed for c for the therapeutic bene fi ts of photoco- nal loss. Therapeutic strategies (pharma- diabetic peripheral neuropathy agulation surgery. The DRS (42) showed cological and nonpharmacological) for starting at diagnosis of type 2 di- that panretinal photocoagulation surgery the relief of symptoms related to painful abetes and 5 years after the diag- reduced the risk of severe vision loss from DPN orautonomicneuropathycan poten- nosis of type 1 diabetes and at PDR from 15.9% in untreated eyes to tially reduce pain (50) and improve qual- least annually thereafter. B 6.4% in treated eyes, with the greatest ity of life. c Assessment should include a care- t ratio in those with baseline fi bene risk – fi lament ful history and 10-g mono disease (disc neovascularization or vitre- Diagnosis testing and at least one of the fol- ous hemorrhage). The ETDRS also veri fi ed Diabetic Peripheral Neuropathy lowing tests: pinprick, tempera- ts of panretinal photocoagula- fi the bene Patients with type 1 diabetes for 5 B ture, or vibration sensation. tion for high-risk PDR and in older-onset or more years and all patients with c Symptoms and signs of autonomic patients with severe NPDR or less-than- type 2 diabetes should be assessed an- neuropathy should be assessed in high-risk PDR. Panretinal laser photoco- nually for DPN using medical history patients with microvascular and agulation is still commonly used to and simple clinical tests. Symptoms neuropathic complications. E manage complications of diabetic reti- vary according to the class of sensory nopathy that involve retinal neovasculari- bers involved. The most common fi Treatment zation and its complications. Optimize glucose control to pre- c early symptoms are induced by the in- Antivascular Endothelial Growth Factor vent or delay the development of volvement of small fi bers and include Treatment neuropathy in patients with type 1 pain and dysesthesias (unpleasant While the ETDRS (43) established the A andtoslowthepro- diabetes sensations of burning and tingling). bene fi t of focal laser photocoagulation gression of neuropathy in patients bers may The involvement of large fi cant surgery in eyes with clinically signi fi with type 2 diabetes. B cause numbness and loss of protective fi macular edema (de ned as retinal c Assess and treat patients to reduce sensation (LOPS). LOPS indicates the mof m edema located at or within 500 pain related to diabetic peripheral presence of distal sensorimotor poly- the center of the macula), current data neuropathy and symptoms of au- B neuropathy and is a risk factor for di- from multiple well-designed clinical tri- tonomic neuropathy and to im- abetic foot ulceration. The following als demonstrate that intravitreal anti- E prove quality of life. clinical tests may be used to assess vascular endothelial growth factor fi small- and large- ber function and (anti-VEGF) agents provide a more ef- The diabetic neuropathies are a hetero- protective sensation: fective treatment regimen for center- geneous group of disorders with diverse involved diabetic macular edema than clinical manifestations. The early recog- 1. Small- ber function: pinprick and fi monotherapy or even combination ther- nition and appropriate management of temperature sensation 46). apy with laser (44 – neuropathy in the patient with diabetes ber function: vibration per- 2. Large- fi Historically, laser photocoagulation is important. ception, 10-g mono fi lament, and an- surgery in both trials was bene fi cial in fl exes kle re 1. Diabetic neuropathy is a diagnosis of reducing the risk of further visual loss lament fi 3. Protective sensation: 10-g mono exclusion. Nondiabetic neuropathies in affected patients but generally not may be present in patients with di- cial in reversing already dimin- bene fi These tests not only screen for the pres- abetes and may be treatable. ished acuity. Now, intravitreal therapy enceofdysfunctionbutalsopredictfuture 2. Numerous treatment options exist for with recombinant monoclonal neutralizing risk of complications. Electrophysiological symptomatic diabetic neuropathy. antibody to VEGF improves vision and has testing or referral to a neurologist is rarely

84 Microvascular Complications and Foot Care S77 care.diabetesjournals.org needed, except in situations where the results are likely to be abnormal in the of painful DPN, may be effective and clinical features are atypical or the diag- setting of recent uncontrolled hypergly- considered for the treatment of painful nosis is unclear. cemia or diabetic ketoacidosis and often cacy studies and fi DPN. Comparative ef In all patients with diabetes and DPN, correlate poorly with symptoms. Con- trials that include quality-of-life out- causes of neuropathy other than diabe- stipation is the most common lower- comes are rare, so treatment decisions tes should be considered, including gastrointestinal symptom but can must consider each patient ’ s presenta- toxins (alcohol), neurotoxic medications alternate with episodes of diarrhea. tion and comorbidities and often de ciency, fi (chemotherapy), vitamin B follow a trial-and-error approach. Given 12 Genitourinary Disturbances hypothyroidism, renal disease, malig- the range of partially effective treatment Diabetic autonomic neuropathy may nancies (multiple myeloma, broncho- options, a tailored and stepwise pharma- also cause genitourinary disturbances. genic carcinoma), infections (HIV), cological strategy with careful attention In men, diabetic autonomic neuropathy ammatory demyelinating chronic in fl to relative symptom improvement, med- may cause erectile dysfunction and/or neuropathy, inherited neuropathies, ication adherence, and medication side retrograde ejaculation. Evaluation of and vasculitis (51). effects is recommended to achieve pain bladder function should be performed reduction and improve quality of life Diabetic Autonomic Neuropathy for individuals with diabetes who have (50,64,65). The symptoms and signs of autonomic recurrent urinary tract infections, pyelo- Orthostatic Hypotension dysfunction should be elicited carefully nephritis, incontinence, or a palpable Treating orthostatic hypotension is chal- during the history and physical exami- bladder. lenging. The therapeutic goal is to min- nation. Major clinical manifestations of imize postural symptoms rather than to diabetic autonomic neuropathy include Treatment restore normotension. Most patients hypoglycemia unawareness, resting Glycemic Control require both nonpharmacological mea- tachycardia, orthostatic hypotension, Near-normal glycemic control, imple- sures (e.g., ensuring adequate salt intake, gastroparesis, constipation, diarrhea, mented early in the course of diabetes, avoiding medications that aggravate hypo- fecal incontinence, erectile dysfunction, has been shown to effectively delay or tension, or using compressive garments neurogenic bladder, and sudomotor prevent the development of DPN and over the legs and abdomen) and pharma- dysfunction with either increased or de- CAN in patients with type 1 diabetes cological measures. Midodrine is the only creased sweating. (55 58). Although the evidence for the – drug approved by the FDA for the treat- fi bene t of near-normal glycemic control Cardiac Autonomic Neuropathy ment of orthostatic hypotension. is not as strong for type 2 diabetes, some CAN is associated with mortality inde- studies have demonstrated a modest Gastroparesis pendent of other cardiovascular risk fac- slowing of progression (59,60) without Gastroparesis may improve with a low- tors (52,53). In its early stages, CAN may reversal of neuronal loss. Several obser- fat, low- fi ber diet, optimized glycemic be completely asymptomatic and de- vational studies suggest that neuro- control, and prokinetic agents such as tected only by decreased heart rate var- pathic symptoms improve not only metoclopramide or erythromycin. In iability with deep breathing. Advanced with optimization of glycemic control 2009, the FDA added a boxed warning disease may be associated with resting but also with the avoidance of extreme to the metoclopramide label highlighting 100 bpm) and orthostatic tachycardia ( . uctuations. blood glucose fl the risks of irreversible tardive dyskinesia hypotension (a fall in systolic or diastolic after long-term use of metoclopramide. . 10 blood pressure by . 20 mmHg or Diabetic Peripheral Neuropathy The chronic use of metoclopramide mmHg, respectively, upon standing DPN symptoms, and especially neuro- should be avoided (66). Metoclopramide without an appropriate increase in heart pathic pain, can be severe and can im- should be reserved for patients with the rate). CAN treatment is generally fo- pact quality of life, limit mobility, and most severe symptoms that are unre- cused on alleviating symptoms. contribute to depression and social dys- sponsive to other therapies. The medica- Gastrointestinal Neuropathies function (61). Several medications have tion should be used at the lowest dose Gastrointestinal neuropathies may in- been demonstrated to be effective for and for the shortest duration possible, volve any portion of the gastrointestinal the treatment of pain associated with generally not to exceed 3 months, and tract with manifestations including DPN, but there is limited clinical evi- side effects should be closely monitored. esophageal dysmotility, gastroparesis, dence regarding which medication is Erectile Dysfunction constipation, diarrhea, and fecal incon- most effective for an individual patient Treatments for erectile dysfunction may tinence. Gastroparesis should be sus- (62,63). include phosphodiesterase type 5 inhib- pected in individuals with erratic The U.S. Food and Drug Administra- itors, intracorporeal or intraurethral glucose control or with upper gastroin- tion (FDA) has approved three medi- prostaglandins, vacuum devices, or pe- testinal symptoms without another cations (pregabalin, duloxetine, and nile prostheses. Interventions for other fi ed cause. Evaluation of gastric identi tapentadol) for the treatment of pain as- manifestations of autonomic neuropa- emptying using the gastric emptying sociated with DPN, but none affords thy are described in the American Dia- breath test, a new noninvasive test complete relief, even when used in com- betes Association (ADA) statement on that does not use radiation-emitting bination. Tricyclic antidepressants, gaba- neuropathy (67). As with DPN treat- compounds (54), or the double-isotope pentin, venlafaxine, carbamazepine, ments, these interventions do not scintigraphy may be performed if symp- tramadol, and topical capsaicin, al- change the underly ing pathology and toms suggest gastroparesis, but test though not approved for the treatment

85 Volume 39, Supplement 1, January 2016 Diabetes Care S78 Microvascular Complications and Foot Care natural history of the disease process brachial index testing should be per- recognition and treatment of patients s quality ’ but may improve the patient formed in patients with symptoms or with diabetes and feet at risk for ulcers of life. signs of PAD. Due to the high estimated and amputations can delay or prevent prevalence of PAD in patients with di- adverse outcomes. FOOT CARE abetes and the fact that many patients The risk of ulcers or amputations is with PAD are asymptomatic, an ADA increased in people who have the fol- Recommendations consensus report on PAD (68) suggested lowing risk factors: c Performa comprehensive foot eval- that ankle-brachial index screening be uation each year to identify risk fac- ○ History of foot ulcer performed in patients 50 years of age B tors for ulcers and amputations. ○ Amputation and older and be considered in patients Obtain a prior history of ulceration, c ○ Foot deformities under 50 years of age who have other amputation, Charcot foot, angio- ○ Peripheral neuropathy with LOPS PAD risk factors (e.g., smoking, hyper- plasty or vascular surgery, cigarette ○ Preulcerative callus or corn tension, dyslipidemia, or duration of di- smoking, retinopathy, and renal dis- ○ PAD abetes . 10 years). ease and assess current symptoms ○ Poor glycemic control of neuropathy (pain, burning, ○ Visual impairment Patient Education numbness) and vascular disease ○ Diabetic nephropathy (especially pa- Patients with diabetes and high-risk foot (leg fatigue, claudication). B tients on dialysis) conditions (history of ulcer or amputa- c The examination should include in- ○ Cigarette smoking tion, deformity, LOPS, or PAD) should be spection of the skin, assessment of educated about their risk factors and foot deformities, neurological assess- Clinicians are encouraged to review ADA appropriate management. Patients at lament ment including 10-g mono fi screening recommendations for further risk should understand the implications testing and pinprick or vibration test- details and practical descriptions of how of foot deformities, LOPS, and PAD; the exes, fl ing or assessment of ankle re to perform components of the compre- proper care of the foot, including nail and vascular assessment including hensive foot examination (67). and skin care; and the importance of B pulses in the legs and feet. foot monitoring on a daily basis. Pa- Patients with a history of ulcers or c Evaluation for Loss of Protective tients with LOPS should be educated amputations, foot deformities, in- Sensation on ways to substitute other sensory mo- sensate feet, and peripheral arte- All adults with diabetes should un- dalities (palpation or visual inspection rial disease are at substantially dergo a comprehensive foot evaluation using a nonbreakable mirror) for sur- increased risk for ulcers and ampu- at least annually to identify high-risk veillance of early foot problems. tations and should have their feet conditions. Clinicians should ask about The selection of appropriate foot- C examined at every visit. history of foot ulcers or amputation, wear and footwear behaviors at home Patients with symptoms of claudi- c neuropathic and peripheral vascular ’ should also be discussed. Patients un- cation or decreased or absent symptoms, impaired vision, renal dis- derstanding of these issues and their pedal pulses should be referred ease, tobacco use, and foot care prac- physical ability to conduct proper foot for ankle-brachial index and for tices. A general inspection of skin surveillance and care should be as- further vascular assessment. C integrity and musculoskeletal defor- sessed. Patients with visual dif fi culties, c A multidisciplinary approach is mities should be performed. Vascular physical constraints preventing move- recommended for individuals assessment should include inspection ment, or cognitive problems that impair with foot ulcers and high-risk feet and assessment of pedal pulses. their ability to assess the condition of (e.g., dialysis patients and those The neurological exam performed as the foot and to institute appropriate re- with Charcot foot, prior ulcers, or part of the foot examination is designed sponses will need other people, such B amputation). to identify LOPS rather than early neu- as family members, to assist in their care. c Refer patients who smoke or who ropathy. The 10-g mono fi lament is the have histories of prior lower- most useful test to diagnose LOPS. Ide- Treatment extremity complications, loss of ally, the 10-g mono lament test should fi People with neuropathy or evidence of protective sensation, structural be performed with at least one other increased plantar pressures (e.g., ery- abnormalities, or peripheral arte- assessment (pinprick, temperature or thema, warmth, or calluses) may be ade- rial disease to foot care specialists vibration sensation using a 128-Hz tun- quately managed with well- tted walking fi for ongoing preventive care and ing fork, or ankle re fl exes). Absent shoes or athletic shoes that cushion the lifelong surveillance. C lament sensation suggests LOPS, mono fi feet and redistribute pressure. People Provide general foot self-care educa- c while at least two normal tests (and no with bony deformities (e.g., hammertoes, B tion to all patients with diabetes. abnormal test) rule out LOPS. prominent metatarsal heads, bunions) Foot ulcers and amputation, which are mayneedextra-wideor-deep shoes. Peo- Evaluation for Peripheral Arterial consequences of diabetic neuropathy ple with bony deformities, including Char- Disease Initial screening for PAD should and/or peripheral arterial disease cot foot, who cannot be accommodated include a history for decreased walking (PAD), are common and represent with commercial therapeutic footwear speed, leg fatigue, claudication, and an major causes of morbidity and mor- will require custom-molded shoes. Spe- assessment of the pedal pulses. Ankle- tality in people wit hdiabetes.Early cial consideration and a thorough workup

86 Microvascular Complications and Foot Care S79 care.diabetesjournals.org function, hypertension, and diabetes. Circulation 21. Cushman WC, Evans GW, Byington RP, should be performed when patients with 35 – 2004;110:32 et al.; ACCORD Study Group. Effects of intensive neuropathy present with an acute onset 9. de Boer IH, Rue TC, Cleary PA, et al.; Diabetes blood-pressure control in type 2 diabetes melli- of a red, hot, swollen foot or ankle, and Control and Complications Trial/Epidemiology 1585 – tus. N Engl J Med 2010;362:1575 Charcot neuroarthropathy should be ex- of Diabetes Interventions and Complications 22. UK Prospective Diabetes Study Group. Tight cluded. Early diagnosis and treatment of Study Research Group. Long-term renal out- blood pressure control and risk of macrovascu- comes of patients with type 1 diabetes mellitus lar and microvascular complications in type 2 Charcot neuroarthropathy is the best way a: an analysis of the and microalbuminuri – 713 diabetes: UKPDS 38. BMJ 1998;317:703 to prevent deformities that increase the 23. Heart Outcomes Prevention Evaluation mplications Trial/ Diabetes Control and Co risk of ulceration and amputation. Study Investigators. Effects of ramipril on car- Epidemiology of Diabetes Interventions and Most diabetic foot infections are poly- diovascular and microvascular outcomes in peo- Complications cohort. Arch Intern Med 2011; microbial, with aerobic gram-positive ple with diabetes mellitus: results of the HOPE 171:412 420 – 10. Molitch ME, Steffes M, Sun W, et al.; Epi- study and MICRO-HOPE substudy. Lancet 2000; cocci. Staphylococci are the most com- demiology of Diabetes Interventions and Com- 259 – 355:253 mon causative organisms. Wounds 24. Pepine CJ, Handberg EM, Cooper-DeHoff plications Study Group. Development and without evidence of soft-tissue or bone ciency with and with- fi progression of renal insuf RM, et al.; INVEST Investigators. A calcium an- infection do not require antibiotic ther- tagonist vs a non-calcium antagonist hyperten- out albuminuria in adults with type 1 diabetes in apy. Empiric antibiotic therapy can be the Diabetes Control and Complications Trial sion treatment strategy for patients with coronary artery disease. The International and the Epidemiology of Diabetes Interventions narrowly targeted at gram-positive and Complications study. Diabetes Care 2010; Verapamil-Trandolapril Study (INVEST): a ran- cocci in many patients with acute infec- domized controlled trial. JAMA 2003;290: 33:1536 – 1543 tions, but those at risk for infection with 11. de Boer IH, Sun W, Cleary PA, et al.; DCCT/ – 2816 2805 antibiotic-resistant organisms or with EDIC Research Group. Intensive diabetes ther- 25. Yusuf S, Teo KK, Pogue J, et al.; ONTARGET chronic, previously treated, or severe apy and glomerular fi ltration rate in type 1 di- Investigators. Telmisartan, ramipril, or both in 2376 – abetes. N Engl J Med 2011;365:2366 patients at high risk for vascular events. N Engl J infections require broader-spectrum 12. Gall M-A, Hougaard P, Borch-Johnsen K, 1559 – Med 2008;358:1547 regimens and should be referred to spe- Parving H-H. Risk factors for development of 26. Berl T, Hunsicker LG, Lewis JB, et al.; Irbe- cialized care centers (69). Foot ulcers sartan Diabetic Nephropathy Trial. Collabora- incipient and overt diabetic nephropathy in pa- and wound care may require care by a tients with non-insulin dependent diabetes mel- tive Study Group. Cardiovascular outcomes in podiatrist, orthopedic or vascular sur- the Irbesartan Diabetic Nephropathy Trial of pa- litus: prospective, observational study. BMJ – 788 1997;314:783 tients with type 2 diabetes and overt nephrop- geon, or rehabilitation specialist experi- 13. The Diabetes Control and Complications – 549 athy. Ann Intern Med 2003;138:542 enced in the management of individuals 27. Smart NA, Dieberg G, Ladhani M, Titus T. (DCCT) Research Group. Effect of intensive ther- with diabetes (69). apy on the development and progression of di- Early referral to specialist nephrology services abetic nephropathy in the Diabetes Control and for preventing the progression to end-stage kid- References – Complications Trial. Kidney Int 1995;47:1703 ney disease. Cochrane Database Syst Rev 2014; 1. Tuttle KR, Bakris GL, Bilous RW, et al. Dia- 6:CD007333 1720 betic kidney disease: a report from an ADA Con- 28. Klein R. Hyperglycemia and microvascular 14. UK Prospective Diabetes Study (UKPDS) sensus Conference. Diabetes Care 2014;37: and macrovascular disease in diabetes. Diabe- Group. Effect of intensive blood-glucose control 2883 – 2864 tes Care 1995;18:258 268 – with metformin on complications in overweight 2. Eknoyan G, Hostetter T, Bakris GL, et al. Pro- 29. Estacio RO, McFarling E, Biggerstaff S, patients with type 2 diabetes (UKPDS 34). Lan- teinuria and other markers of chronic kidney Jeffers BW, Johnson D, Schrier RW. Overt albu- 865 cet 1998;352:854 – disease: a position statement of the National minuria predicts diabetic retinopathy in His- 15. UK Prospective Diabetes Study (UKPDS) Kidney Foundation (NKF) and the National In- Group. Intensive blood-glucose control with sul- panics with NIDDM. Am J Kidney Dis 1998;31: stitute of Diabetes and Digestive and Kidney 947 953 – phonylureas or insulin compared with conven- Diseases (NIDDK). Am J Kidney Dis 2003;42: 30. Leske MC, Wu S-Y, Hennis A, et al.; Barba- tional treatment and risk of complications in – 622 617 dos Eye Study Group. Hyperglycemia, blood patients with type 2 diabetes (UKPDS 33). Lan- 3. Levey AS, Coresh J, Balk E, et al.; National pressure, and the 9-year incidence of diabetic cet 1998;352:837 – 853 Kidney Foundation. National Kidney Foundation 16. Patel A, MacMahon S, Chalmers J, et al.; retinopathy: the Barbados Eye Studies. Oph- practice guidelines for chronic kidney disease: 805 – thalmology 2005;112:799 ADVANCE Collaborative Group. Intensive blood fi cation. Ann fi cation, and strati evaluation, classi 31. Chew EY, Davis MD, Danis RP, et al.; Action glucose control and vascular outcomes in pa- 147 – Intern Med 2003;139:137 to Control Cardiovascular Risk in Diabetes Eye tients with type 2 diabetes. N Engl J Med 4. Levey AS, Bosch JP, Lewis JB, Greene T, Study Research Group. The effects of medical 2008;358:2560 – 2572 fi cation of Diet in Renal Rogers N, Roth D; Modi 17. Ismail-Beigi F, Craven T, Banerji MA, et al.; management on the progression of diabetic ret- Disease Study Group. A more accurate method ACCORD Trial Group. Effect of intensive treat- inopathy in persons with type 2 diabetes: the to estimate glomerular fi ltration rate from se- ment of hyperglycaemia on microvascular out- Action to Control Cardiovascular Risk in Diabe- rum creatinine: a new prediction equation. Ann comes in type 2 diabetes: an analysis of the tes (ACCORD) Eye Study. Ophthalmology 2014; Intern Med 1999;130:461 – 470 ACCORD randomised trial. Lancet 2010;376: 2451 – 121:2443 5. National Kidney Foundation. KDOQI clinical 32. Chew EY, Ambrosius WT, Davis MD, et al.; 430 – 419 practice guideline for diabetes and CKD: 2012 18. Skupien J, Warram JH, Smiles A, Galecki A, ACCORD Study Group; ACCORD Eye Study – 886 update. Am J Kidney Dis 2012;60:850 Stanton RC, Krolewski AS. Improved glycemic Group. Effects of medical therapies on retinop- 6. Krolewski AS, Niewczas MA, Skupien J, et al. RD in patients with control and risk of ES athy progression in type 2 diabetes. N Engl J Early progressive renal decline precedes the onset type 1 diabetes and proteinuria. J Am Soc Neph- 244 Med 2010;363:233 – of microalbuminuria and its progression to macro- 33. Fong DS, Aiello LP, Ferris FL 3rd, Klein R. rol 2014;25:2916 – 2925 albuminuria. Diabetes Care 2014;37:226 – 234 19. Lipska KJ, Bailey CJ, Inzucchi SE. Use of met- Diabetic retinopathy. Diabetes Care 2004;27: 7. Garg JP, Bakris GL. Microalbuminuria: formin in the setting of mild-to-moderate renal 2553 – 2540 marker of vascular dysfunction, risk factor for 34. Diabetes Control and Complications Trial Re- fi ciency. Diabetes Care 2011;34:1431 insuf – 43 cardiovascular disease. Vasc Med 2002;7:35 – search Group. Effect of pregnancy on microvascular 1437 8. Klausen K, Borch-Johnsen K, Feldt-Rasmussen 20. Emdin CA, Rahimi K, Neal B, Callender T, complications in the diab etes control and compli- B, et al. Very low levels of microalbuminuria are Perkovic V, Patel A. Blood pressure lowering in cations trial. Diabetes Care 2000;23:1084 – 1091 associated with increased risk of coronary heart 35. Agardh E, Tababat-Khani P. Adopting 3-year type 2 diabetes: a systematic review and meta- disease and death independently of renal screening intervals for sight-threatening retinal – analysis. JAMA 2015;313:603 615

87 Volume 39, Supplement 1, January 2016 Diabetes Care S80 Microvascular Complications and Foot Care vascular lesions in type 2 diabetic subjects with- 49. Martin CL, Albers JW, Pop-Busui R; DCCT/ and Complications study (DCCT/EDIC). Circula- – out retinopathy. Diabetes Care 2011;34:1318 EDIC Research Group. Neuropathy and related – tion 2009;119:2886 2893 1319 ndings in the Diabetes Control and Complica- fi 59. Callaghan BC, Little AA, Feldman EL, Hughes 36. Bragge P, Gruen RL, Chau M, Forbes A, tions Trial/Epidemiology of Diabetes Interven- ntrol for preventing RA. Enhanced glucose co Taylor HR. Screening for presence or absence tions and Complications study. Diabetes Care and treating diabetic neuropathy. Cochrane Da- of diabetic retinopathy: a meta-analysis. Arch 38 2014;37:31 – tabase Syst Rev 2012;6:CD007543 444 Ophthalmol 2011;129:435 – 50. Bril V, England J, Franklin GM, et al.; Amer- 60. Riddle MC, Ambrosius WT, Brillon DJ, et al.; 37. Ahmed J, Ward TP, Bursell S-E, Aiello LM, ican Academy of Neurology; American Associa- Action to Control Cardiovascular Risk in Diabe- Cavallerano JD, Vigersky RA. The sensitivity and tion of Neuromuscular and Electrodiagnostic tes Investigators. Epidemiologic relationships city of nonmydriatic digital stereoscopic speci fi Medicine; American Academy of Physical Med- between A1C and all-cause mortality during a retinal imaging in detecting diabetic retinopa- icine and Rehabilitation. Evidence-based guide- median 3.4-year follow-up of glycemic treat- 2209 thy. Diabetes Care 2006;29:2205 – line: treatment of painful diabetic neuropathy: ment in the ACCORD trial. Diabetes Care 2010; 38. Hooper P, Boucher MC, Cruess A, et al. report of the American Academy of Neurology, 33:983 – 990 Canadian Ophthalmological Society evidence- the American Association of Neuromuscular 61. Sadosky A, Schaefer C, Mann R, et al. based clinical practice guidelines for the and Electrodiagnostic Medicine, and the Amer- Burden of illness associated with painful di- management of diabetic retinopathy. Can J ican Academy of Physical Medicine and Rehabil- abetic peripheral neuropathy among adults Ophthalmol 2012;47(Suppl. 2):S1 S54 – S30, S31 – itation. Neurology 2011;76:1758 1765 – seeking treatment in the US: results from 39. Axer-Siegel R, Hod M, Fink-Cohen S, et al. 51. Freeman R. Not all neuropathy in diabetes is a retrospective chart review and cross-sectional Diabetic retinopathy during pregnancy. Oph- of diabetic etiology: differential diagnosis of dia- survey. Diabetes Metab Syndr Obes 2013;6: 92 1819 thalmology 1996;103:1815 – betic neuropathy. Curr Diab Rep 2009;9:423 431 – 79 – 62. Snedecor SJ, Sudharshan L, Cappelleri JC, 40. Best RM, Chakravarthy U. Diabetic retinop- 52. Pop-Busui R, Evans GW, Gerstein HC, et al.; Sadosky A, Mehta S, Botteman M. Systematic athy in pregnancy. Br J Ophthalmol 1997;81: Action to Control Cardiovascular Risk in Diabetes review and meta-analysis of pharmacological 251 249 – Study Group. Effects of cardiac autonomic dys- therapies for painful diabetic peripheral neu- 41. Gunderson EP, Lewis CE, Tsai A-L, et al. A function on mortality risk in the Action to Control ropathy. Pain Pract 2014;14:167 – 184 20-year prospective study of childbearing and Cardiovascular Risk in Diabetes (ACCORD) trial. 63. Boulton AJM, Vinik AI, Arezzo JC, et al.; incidence of diabetes in young women, control- 1584 – Diabetes Care 2010;33:1578 American Diabetes Association. Diabetic neu- ling for glycemia before conception: the Coro- 53. Young LH, Wackers FJT, Chyun DA, et al.; ropathies: a statement by the American Diabe- nary Artery Risk Development in Young Adults DIAD Investigators. Cardiac outcomes after tes Association. Diabetes Care 2005;28:956 – 2996 – (CARDIA) study. Diabetes 2007;56:2990 screening for asymptomatic coronary artery dis- 962 42. The Diabetic Retinopathy Study Research ease in patients with type 2 diabetes: the DIAD 64. Griebeler ML, Morey-Vargas OL, Brito JP, Group. Preliminary report on effects of photo- study: a randomized controlled trial. JAMA et al. Pharmacologic interventions for painful coagulation therapy. Am J Ophthalmol 1976;81: – 1555 2009;301:1547 diabetic neuropathy: an umbrella systematic re- 383 – 396 54. U.S. Food and Drug Administration. FDA ap- view and comparative effectiveness network 43. Early Treatment Diabetic Retinopathy proves breath test to aid in diagnosis of delayed meta-analysis. Ann Intern Med 2014;161:639 – Study Research Group. Photocoagulation for di- gastric emptying [Internet], 2015. Available from 649 abetic macular edema. Early Treatment Diabetic http://www.fda.gov/NewsEvents/Newsroom/ 65. Ziegler D, Fonseca V. From guideline to pa- Retinopathy Study report number 1. Arch Oph- PressAnnouncements/ucm441370.htm.Accessed tient: a review of recent recommendations for thalmol 1985;103:1796 – 1806 28 July 2015 pharmacotherapy of painful diabetic neuropa- 44. Elman MJ, Aiello LP, Beck RW, et al.; Dia- 55. Diabetes Control and Complications Trial 156 – thy. J Diabetes Complications 2015;29:146 betic Retinopathy Clinical Research Network. (DCCT) Research Group. Effect of intensive di- 66. U.S. Food and Drug Administration. FDA re- Randomized trial evaluating ranibizumab plus abetes treatment on nerve conduction in the quires boxed warning and risk mitigation strategy prompt or deferred laser or triamcinolone plus Diabetes Control and Complications Trial. Ann for metoclopramide-containing drugs [Internet], prompt laser for diabetic macular edema. Oph- – Neurol 1995;38:869 880 2009. Available from http://www.fda.gov/ thalmology 2010;117:1064 – 1077.e35 56. Diabetes Control and Co mplications Trial Re- newsevents/newsroom/pressannouncements/ 45. Mitchell P, Bandello F, Schmidt-Erfurth U, search Group. The effect of intensive diabetes ther- ucm149533.htm. Accessed 6 July 2015 et al.; RESTORE Study Group. The RESTORE study: apy on measures of autonomic nervous system 67. Boulton AJM, Armstrong DG, Albert SF, ranibizumab monotherapy or combined with la- function in the Diabetes Control and Complications et al.; American Diabetes Association; American ser versus laser monotherapy for diabetic macu- 423 – Trial (DCCT). Diabetologia 1998;41:416 Association of Clinical Endocrinologists. Com- 625 lar edema. Ophthalmology 2011;118:615 – 57. Albers JW, Herman WH, Pop-Busui R, et al.; prehensive foot examination and risk assess- 46. Elman MJ, Bressler NM, Qin H, et al.; Dia- Diabetes Control and Complications Trial/Epi- ment: a report of the task force of the foot betic Retinopathy Clinical Research Network. demiology of Diabetes Interventions and Com- care interest group of the American Diabetes Expanded 2-year follow-up of ranibizumab plications Research Group. Effect of prior Association, with endorsement by the American plus prompt or deferred laser or triamcinolone intensive insulin treatment during the Diabetes Association of Clinical Endocrinologists. Diabe- plus prompt laser for diabetic macular edema. Control and Complications Trial (DCCT) on pe- 1685 tes Care 2008;31:1679 – Ophthalmology 2011;118:609 – 614 ripheral neuropathy in type 1 diabetes during 68. American Diabetes Association. Peripheral 47. Nguyen QD, Brown DM, Marcus DM, et al.; the Epidemiology of Diabetes Interventions and arterial disease in people with diabetes. Diabe- RISE and RIDE Research Group. Ranibizumab for Complications (EDIC) Study. Diabetes Care tes Care 2003;26:3333 3341 – diabetic macular edema: results from 2 phase III – 2010;33:1090 1096 69. Lipsky BA, Berendt AR, Cornia PB, et al.; In- randomized trials: RISE and RIDE. Ophthalmol- 58. Pop-Busui R, Low PA, Waberski BH, et al.; fectious Diseases Society of America. 2012 In- 801 – ogy 2012;119:789 DCCT/EDIC Research Group. Effects of prior in- fectious Diseases Soci ety of America clinical 48. Ang L, Jaiswal M, Martin C, Pop-Busui R. tensive insulin therapy on cardiac autonomic practice guideline for the diagnosis and treat- Glucose control and diabetic neuropathy: les- nervous system function in type 1 diabetes mel- ment of diabetic foot infections. Clin Infect Dis sons from recent large clinical trials. Curr Diab litus: the Diabetes Control and Complications 2012;54:e132 – e173 Rep 2014;14:528 Trial/Epidemiology of Diabetes Interventions

88 Diabetes Care Volume 39, Supplement 1, January 2016 S81 American Diabetes Association 10. Older Adults Diabetes Care 2016;39(Suppl. 1):S81 S85 | DOI: 10.2337/dc16-S013 – Recommendations c Consider the assessment of medical, functional, mental, and social geriatric domains for diabetes management in older adults to provide a framework to E determine targets and therapeutic approaches. Screening for geriatric syndromes may be appropriate in older adults experi- c encing limitations in their basic and instrumental activities of daily living, as E they may affect diabetes self-management. 65 years of age) with diabetes should be considered a high- $ Older adults ( c B priority population for depression screening and treatment. c Hypoglycemia should be avoided in older adults with diabetes. It should be screened for and managed by adjusting glycemic targets and pharmacological 10. OLDER ADULTS B interventions. cant life Older adults who are functional and cognitively intact and have signi c fi expectancy may receive diabetes care with goals similar to those developed for E younger adults. Glycemic goals for some older adults might reasonably be relaxed, using indi- c vidual criteria, but hyperglycemia leading to symptoms or risk of acute hyper- E glycemic complications should be avoided in all patients. Screening for diabetes complications should be individualized in older adults, c but particular attention should be paid to complications that would lead to E functional impairment. c Other cardiovascular risk factors should be treated in older adults with con- fi sideration of the time frame of bene t and the individual patient. Treatment of hypertension is indicated in virtually all older adults, and lipid-lowering and t those with life expectancy at least equal to the fi aspirin therapy may bene E time frame of primary or secondary prevention trials. When palliative care is needed in older adults with diabetes, strict blood c pressure control may not be necessary, and withdrawal of therapy may be appropriate. Similarly, the intensity of lipid management can be relaxed, and E withdrawal of lipid-lowering therapy may be appropriate. c Consider diabetes education for the staff of long-term care facilities to improve E the management of older adults with diabetes. Patients with diabetes residing in long-term care facilities need careful assess- c ment to establish a glycemic goal and to make appropriate choices of glucose- E lowering agents based on their clinical and functional status. Overall comfort, preventionof distressingsymptoms, and preservation of quality c E of life and dignity are primary goals for diabetes management at the end of life. OVERVIEW ; Diabetes is an important health condition for the aging population; 26% of pa- tients over the age of 65 years have diabetes (1), and this number is expected to grow rapidly in the coming decades. Older individuals with diabetes have higher bility, and coexisting illnesses, such as rates of premature death, functional disa Suggested citation: American Diabetes Associa- hypertension, coronary heart disease, and stroke, than those without diabetes. Older tion. Older adults. Sec. 10. In Standards of Med- adults with diabetes also are at a greater risk than other older adults for several ical Care in Diabetes d 2016 . Diabetes Care common geriatric syndromes, such as polypharmacy, cognitive impairment, urinary 2016;39(Suppl. 1):S81 S85 – incontinence, injurious falls, and persistent pain. Screening for diabetes complications © 2016 by the American Diabetes Association. in older adults also should be individualized and periodically revisited, since the results Readers may use this article as long as the work of screening tests may impact therapeutic approaches and targets. Older adults are at is properly cited, the use is educational and not for pro t, and the work is not altered. fi increased risk for depression and should therefore be screened andtreatedaccordingly

89 Volume 39, Supplement 1, January 2016 Diabetes Care S82 Older Adults (2). Diabetes management may require no complications. Some older adults maintain cognitive function in older assessment of medical, functional, mental, with diabetes are frail and have other adults. However, studies examining the and social domains. This may provide a underlying chronic conditions, substan- effects of intensive glycemic and blood framework to determine targets and tial diabetes-related comorbidity, or c tar- pressure control to achieve speci fi therapeutic approaches. Particular at- limited physical or cognitive function- gets have not demonstrated a reduction tention should be paid to complications ing. Other older individuals with diabe- in brain function decline (12). that can develop over short periods of tes have little comorbidity and are Older adults with diabetes should be time and/or that would signi cantly fi active. Life expectancies are highly vari- carefully screened and monitoredfor cog- impair functional status, such as visual able for this population but are often nitive impairment (3). Several organiza- and lower-extremity complications. Please longer than clinicians realize. Providers tions have released simple assessment refer to the American Diabetes Associa- caring for older adults with diabetes tools, such as the Mini-Mental State Ex- tion (ADA) consensus report Diabetes in “ must take this heterogeneity into con- amination (MMSE) and the Montreal Older Adults for details (3). ” sideration when setting and prioritizing Cognitive Assessment (MoCA), which ). Table 10.1 treatment goals ( may help to identify patients requiring NEUROCOGNITIVE FUNCTION neuropsychological evaluation, particu- Healthy Patients With Good larly those in whom dementia is sus- Older adults with diabetes are at higher Functional Status pected (i.e., experiencing memory loss risk of cognitive decline and institution- There are few long-term studies in and decline in their basic and instrumen- alization (4,5). The presentation of cog- older adults demonstrating the bene- tal activities of daily living). nitive impairment ranges from subtle ts of intensive glycemic, blood pres- fi executive dysfunction to memory loss sure, and lipid control. Patients who HYPOGLYCEMIA and overt dementia. Diabetes increases can be expected to live long enough the incidence of all-cause dementia, It is important to prevent hypoglycemia to reap the bene ts of long-term inten- fi Alzheimer disease, and vascular demen- to reduce the risk of cognitive decline sive diabetes management, who have tia when compared with rates in people and to carefully assess and reassess pa- good cognitive and physical function, with normal glucose tolerance (6). The tients ’ risk for worsening of glycemic and who choose to do so via shared de- effects of hyperglycemia and hyperinsu- control and functional decline. Older cision making may be treated using linemia on the brain are areas of intense adults are at higher risk of hypoglycemia therapeutic interventions and goals research interest. Clinical trials of spe- for many reasons, including insulin de- similar to those for younger adults including cholines- d c interventions ci fi ciency and progressive renal insuf fi fi - with diabetes. As with all patients terase inhibitors and glutamatergic ciency. In addition, older adults tend to with diabetes, diabetes self-management antagonists have not shown positive d fi ed cogni- have higher rates of unidenti education and ongoing diabetes self- therapeutic bene fi t in maintaining or cits, causing dif fi culty in com- tive de fi management support are vital compo- cantly improving cognitive func- fi signi plex self-care activities (e.g., glucose nents of diabetes care for older adults tion or in preventing cognitive decline monitoring, adjusting insulin doses, and their caregivers. (7). Recent pilot studies in patients etc.). These de cits have been associ- fi with mild cognitive impairment evaluat- ated with increased risk of hypoglyce- Patients With Complications and ts of intranasal fi ing the potential bene mia and with severe hypoglycemia Reduced Functionality insulin therapy or metformin therapy linked to increased dementia. There- For patients with advanced diabetes com- provide insights for future clinical trials fore, it is important to routinely screen plications, life-limiting comorbid illness, or and mechanistic studies (8 – 10). older adults for cognitive dysfunction substantial cognitive or functional impair- The presence of cognitive impairment and discuss ndings with the caregivers. fi ment, it is reasonable to set less intensive can make it challenging for clinicians to Hypoglycemic events should be dili- glycemic target goals. These patients are help their patients to reach individual- gently monitored and avoided, whereas t fromreducingthe risk fi less likely to bene ized glycemic, blood pressure, and lipid glycemic targets and pharmacological of microvascular complications and more targets. Cognitive dysfunction makes it interventions may need to be adjusted likely to suffer serious adverse effects fi dif cult for patients to perform complex to accommodate for the changing needs from hypoglycemia. However, patients self-care tasks, such as glucose monitor- of the older adult (3). with poorly controlled diabetes may be ing and adjusting insulin doses. It also subject to acute complications of diabe- TREATMENT GOALS hinders their ability to appropriately tes, including dehydration, poor wound maintain the timing and content of diet. Rationale healing, and hyperglycemic hyperosmolar The care of older adults with diabetes is When clinicians are managing these coma. Glycemic goals at a minimum complicated by their clinical and func- types of patients, it is critical to simplify should avoid these consequences. tional heterogeneity. Some older indi- drug regimens and to involve caregivers viduals may have developed diabetes in all aspects of care. Vulnerable Patients at the End of Life For patients receiving palliative care and years earlier and have signi cant com- fi Poor glycemic control is associated end-of-life care, the focus should be to plications, others are newly diagnosed with a decline in cognitive function (11), avoid symptoms and complications from and may have had years of undiagnosed and longer duration of diabetes worsens glycemic management. Thus, when organ diabetes with resultant complications, cognitive function. There are ongoing failure develops, several agents will have and still other older adults may have studies evaluating whether preventing to be titrated or discontinued. For the truly recent-onset disease with few or or delaying diabetes onset may help to

90 Older Adults S83 care.diabetesjournals.org — Framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia in older adults with Table 10.1 diabetes Patient Fasting or preprandial characteristics/ Reasonable A1C Rationale glucose goal ‡ Bedtime glucose Blood pressure Lipids health status – 90 – 90 7.5% , Longer remaining Healthy (few coexisting 130 mg/dL 140/90 mmHg Statin unless , 150 mg/dL (5.0 7.2 mmol/L) life expectancy (58 mmol/mol) (5.0 – chronic illnesses, intact contraindicated – 8.3 mmol/L) cognitive and functional or not tolerated status) 90 – 8.0% Complex/intermediate , 150 mg/dL , 100 Intermediate – 140/90 mmHg Statin unless 180 mg/dL (multiple coexisting (5.0 – (64 mmol/mol) 8.3 mmol/L) 10.0 mmol/L) – (5.6 remaining life contraindicated chronic illnesses* or expectancy, high or not tolerated 2 1 instrumental ADL treatment burden, hypoglycemia impairments or mild-to- vulnerability, moderate cognitive impairment) fall risk , , 200 mg/dL – 110 150/90 mmHg Consider Very complex/poor health Limited remaining 180 mg/dL – 100 8.5% † (LTC or end-stage chronic (69 mmol/mol) – 11.1 mmol/L) likelihood of life expectancy (5.6 10.0 mmol/L) – (6.1 twith fi illnesses** or moderate- fi bene t makes bene statin(secondary uncertain to-severe cognitive prevention more impairment or 2 ADL 1 so than primary) dependencies) . The patient This represents a consensus framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia in older adults with diabetes iver preferences is an characteristic categories are general concepts. Not every patient will cl early fall into a particular category. Consideration of patient and careg ’ s health status and preferences may change over time. ADL, activities of daily living. dualization. Additionally, a patient important aspect of treatment indivi A lower A1C goal may be set for an individual if achievable without recurrent or severe hypoglycemia or undue treatment burden. ‡ *Coexisting chronic illnesses are conditions serious enough to require medications or lifestyle management and may include arthritis, cancer, ion, congestive heart failure, depression, emphysema, falls, hypertension, incontinence, stage 3 or worse chronic kidney disease, myocardial infarct multiple, ” we mean at least three, but many patients may have fi ve or more (27). and stroke. By “ – 4 congestive heart failure or oxygen-dependent lung disease, chronic kidney disease requiring **The presence of a single end-stage chronic illness, such as stage 3 fi fi cantly reduce life expectancy. dialysis, or uncontrolled metastatic cancer, may cause signi cant symptoms or impairment of functional status and signi † A1C of 8.5% (69 mmol/mol) equates to an estimated average glucose of ; 200 mg/dL (11.1 mmol/L). Looser A1C targets above 8.5% (69 mmol/mol) are not recommended as they may expose patients to more frequent higher glucose values and the acute risks from glycosuria, dehydration, hyperglycemic hyperosmolar syndrome, and poor wound healing. Insulin Sensitizers dying patient most agents for type 2 di- hypoglycemia, and its use requires that fi rst-line agent in older Metformin is the abetes may be removed. There is, how- patients or caregivers have good visual adults with type 2 diabetes. However, it ever, no consensus for the management and motor skills and cognitive ability. is contraindicated in patients with renal of type 1 diabetes in this scenario (13,14). Incretin-Based Therapies fi insuf cant heart failure. fi ciency or signi Glucagon-like peptide 1 receptor ago- Since serum creatinine levels do not ad- Beyond Glycemic Control nists and dipeptidyl peptidase 4 inhibi- Although hyperglycemia control may be ect renal function in older equately re fl tors have few side effects, but their important in older individuals with dia- people (muscle mass losses are associ- costs may be a barrier to some older betes, greater reductions in morbidity ated with chronic conditions and func- patients. A systematic review concluded and mortality are likely to result from tional decline), a timed urine collection that incretin-based agents do not in- control of other cardiovascular risk fac- to assess creatinine clearance has been crease major adverse cardiovascular tors rather than from tight glycemic con- recommended, particularly in those events (19). Glucagon-like peptide 1 trol alone. There is strong evidence from 80 years. Metformin may be aged $ receptor agonists are injectable agents, clinical trials of the value of treating hy- temporarily discontinued before proce- which require visual, motor, and cogni- pertension in the elderly (15,16). There is dures, during hospitalizations, and tive skills. less evidence for lipid-lowering and aspirin when acute illness may compromise re- therapy, although the bene fi ts of these in- nal or liver function. Thiazolidinediones, Sodium – Glucose Cotransporter 2 terventions for primary and secondary if used at all, should be used very cau- Inhibitors prevention are likely to apply to older tiously in those with, or at risk for, con- Sodium – glucose cotransporter 2 inhibi- adults whose life expectancies equal or ex- gestive heart failure and have been tors offer an oral route, which may be ceed the time frames seen in clinical trials. associated with fractures. convenient for older adults with diabe- tes; however, long-term experience is PHARMACOLOGICAL THERAPY Insulin Secretagogues cacy and fi limited despite the initial ef Sulfonylureas and other insulin secre- Special care is required in prescribing safety data reported with these agents. tagogues are associated with hypo- and monitoring pharmacological ther- glycemia and should be used with apy in older adults (17). Cost may be a Other Factors to Consider The needs of older adults with diabetes cant factor, especially as older caution. Glyburide is contraindicated signi fi and their caregivers should be evaluated adults tend to be on many medications. in older adults (18). Insulin can also cause

91 Volume 39, Supplement 1, January 2016 Diabetes Care S84 Older Adults END-OF-LIFE CARE to construct a tailored care plan. Social intake and contribute to unintentional fi culties may impair their quality of dif weight loss and undernutrition. Diets tai- The management of the older adult at life and increase the risk of functional lored to a patient s culture, preferences, ’ the end of life receiving palliative medi- dependency. The patient s living situa- ’ and personal goals might increase qual- cine or hospice is a unique situation. tion must be considered, as it may affect ity of life, satisfaction with meals, and Overall, palliative medicine promotes diabetes management and support. nutrition status (22). comfort, symptom control, and preven- Older adults in assisted living facilities tion (pain, hypoglycemia and hyperglyce- may not have support to administer Hypoglycemia mia, dehydration) and preservation of their own medications, whereas those Older adults with diabetes in LTC are dignity and quality of life in patients living in a nursing home (community liv- especially vulnerable to hypoglycemia. with limited life expectancy (21,24). A pa- ing centers) may rely completely on the They have a disproportionately high tient has the right to refuse testing and care plan and nursing support. Those re- number of clinical complications and co- treatment, whereas providers may con- ceiving palliative care (with or without morbidities that can increase hypogly- sider withdrawing treatment and limiting hospice) may require an approach that ed renal function, cemia risk: impair diagnostic testing, including a reduction emphasizes comfort and symptom man- slowed hormonal regulation and coun- nger-stick testing fi in the frequency of agement, while deemphasizing strict terregulation, and suboptimal hydra- (25). Glucose targets should aim to pre- metabolic and blood pressure control. tion, variable appetite and nutritional vent hypoglycemia and hyperglycemia. intake, polypharmacy, and slowed intes- Treatment interventions need to be TREATMENT IN SKILLED NURSING tinal absorption (23). mindful of quality of life. Careful monitor- FACILITIES AND NURSING HOMES Another consideration for the LTC set- ing of oral intake is warranted. The de- Management of diabetes in the long- ting is that unlike the hospital setting, cision process may need to involve the term care (LTC) setting (i.e., nursing medical providers are not required to patient, family, and caregivers, leading homes and skilled nursing facilities) is evaluate the patients daily. According to a care plan that is both convenient unique. Individualization of health care to federal guidelines, assessments and effective for the goals of care (26). is important in all patients; however, should be done at least every 30 days The pharmacological therapy may in- practical guidance is needed for medical fi for the rst 90 days after admission rst line, followed clude oral agents as fi providersaswellastheLTCstaffand and then at least once every 60 days. fi ed insulin regimen. If needed, by a simpli caregivers. The American Medical Di- Although in practice the patients may basal insulin can be implemented, ac- rectors Association (AMDA) guidelines actually be seen more frequently, the companied by oral agents and without offer a 12-step program for staff (20). concern is that patients may have uncon- rapid-acting insulin. Agents that can This training includes diabetes detection trolled glucose levels or wide excursions cause gastrointestinal symptoms such and institutional quality assessment. It fi without the practitioner being noti ed. as nausea or excess weight loss may not is also recommended that LTC facilities Providers may make adjustments to be good choices in this setting. As symp- develop their own policies and proce- treatment regimens by telephone, toms progress, some agents may be dures for prevention and management fax, or order directly at the LTC facili- slowly tapered down and discontinued. of hypoglycemia. ties provided they are given timely no- Strata have been proposed for diabe- cation from a standardized alert fi ti Resources tes management in those with advanced system. Staff of LTC facilities should receive ap- disease (14). The following alert strategy could be propriate diabetes education to improve considered: the management of older adults with di- 1. A stable patient :continuewiththe abetes. Major organizations such as the patient ’ s previous regimen, with a Call provider immediately :incase 1. ADA, the American Geriatrics Society focus on the prevention of hypogly- of hypoglycemia ( , 70 mg/dL (AGS), the International Association of cemia and the management of hy- [3.9 mmol/L]). Low nger-stick blood fi Gerontology and Geriatrics (IAGG), and perglycemia, keeping levels below glucose values should be con rmed fi the European Diabetes Working Party the renal threshold of glucose. There by laboratory glucose measurement. for Older People (EDWPOP) concur with is very little role for A1C monitoring :a)glucose Call as soon as possible 2. the AMDA on the need to individualize and lowering. values between 70 and 100 mg/dL treatments for each patient, the need to : pre- 2. A patient with organ failure (between 3.9 and 5.6 mmol/L) avoid both hypoglycemia and the meta- venting hypoglycemia is of greater (regimen may need to be adjusted), bolic complications of diabetes, and the cance.Dehydrationmust bepre- fi signi b) glucose values greater than need to provide adequate diabetes train- vented and handled. In people with 250 mg/dL (13.9 mmol/L) within a ing to LTC staff (3,21). type 1 diabetes, insulin administration 24-h period, c) glucose values greater may be reduced as the oral intake of than 300 mg/dL (16.7 mmol/L) within Nutrition Considerations food decreases. For those with type 2 An older adult residing in an LTC facility 2 consecutive days, d) or when any diabetes, agents that may cause hypo- may have irregular and unpredictable reading is too high, e) or the patient glycemia should be titrated. The main meal consumption, undernutrition, an- is sick, with vomiting or other malady goal is to avoid hypoglycemia, allow- orexia, and impaired swallowing. Fur- ect hyperglycemic crisis, that can re fl ing for glucose values in the upper thermore, therapeutic diets may may lead to poor oral intake, and thus level of the desired target range. inadvertently lead to decreased food requires regimen adjustment.

92 Older Adults S85 care.diabetesjournals.org amnestic mild cognitive impairment: a pilot clin- 19. Rotz ME, Ganetsky VS, Sen S, Thomas TF. : for patients with A dying patient 3. ical trial. Arch Neurol 2012;69:29 – 38 Implicationsofincretin-basedtherapiesoncardio- type 2 diabetes, the discontinuation 9. Freiherr J, Hallschmid M, Frey WH 2nd, et al. vascular disease. Int J Clin Pract 2015;69:531 – 549 of all medications may be a pertinent Intranasal insulin as a treatment for Alzheimer s ’ 20. American Medical Directors Association. approach, as they are unlikely to have disease: a review of basic research and clinical Diabetes management in the long-term care any oral intake. In patients with type 1 – 514 evidence. CNS Drugs 2013;27:505 setting [Internet]. Available from http://www 10. Alagiakrishnan K, Sankaralingam S, Ghosh .amda.com/tools/guidelines.cfm#diabetes. Ac- diabetes, there is no consensus, but a M, Mereu L, Senior P. Antidiabetic drugs and cessed 5 October 2015 small amount of basal insulin may their potential role in treating mild cognitive ~ 21. Sinclair A, Morley JE, Rodriguez-Ma nas L, maintain glucose levels and prevent impairment and Alzheimer s disease. Discov ’ et al. Diabetes mellitus in older people: position acute hyperglycemic complications. 286 – Med 2013;16:277 statement on behalf of the International Asso- 11. Yaffe K, Falvey C, Hamilton N, et al. Diabe- ciation of Gerontology and Geriatrics (IAGG), tes, glucose control, and 9-year cognitive de- the European Diabetes Working Party for Older References cline among older adults without dementia. People (EDWPOP), and the International Task 1. Centers for Disease Control and Prevention. Arch Neurol 2012;69:1170 1175 – Force of Experts in Diabetes. J Am Med Dir Assoc National diabetes statistics report: estimates of – 502 2012;13:497 12. Launer LJ, Miller ME, Williamson JD, et al.; diabetes and its burden in the United States, ACCORD MIND Investigators. Effects of inten- 22. Dorner B, Friedrich EK, Posthauer ME. Prac- 2014 [Internet]. Available from http://www.cdc sive glucose lowering on brain structure and tice paper of the American Dietetic Association: .gov/diabetes/data/statistics/2014statisticsreport function in people with type 2 diabetes individualized nutrition approaches for older .html. Accessed 1 October 2015 (ACCORD MIND): a randomised open-label sub- adults in health care communities. J Am Diet 2. Kimbro LB, Mangione CM, Steers WN, et al. – study. Lancet Neurol 2011;10:969 977 1563 – Assoc 2010;110:1554 Depression and all-cause mortality in persons 13. Sinclair A, Dunning T, Colagiuri S. Managing 23. Migdal A, Yarandi SS, Smiley D, Umpierrez with diabetes mellitus: are older adults at older people with type 2 diabetes: global guide- GE. Update on diabetes in the elderly and in higher risk? Results from the Translating line. International Diabetes Federation, 2013 nursing home residents. J Am Med Dir Assoc Research Into Action for Diabetes Study. J Am 632.e2 – 2011;12:627 14. Angelo M, Ruchalski C, Sproge BJ. An ap- – 1022 Geriatr Soc 2014;62:1017 proach to diabetes mellitus in hospice and pal- 24. Quinn K, Hudson P, Dunning T. Diabetes man- 3. Kirkman MS, Briscoe VJ, Clark N, et al. Diabe- 87 – liative medicine. J Palliat Med 2011;14:83 agement in patients receiving palliative care. tes in older adults. Diabetes Care 2012;35: 15. Beckett NS, Peters R, Fletcher AE, et al.; J Pain Symptom Manage 2006;32:275 – 286 – 2650 2664 HYVET Study Group. Treatment of hypertension 25. Ford-Dunn S, Smith A, Quin J. Management 4. Cukierman T, Gerstein HC, Williamson JD. in patients 80 years of age or older. N Engl J Med of diabetes during the last days of life: attitudes Cognitive decline and dementia in diabetes: sys- 1898 – 2008;358:1887 of consultant diabetologists and consultant pal- tematic overview of prospective observational liative care physicians in the UK. Palliat Med 16. James PA, Oparil S, Carter BL, et al. 2014 2469 – studies. Diabetologia 2005;48:2460 – 203 2006;20:197 evidence-based guideline for the management 5. Roberts RO, Knopman DS, Przybelski SA, of high blood pressure in adults: report from 26. Mallery LH, Ransom T, Steeves B, Cook B, et al. Association of type 2 diabetes with brain the panel members appointed to the Eighth Dunbar P, Moorhouse P. Evidence-informed atrophy and cognitive impairment. Neurology Joint National Committee (JNC 8). JAMA 2014; guidelines for treating frail older adults with – 2014;82:1132 1141 520 – 311:507 type 2 diabetes: from the Diabetes Care Pro- 6. Xu WL, von Strauss E, Qiu CX, Winblad B, 17. Valencia WM, Florez H. Pharmacological gram of Nova Scotia (DCPNS) and the Palliative Fratiglioni L. Uncontrolled diabetes increases the treatment of diabetes in older people. Diabetes and Therapeutic Harmonization (PATH) pro- s disease: a population-based ’ risk of Alzheimer Obes Metab 2014;16:1192 – 1203 808 – gram. J Am Med Dir Assoc 2013;14:801 cohort study. Diabetologia 2009;52:1031 – 1039 18. Campanelli CM; American Geriatrics Society 7. Ghezzi L, Scarpini E, Galimberti D. Disease- 27. Laiteerapong N, Iveniuk J, John PM, 2012 Beers Criteria Update Expert Panel. Ameri- modifying drugs in Alzheimer ’ sdisease.Drug cation of older Laumann EO, Huang ES. Classi fi can Geriatrics Society updated Beers Criteria for Des Devel Ther 2013;7:1471 1478 – adults who have diabetes by comorbid condi- potentially inappropriate medication use in older 8. Craft S, Baker LD, Montine TJ, et al. Intranasal tions, United States, 2005-2006. Prev Chronic adults. J Am Geriatr Soc 2012;60:616 – 631 insulin therapy for Alzheimer disease and Dis 2012;9:E100

93 S86 Diabetes Care Volume 39, Supplement 1, January 2016 American Diabetes Association 11. Children and Adolescents Diabetes Care 2016;39(Suppl. 1):S86 S93 | DOI: 10.2337/dc16-S014 – TYPE 1 DIABETES 18 years , Three-quarters of all cases of type 1 diabetes are diagnosed in individuals of age. The provider must consider the unique aspects of care and management of children and adolescents with type 1 diabetes, such as changes in insulin sensitivity related to physical growth and sexual maturation, ability to provide self-care, su- pervision in the child care and school environment, and neurological vulnerability to hypoglycemia and hyperglycemia in young children, as well as possible adverse neurocognitive effects of diabetic ketoacidosis (1,2). Attention to family dynamics, developmental stages, and physiological differences related to sexual maturity are all essential in developing and implementing an optimal diabetes regimen (3). Due to the paucity of clinical research in children, the recommendations for children and adolescents are less likely to be based on clinical trial evidence. However, expert opinion and a review of available and relevant experimental data are summarized in the American Diabetes Association (ADA) position statement “ Care of Children and (4) and have been updated in the ADA position ” Adolescents With Type 1 Diabetes statement (5). ” Type 1 Diabetes Through the Life Span “ A multidisciplinary team of specialists trained in pediatric diabetes management and sensitive to the challenges of children and adolescents with type 1 diabetes and their families should provide care for this population. It is essential that diabetes 11. CHILDREN AND ADOLESCENTS self-management education (DSME) and support (DSMS), medical nutrition ther- apy, and psychosocial support be provided at diagnosis and regularly thereafter by individuals experienced with the educational, nutritional, behavioral, and emotional needs of the growing child and family. The appropriate balance between adult fi ned at the rst interaction fi supervision and independent self-care should be de and reevaluated at subsequent clinic visits. The balance between adult supervision s the adolescent gradually becomes an and independent self-care will evolve a emerging young adult. Diabetes Self-management Education and Support Recommendation 18 , Youth with type 1 diabetes and parents/caregivers (for patients aged c years) should receive culturally sensitive and developmentally appropriate individualized diabetes self-management education and support according to national standards at diagnosis and routinely thereafter. B No matter how sound the medical regimen, it can only be effective if the family and/ or affected individuals are able to implement it. Family involvement is a vital com- ponent of optimal diabetes management throughout childhood and adolescence. Health care providers (the diabetes care team) who care for children and adoles- cents must be capable of evaluating the educational, behavioral, emotional, and psychosocial factors that impact implementation of a treatment plan and must work ne goals as appropriate. with the individual and family to overcome barriers or rede fi ent, especially as the youth grows, DSME and DSMS require periodic reassessm develops, and acquires the need for greater independent self-care skills. In addition, Suggested citation: American Diabetes Associa- it is necessary to assess the educational needs and skills of day care providers, school tion. Children and adolescents. Sec. 11. In Stan- nurses, or other school personnel who participate in the care of the young child with dards of Medical Care in Diabetes d 2016 . Diabetes Care 2016;39(Suppl. 1):S86 S93 – diabetes (6). © 2016 by the American Diabetes Association. School and Child Care Readers may use this article as long as the work As a large portion of a child ’ s day is spent in school, close communication with and is properly cited, the use is educational and not the cooperation of school or day care personnel are essential for optimal diabetes t, and the work is not altered. fi for pro

94 Children and Adolescents S87 care.diabetesjournals.org Screening management, safety, and maximal aca- impairmentafterepisodesofseverehypo- Screening for psychosocial distress and demic opportunities. Refer to the ADA rmed fi glycemia, current data have not con mental health problems is an important position statements Diabetes Care in “ – this notion (18 20). Furthermore, new component of ongoing care. It is impor- CareofYoung (7) and “ the School Setting ” therapeutic modalities, such as rapid- tant to consider the impact of diabetes Children With Diabetes in the Child Care and long-acting insulin analogs, techno- on quality of life as well as the develop- ” (8) for additional details. Setting logical advances (e.g., continuous glucose ment of mental health problems related monitors, low glucose suspend insulin Psychosocial Issues to diabetes distress, fear of hypoglyce- pumps), and education may mitigate the Recommendations mia (and hyperglycemia), symptoms of incidence of severe hypoglycemia (21). c At diagnosis and during routine anxiety, disordered eating behaviors as The Diabetes Control and Complica- follow-up care, assess psychosocial well as eating disorders, and symptoms tions Trial (DCCT) demonstrated that issuesandfamily stresses thatcould of depression (15). Consider screening near-normalization of blood glucose levels impact adherence to diabetes man- for depression and disordered eating was more dif fi cult to achieve in adoles- agement and provide appropriate behaviors using available screening cents than in adults. Nevertheless, the in- referrals to trained mental health tools (9,16), and, with respect to disor- – bolus regimens, creased use of basal professionals, preferably experi- dered eating, it is important to recognize insulin pumps, frequent blood glucose enced in childhood diabetes. E the unique and dangerous disordered monitoring, goal setting, and improved c Encourage developmentally appro- eating behavior of insulin omission for patient education in youth from infancy priate family involvement in diabetes weight control in type 1 diabetes (17). through adolescence have been associ- management tasks for children and The presence of a mental health profes- ated with more children reaching the adolescents, recognizing that prema- sional on pediatric multidisciplinary blood glucose targets set by the ADA ture transfer of diabetes care to the teams highlights the importance of at- 25) in those families in which both – (7,22 child can result in nonadherence and tending to the psychosocial issues of di- the parents and the child with diabetes B deterioration in glycemic control. abetes. These psychosocial factors are participate jointlytoperform the required Consider mental health professionals c signi cantly related to nonadherence, fi diabetes-related tasks. Furthermore, as integral members of the pediatric suboptimal glycemic control, reduced studies documenting neurocognitive imag- E diabetes multidisciplinary team. quality of life, and higher rates of acute ing differences related to hyperglycemia and chronic diabetes complications. in children provide another compelling Diabetes management throughout child- motivation for lowering glycemic targets (1). Glycemic Control hood and adolescence places substantial In selecting glycemic goals, the long- burdens on the youth and family, neces- Recommendation term health bene fi ts of achieving a lower sitating ongoing assessment of psychoso- , c An A1C goal of 7.5% (58 mmol/mol) A1C should be balanced against the risks cial issues and distress during routine is recommended across all pediatric of hypoglycemia and the developmental diabetes visits (9 11). Further, the com- – age-groups. E burdens of intensive regimens in children plexities of diabetes management require and youth. In addition, achieving lower Current standards for diabetes manage- ongoing parental involvement in care A1C levels is more likely to be related to ment re ect the need to lower glucose as fl throughout childhood with developmen- setting lower A1C targets (26,27). A1C safely as possible. This should be done tally appropriate family teamwork be- Table 11.1 goals are presented in . with stepwise goals.Specialconsideration tween the growing child/teen and Autoimmune Conditions should be given to the risk of hypoglyce- parent in order to maintain adherence mia in young children (aged 6 years) , and to prevent deterioration in glycemic Recommendation who are often unable to recognize, artic- cfam- fi control (12,13). As diabetes-speci Assess for the presence of additional c ulate, and/or manage their hypoglycemic ily con fl ict is related to poorer adherence autoimmune conditions soon after the hypoglycemia unaware- symptoms. This “ and glycemic control, it is appropriate to E diagnosis and if symptoms develop. ness should be considered when estab- ” ict during visits fl inquire about such con Because of the increased frequency of lishing individualized glycemic targets. and to either help to negotiate a plan other autoimmune diseases in type 1 Although it was previously thought that for resolution or refer to an appropriate diabetes, screening for thyroid dysfunction young children were at risk for cognitive mental health specialist (14). — Table 11.1 Blood glucose and A1C goals for type 1 diabetes across all pediatric age-groups Blood glucose goal range A1C Rationale Before meals Bedtime/overnight 130 mg/dL , 90 7.0% [53 mmol/mol]) is reasonable if it can be 90 – 150 mg/dL – A lower goal ( 7.5% , 8.3 mmol/L) – – (5.0 7.2 mmol/L) achieved without excessive hypoglycemia (5.0 (58 mmol/mol) Key concepts in setting glycemic goals: Goals should be , and lower goals may be reasonable based on a bene fi t c risk assessment. – individualized Blood glucose goals should be modi ed in children with frequent hypoglycemia or hypoglycemia unawareness. c fi c Postprandial blood glucose values should be measured when there is a discrepancy between preprandial blood glucose values and A1C levels and to assess preprandial insulin doses in those on basal – bolus regimens.

95 Volume 39, Supplement 1, January 2016 Diabetes Care S88 Children and Adolescents Celiac Disease and celiac disease should be considered. antibody positivity on a separate blood Periodic screening in asymptomatic indi- sample). It is also advisable to check for Recommendations viduals has been recommended, but the HLA types in patients who are diagnosed Consider screening children with c fi t of screen- optimal frequency and bene without a small intestinal biopsy. Asymp- type 1 diabetes for celiac disease ing are unclear. tomaticat-riskchildrenshouldhaveanin- by measuring either tissue transglu- Although much less common than ce- testinal biopsy (37). taminase or deamidated gliadin an- liac disease and thyroid dysfunction, In symptomatic children with type 1 di- tibodies, with documentation of other autoimmune conditions, such as rmed celiac disease, abetes and con fi normal total serum IgA levels, soon Addison disease (primary adrenal insuf- gluten-free diets reduce symptoms and E after the diagnosis of diabetes. ciency), autoimmune hepatitis, auto- fi rates of hypoglycemia (38). The challeng- Consider screening in children who c immune gastritis, dermatomyositis, ing dietary restrictions associated with rst-degree relative with celiac fi have a and myasthenia gravis, occur more com- having both type 1 diabetes and celiac dis- disease, growth failure, weight loss, monly in the population with type 1 dia- fi ease place a signi cant burden on individ- atu- fl failure to gain weight, diarrhea, betes than in the general pediatric uals. Therefore, we recommend a biopsy lence, abdominal pain, or signs of population and should be assessed and to con rm the diagnosis of celiac disease, fi malabsorption or in children with fre- monitored as clinically indicated. especially in asymptomatic children, be- quent unexplained hypoglycemia or fi fore endorsing signi cant dietary changes. E deterioration in glycemic control. Thyroid Disease rmed celiac fi Children with biopsy-con c Management of Cardiovascular Risk Recommendations diseaseshouldbeplacedonagluten- Factors c Consider testing children with free diet and have a consultation Hypertension type 1 diabetes for antithyroid per- with a dietitian experienced in manag- oxidase and antithyroglobulin anti- Recommendations ing both diabetes and celiac disease. B bodies soon after the diagnosis. E Screening c Measure thyroid-stimulating hor- Celiac disease is an immune-mediated dis- Blood pressure should be measured c mone concentrations soon after the order that occurs with increased fre- at each routine visit. Children found diagnosis of type 1 diabetes and after quency in patients with type 1 diabetes to have high-normal blood pressure glucose control has been estab- (1.6 – 16.4% of individuals compared with (systolic blood pressure or diastolic lished. If normal, consider rechecking 0.3 – 1% in the general population) (33 – 35). $ 90th percentile blood pressure – every 1 2 years or sooner if the pa- for age, sex, and height) or hyper- Testing for celiac disease in- Testing. tient develops symptoms suggestive tension (systolic blood pressure or cludes measuring serum levels of IgA of thyroid dysfunction, thyromegaly, 95th per- $ diastolic blood pressure and antitissue transglutaminase anti- an abnormal growth rate, or an un- centile for age, sex, and height) fi bodies, or, with IgA de ciency, screening explained glycemic variation. E should have blood pressure con- can include measuring IgG tissue transglu- B rmed on 3 separate days. fi taminase antibodies or IgG deamidated Autoimmune thyroid disease is the gliadin peptide antibodies. Because most most common autoimmune disorder Treatment cases of celiac disease are diagnosed associated with diabetes, occurring in Initial treatment of high-normal c within the fi rst 5 years after the diagnosis 30% of patients with type 1 diabe- – 17 blood pressure (systolic blood pres- of type 1 diabetes, screening should be tes (28). At the time of diagnosis, about sure or diastolic blood pressure con- considered at the time of diagnosis and 25% of children with type 1 diabetes 90th percentile for age, $ sistently repeated within 2 and 5 years thereafter. have thyroid autoantibodies (29); sex, and height) includes dietary Although celiac disease can be diag- their presence is predictive of thyroid fi modi cation and increased exercise, nosed more than 10 years after diabe- dysfunction most commonly hypothy- d if appropriate, aimed at weight con- cient data tes diagnosis, there are insuf fi roidism, although hyperthyroidism trol. If target blood pressure is not after 5 years to determine the optimal 0.5% of cases (30,31). Thy- ; occurs in 6 months of initiating reached with 3 – screening frequency. Testing for antitis- roid function tests may be misleading on, pharmacologi- lifestyle interventi sue transglutaminase antibody should (euthyroid sick syndrome) if performed cal treatment should be considered. E be considered at other times in patients at time of diagnosis owing to the effect In addition to lifestyle modi cation, fi c with symptoms suggestive of celiac disease of previous hyperglycemia, ketosis or pharmacological treatment of hyper- (35). A small-bowel biopsy in antibody- ketoacidosis, weight loss, etc. There- tension (systolic blood pressure or positive children is recommended to fore, thyroid function tests should be diastolic blood pressure consistently rm the diagnosis (36). European fi con performed soon after a period of meta- $ 95th percentile for age, sex, and guidelines on screening for celiac dis- bolic stability and good glycemic con- height) should be considered as ease in children (not speci c to children fi trol. Subclinical hypothyroidism may soon as hypertension is con rmed. fi E with type 1 diabetes) suggest that bi- be associated with increased risk of ACE inhibitors or angiotensin recep- c opsy may not be necessary in symptom- symptomatic hypoglycemia (32) and re- tor blockers should be considered atic children with high antibody titers duced linear growth r ate. Hyperthyroid- for theinitialpharmacologicaltreat- ism alters glucose metabolism and (i.e., greater than 10 times the upper limit ment of hypertension, following re- usually causes deterioration of meta- of normal) provided that further testing is productive counseling due to the bolic control. cation of endomysial fi performed (veri

96 Children and Adolescents S89 care.diabetesjournals.org potential teratogenic effects of have two or more cardiovascular disease however, studies have shown short- both drug classes. E 42), and the preva- – (CVD) risk factors (40 term safety equivalent to that seen in c The goal of treatment is blood cacy in lowering LDL cho- fi adults and ef lence of CVD risk factors increases with 90th per- , pressure consistently lesterol levels in familial hypercholes- age (42), with girls having a higher risk centile for age, sex, and height. E terolemia or severe hyperlipidemia, burden than boys (41). improving endothelial function, and Pathophysiology. The atherosclerotic urements should Blood pressure meas causing regression of carotid intimal process begins in childhood, and al- be determined using the appropriate thickening (54,55). Statins are not ap- though CVD events are not expected size cuff with the child seated and re- , proved for patients aged 10 years, to occur during childhood, observations laxed. Hypertension should be con- andstatintreatmentshouldgenerally using a variety of methodologies show rmed on at least 3 separate days. fi notbeusedinchildrenwithtype1 that youth with type 1 diabetes may have Evaluation should proceed as clinically diabetes before this age. Statins are subclinical CVD abnormalities within the indicated. Treatment is generally initi- category X in pregnancy; therefore, rst decade of diagnosis (43 fi 45). Studies – ated with an ACE inhibitor, but an angio- pregnancy prevention is of paramount of carotid intima-media thickness have tensin receptor blocker can be used if importance for postpubertal girls (see yielded inconsistent results (39). the ACE inhibitor is not tolerated (e.g., “ Section 12 Management of Diabetes in Treatment. Pediatric lipid guidelines pro- due to cough). Normal blood pressure for more information). Pregnancy ” vide some guidance relevant to children levels for age, sex, and height and ap- Smoking 48); however, with type 1 diabetes (46 – propriate methods for measurement there are few studies on modifying lipid Recommendation are available online at www.nhlbi.nih levels in children with type 1 diabetes. A c Elicit a smoking history at initial .gov/health/prof/heart/hbp/hbp_ped 6-month trial of dietary counseling and follow-up diabetes visits and .pdf (39). cant improvement in fi produced a signi discourage smoking in youth who Dyslipidemia do not smoke and encourage lipid levels (49); likewise, a lifestyle smoking cessation in those who intervention trial with 6 months of ex- Recommendations do smoke. B ercise in adolescents demonstrated im- Testing provement in lipid levels (50). Obtain a fasting lipid pro c fi le in chil- The adverse health effects of smoking Although interventi on data are sparse, $ 10 years of age soon after dren are well recognized with respect to fu- the American Heart Association (AHA) cat- the diagnosis (after glucose con- ture cancer and CVD risk. In youth with egorizes children with type 1 diabetes in E trol has been established). diabetes, it is important to avoid addi- the highest tier for cardiovascular risk and If lipids are abnormal, annual c tional CVD risk factors. Smoking increases recommends both lifestyle and pharmaco- monitoring is reasonable. If LDL the risk of onset of albuminuria; there- logical treatment for those with elevated cholesterol values are within the fore, smoking avoidance is important LDL cholesterol levels (48,51). Initial ther- 100 mg/dL , accepted risk level ( to prevent both microvascular and mac- apy should be with a Step 2 AHA diet, [2.6 mmol/L]), a lipid pro fi le re- rovascular complica tions (46,56). Dis- which restricts saturated fat to 7% of total peated every 3 – 5 years is rea- couraging cigarette smoking, including calories and restricts dietary cholesterol to sonable. E e-cigarettes, is an important part of rou- 200 mg/day. Data from randomized clini- tine diabetes care. In younger children, it cal trials in children as young as 7 months Treatment is important to assess exposure to ciga- of age indicate that this diet is safe and Initial therapy should consist of c rette smoke in the home due to the ad- does not interfere with normal growth optimizing glucose control and verse effects of secondhand smoke and and development (52). medical nutrition therapy using a to discourage youth from ever smoking cant family For children with a signi fi Step 2 American Heart Association if exposed to smokers in childhood. history of CVD, the National Heart, Lung, diet to decrease the amount of and Blood Institute recommends ob- B saturated fat in the diet. Microvascular Complications taining a fasting lipid panel beginning c After the age of 10 years, addition Nephropathy at 2 years of age (46). Abnormal results of a statin is suggested in patients from a random lipid panel should be who, despite medical nutrition ther- Recommendations rmed with a fasting lipid panel. fi con apy and lifestyle changes, continue Screening Data from the SEARCH for Diabetes in 160 mg/dL . to have LDL cholesterol c Annual screening for albuminuria Youth (SEARCH) study show that im- (4.1 mmol/L) or LDL cholesterol with a random spot urine sample proved glucose control over a 2-year pe- . 130 mg/dL (3.4 mmol/L) and one for albumin creatinine ra- to – – riod is associated with a more favorable or more cardiovascular disease risk tio should be considered once lipid pro fi le; however, improved glyce- factors. E the child has had diabetes for mic control alone will not normalize lip- The goal of therapy is an LDL c B 5years. ids in youth with type 1 diabetes and , cholesterol value 100 mg/dL ltration rate fi Estimate glomerular c dyslipidemia (53). E (2.6 mmol/L). at initial evaluation and then Neither long-term safety nor cardio- based on age, diabetes duration, vascular outcome ef fi cacy of statin ther- Population-based studies estimate that and treatment. E – 14 45% of children with type 1 diabetes apy has been established for children;

97 Volume 39, Supplement 1, January 2016 Diabetes Care S90 Children and Adolescents team, including a physician, diabetes 2 years. Referrals – duration of only 1 Treatment nurse educator, registered dietitian, should be made to eye care professionals c Treatment with an ACE inhibitor, and behavioral specialist or social with expertise in diabetic retinopathy titrated tonormalizationofalbumin worker, is essential. In addition to blood and experience in counseling the pedi- excretion, should be considered glucose control, treatment must in- atric patient and family onthe importance – when elevated urinary albumin clude management of comorbidities of early prevention and intervention. creatinine ratio ( – to 30 mg/g) is . such as obesity, dyslipidemia, hyperten- Neuropathy documented with at least two of sion, and albumin levels from the outset. three urine samples. These should Recommendation Presentation with ketosis or ketoacidosis be obtained over a 6-month inter- c Consider an annual comprehensive requires a period of insulin therapy un- val following efforts to improve foot exam for the child at the start til fasting and postprandial glycemia glycemic control and normalize 10 years, $ of puberty or at age have been restored to normal or near- blood pressure. B whichever is earlier, once the youth normal. Metformin therapy may be E has had type 1 diabetes for 5 years. used as an adjunct after resolution of , Data from 7,549 participants 20 years ketosis/ketoacidosis. Initial treatment of age in the T1D Exchange clinic registry Neuropathy rarely occurs in prepubertal should also be with insulin when the emphasize the importance of good gly- 2 years of diabe- children or after only 1 – distinction between type 1 diabetes cemic and blood pressure control, par- tes (60). A comprehensive foot exam, in- and type 2 diabetes is unclear and ticularly as diabetes duration increases, cluding inspection, palpation of dorsalis in patients who have random blood in order to reduce the risk of nephropa- pedis and posterior tibial pulses, assess- glucose concentrations $ 250 mg/dL thy. The data also underscore the impor- exes, fl ment of the patellar and Achilles re (13.9 mmol/L) and/or A1C 9% . tance of routine screening to ensure and determination of proprioception, vi- (75 mmol/mol) (65). early diagnosis and timely treatment of lament sensation, fi bration, and mono Patients and their families must prior- albuminuria (57). An estimation of glo- should be performed annually along itize lifestyle modi fi cations such as ltration rate (GFR), calculated merular fi with assessment of symptoms of neuro- eating a balanced diet, maintaining a using GFR estimating equations from pathic pain. Foot inspection can be per- healthy weight, and exercising regu- the serum creatinine, height, age, and formed at each visit to educate youth larly. A family-centered approach to nu- sex (58), should be determined at base- regarding the importance of foot care. trition and lifestyle modi fi cation is line and repeated as indicated based on essential in children with type 2 diabe- clinical status, age, diabetes duration, TYPE 2 DIABETES tes. Nutrition recommendations should and therapies. Estimated GFR is calcu- be culturally appropriate and sensitive For information on testing for type 2 lated from a serum creatinine measure- to family resources (see Section 3 diabetes and prediabetes in children ment using an estimating equation. This “ Foundations of Care and Comprehen- and adolescents, please refer to Sec- is not a recommendation to perform a sive Medical Evaluation ” ). cation and Diagnosis of tion 2 Classi “ fi measurement of creatinine clearance (in- When insulin treatment is not re- Diabetes. ” volves timed urine collection) every year. quired, initiation of metformin, currently The Centers for Disease Control and There are ongoing clinical trials assessing the only oral hypoglycemic agent speci - fi Preventionrecentlypublishedprojections cacy of early treatment of persis- fi the ef cally approved for use in children with for type 2 diabetes prevalence using the tent albuminuria with ACE inhibitors (59). type 2 diabetes, is recommended. How- SEARCH database. Assuming a 2.3% an- ever, the Treatment Options for type 2 Di- nual increase, the prevalence of type 2 Retinopathy abetes in Adolescents and Youth (TODAY) diabetes in those under 20 years of age Recommendations study found that metformin alone pro- will quadruple in 40 years (61,62). Given An initial dilated and comprehen- c vided durable glycemic control (A1C the current obesity epidemic, distinguish- sive eye examination is recom- # 8% [64 mmol/mol] for 6 months) in ap- ing between type 1 and type 2 diabetes in mended at age 10 years or $ subjects (66), sug- proximately half of the cult. For example, ex- fi children can be dif after puberty has started, which- gesting that many youth with type 2 cessive weight iscommon in childrenwith ever is earlier, once the youth diabetes are likely to require combination rthermore, diabetes- type 1 diabetes (63). Fu has had diabetes for 3 5years. – B treatment within a few years of diagnosis. associated autoantibodies and ketosis After the initial examination, an- c may be present in patients with features nual routine follow-up is generally Comorbidities of type 2 diabetes (including obesity and recommended. Less frequent ex- Comorbidities may already be present at acanthosis nigricans) (64). Nevertheless, aminations, every 2 years, may the time of diagnosis in youth with accurate diagnosis is critical as treatment type 2 diabetes (67). Therefore, blood be acceptable on the advice of an regimens, educational approaches, die- pressure measurement, a fasting lipid eye care professional. E tary advice, and outcomes differ mark- panel, assessment for albumin excre- edly between the two diagnoses. Although retinopathy (like albuminuria) tion, and a dilated eye examination most commonly occurs after the onset should be performed at diagnosis. Treatment of puberty and after 5 10 years of dia- – The general treatment goals for type 2 Thereafter, screening guidelines and betes duration (60), it has been reported diabetes are the same as those for type treatment recommendations for hyper- 1 diabetes. A multidisciplinary diabetes in prepubertal children and with diabetes tension, dyslipidemia, albumin excretion,

98 Children and Adolescents S91 care.diabetesjournals.org with type 1 diabetes. Pediatrics 2013;132: and retinopathy are similar to those for c evidence is limited, fi Although scienti e1395 e1402 – youth with type 1 diabetes. Additional it is clear that comprehensive and coordi- 10. Hood KK, Beavers DP, Yi-Frazier J, et al. Psy- problems that may need to be addressed nated planning that begins in early ado- chosocial burden and glycemic control during include polycystic ovary disease and lescence, or at least 1 year before the the fi rst 6 years of diabetes: results from the other comorbidities associated with pe- dateoftransition,isnecessarytofacilitate SEARCH for Diabetes in Youth study. J Adolesc – Health 2014;55:498 504 diatric obesity, such as sleep apnea, a seamless transition from pediatric to 11. Ducat L, Philipson LH, Anderson BJ. The hepatic steatosis, orthopedic complica- adult health care (71,72). A comprehen- mental health comorbidities of diabetes. JAMA tions, and psychosocial concerns. The sive discussion regarding the challenges 692 – 2014;312:691 Type 2 Diabetes “ ADA consensus report fi faced during thisperiod,includingspeci c 12. Katz ML, Volkening LK, Butler DA, Anderson (68) and a ” in Children and Adolescents recommendations, is found in the ADA ased psychoeducation BJ, Laffel LM. Family-b and care ambassador intervention to improve more recent American Academy of Pe- position statement Diabetes Care for “ glycemic control in youth with type 1 diabetes: a diatrics clinical practice guideline (69) Emerging Adults: Recommendations for randomized trial. Pediatr Diabetes 2014;15: provide guidance on the prevention, Transition From Pediatric to Adult Diabe- 142 – 150 screening, and treatment of type 2 di- tes Care Systems ” (72). 13. Laffel LM, Vangsness L, Connell A, Goebel- abetes and its comorbidities in children The National Diabetes Education Pro- Fabbri A, Butler D, Anderson BJ. Impact of ambulatory, family-focused teamwork inter- and adolescents. gram (NDEP) has materials available to vention on glycemic control in youth with facilitate the transition process (http:// – 416 type 1 diabetes. J Pediatr 2003;142:409 TRANSITION FROM PEDIATRIC TO ndep.nih.gov/transitions), and the En- 14. Anderson BJ, Vangsness L, Connell A, Butler ADULT CARE docrine Society in collaboration with fl D, Goebel-Fabbri A, Laffel LM. Family con ict, the ADA and other organizations has de- Recommendations adherence, and glycaemic control in youth with short duration type 1 diabetes. Diabet Med veloped transition tools for clinicians Health care providers and families c 2002;19:635 – 642 and youth and families (http://www should begin to prepare youth in 15. Lawrence JM, Yi-Frazier JP, Black MH, et al.; .endo-society.org/ clinicalpractice/ early to mid-adolescence and, at SEARCH for Diabetes in Youth Study Group. De- transition_of_care.cfm). the latest, at least 1 year before mographic and clinical correlates of diabetes- related quality of life among youth with type 1 E the transition to adult health care. diabetes. J Pediatr 2012;161:201 – 207.e2 References Both pediatricians and adult c 16. Markowitz JT, Butler DA, Volkening LK, 1. Barnea-Goraly N, Raman M, Mazaika P, et al.; health care providers should assist ffel LM. Brief screening Antisdel JE, Anderson BJ, La Diabetes Research in Children Network (DirecNet). in providing support and links to tool for disordered eating in diabetes: internal con- Alterations in white matter structure in young chil- resources for the teen and emerg- sistency and external validity in a contemporary dren with type 1 diabetes. Diabetes Care 2014;37: sample of pediatric patients with type 1 diabetes. B ing adult. 332 – 340 Diabetes Care 2010;33:495 – 500 2. Cameron FJ, Scratch SE, Nadebaum C, et al.; 17. Wisting L, Frøisland DH, Skrivarhaug T, DKA Brain Injury Study Group. Neurological conse- Care and close supervision of diabetes Dahl-Jørgensen K, Rø O. Disturbed eating be- quences of diabetic ketoacidosis at initial presenta- management are increasingly shifted havior and omission of insulin in adolescents tion of type 1 diabetes in a prospective cohort study from parents and other adults to the receiving intensi fi ed insulin treatment: a na- 1562 – of children. Diabetes Care 2014;37:1554 youth with diabetes throughout child- tionwide population-based study. Diabetes 3. Markowitz JT, Garvey KC, Laffel LM. Devel- Care 2013;36:3382 – 3387 hood and adolescence. The shift from opmental changes in the roles of patients and 18. Seaquist ER, Anderson J, Childs B, et al. Hy- families in type 1 diabetes management. Curr pediatrics to adult health care providers, poglycemia and diabetes: a report of a work- 238 – Diabetes Rev 2015;11:231 however, often occurs abruptly as the group of the American Diabetes Association 4. Silverstein J, Klingensmith G, Copeland K, older teen enters the next developmen- and the Endocrine Society. Diabetes Care et al.; American Diabetes Association. Care of tal stage referred to as emerging adult- – 1395 2013;36:1384 children and adolescents with type 1 diabetes: 19. Wysocki T, Harris MA, Mauras N, et al. Ab- a statement of the American Diabetes Associa- hood (70), which is a critical period for sence of adverse effects of severe hypoglycemia 212 – tion. Diabetes Care 2005;28:186 young people who have diabetes. During on cognitive function in school-aged children 5. Chiang JL, Kirkman MS, Laffel LM, Peters AL; this period of major life transitions, youth with diabetes over 18 months. Diabetes Care Authors. Type 1 di- Type 1 Diabetes Sourcebook ’ home begin to move out of their parents – 2003;26:1100 1105 abetes through the life span: a position state- and must become fully responsible for 20. Blasetti A, Chiuri RM, Tocco AM, et al. The ment of the American Diabetes Association. effect of recurrent severe hypoglycemia on cog- Diabetes Care 2014;37:2034 – 2054 their diabetes care. Their new responsi- nitive performance in children with type 1 di- 6. Driscoll KA, Volkening LK, Haro H, et al. Are bilities include self-management of abetes: a meta-analysis. J Child Neurol 2011;26: children with type 1 diabetes safe at school? their diabetes, making medical appoint- – 1383 1391 Examining parent perceptions. Pediatr Diabe- nancing health care, once ments, and fi Connell SM, Davis EA, Jones ’ 21. Cooper MN, O tes. 30 September 2014 [Epub ahead of print]. they are no longer covered by their par- TW. A population-based study of risk factors for DOI: 10.1111/pedi.12204 severe hypoglycaemia in a contemporary cohort 7. Jackson CC, Albanese-O Neill A, Butler KL, ’ health insurance plan (ongoing ents ’ of childhood-onset type 1 diabetes. Diabetolo- et al. Diabetes care in the school setting: a po- coverage until age 26 years is possible – gia 2013;56:2164 2170 sition statement of the American Diabetes As- with recent U.S. health care reform). In 22. Rosenbauer J, Dost A, Karges B, et al.; DPV sociation. Diabetes Care 2015;38:1958 – 1963 addition to lapses in health care, this is Initiative and the German BMBF Competence 8. Siminerio LM, Albanese-O ’ Neill A, Chiang JL, also a period associated with deteriora- Network Diabetes Mellitus. Improved metabolic et al.; American Diabetes Association. Care of control in children and adolescents with type 1 young children with diabetes in the child care tion in glycemic control; increased occur- diabetes: a trend analysis using prospective setting: a position statement of the American rence of acute complications; psychosocial, multicenter data from Germany and Austria. Diabetes Association. Diabetes Care 2014;37: emotional, and behavioral challenges; and Diabetes Care 2012;35:80 86 – – 2842 2834 the emergence of chronic complications 23. Cameron FJ, de Beaufort C, Aanstoot HJ, 9. Corathers SD, Kichler J, Jones NH, et al. Im- et al.; Hvidoere International Study Group. proving depression screening for adolescents (71 – 74).

99 Volume 39, Supplement 1, January 2016 Diabetes Care S92 Children and Adolescents Gastroenterology, Hepatology, and Nutrition. structured dietician training to a Mediterranean- Lessons from the Hvidoere International Study European Society for Pediatric Gastroenterol- – 168 style diet. J Endocrinol Invest 2012;35:160 Group on childhood diabetes: be dogmatic 50. Salem MA, Aboelasrar MA, Elbarbary NS, ogy, Hepatology, and Nutrition guidelines for fl exible in approach. Pediatr about outcome and Elhilaly RA, Refaat YM. Is exercise a therapeutic the diagnosis of coeliac disease. J Pediatr Gas- Diabetes 2013;14:473 – 480 tool for improvement of cardiovascular risk fac- 24. Nimri R, Weintrob N, Benzaquen H, Ofan R, – 160 troenterol Nutr 2012;54:136 38. Abid N, McGlone O, Cardwell C, McCallion W, tors in adolescents with type 1 diabetes melli- Fayman G, Phillip M. Insulin pump therapy in Carson D. Clinical and metabolic effects of gluten tus? A randomised controlled trial. Diabetol youth with type 1 diabetes: a retrospective free diet in children with type 1 diabetes and coe- Metab Syndr 2010;2:47 paired study. Pediatrics 2006;117:2126 – 2131 51. McCrindle BW, Urbina EM, Dennison BA, 25. Doyle EA, Weinzimer SA, Steffen AT, Ahern liac disease. Pediatr Diabetes 2011;12:322 – 325 39. de Ferranti SD, de Boer IH, Fonseca V, et al. et al. Drug therapy of high-risk lipid abnormali- JA, Vincent M, Tamborlane WV. A randomized, Type 1 diabetes mellitus and cardiovascular dis- c fi ties in children and adolescents: a scienti cacy of con- prospective trial comparing the ef fi ease: a scienti fi c statement from the American statement from the American Heart Association tinuous subcutaneous insulin infusion with mul- Heart Association and American Diabetes Asso- Atherosclerosis, Hypertension, and Obesity in tiple daily injections using insulin glargine. ciation. Diabetes Care 2014;37:2843 – 2863 Youth Committee, Council of Cardiovascular Diabetes Care 2004;27:1554 – 1558 40. Rodriguez BL, Fujimoto WY, Mayer-Davis EJ, 26. Swift PGF, Skinner TC, de Beaufort CE, et al.; Disease in the Young, with the Council on Car- et al. Prevalence of cardiovascular disease risk diovascular Nursing. Circulation 2007;115: Hvidoere Study Group on Childhood Diabetes. factors in U.S. children and adolescents with di- Target setting in intensive insulin management – 1967 1948 ̈ ̈ ̈ abetes: the SEARCH for Diabetes in Youth study. al am ainen M, et al. Serum 52. Salo P, Viikari J, H is associated with metabolic control: the Hvi- Diabetes Care 2006;29:1891 – 1896 cholesterol ester fatty acids in 7- and 13-month- doere childhood diabetes study group centre 41. Margeirsdottir HD, Larsen JR, Brunborg C, old children in a prospective randomized trial differences study 2005. Pediatr Diabetes 2010; Overby NC, Dahl-Jørgensen K; Norwegian Study of a low-saturated fat, low-cholesterol diet: 11:271 – 278 Group for Childhood Diabetes. High prevalence 27. Maahs DM, Hermann JM, DuBose SN, et al.; the STRIP baby project. Special Turku coronary of cardiovascular risk factors in children and ad- Risk factor Intervention Project for children. DPV Initiative; T1D Exchange Clinic Network. olescents with type 1 diabetes: a population- 512 Acta Paediatr 1999;88:505 – Contrasting the clinical care and outcomes of 561 based study. Diabetologia 2008;51:554 – ’ Agostino RB Jr, 53. Maahs DM, Dabelea D, D 2,622 children with type 1 diabetes less than 42. Schwab KO, Doerfer J, Hecker W, et al.; DPV et al.; SEARCH for Diabetes in Youth Study. Glu- 6 years of age in the United States T1D Exchange Initiative of the German Working Group for Pedi- cose control predicts 2-year change in lipid pro- and German/Austrian DPV registries. Diabeto- atric Diabetology. Spectrum and prevalence of le in youth with type 1 diabetes. J Pediatr 2013; fi logia 2014;57:1578 – 1585 ́ atherogenic risk factors in 27,358 children, ado- 162:101 – 107.e1 28. Rold an MB, Alonso M, Barrio R. Thyroid au- lescents, and young adults with type 1 diabetes: fi 54. McCrindle BW, Ose L, Marais AD. Ef cacy toimmunity in children and adolescents with cross-sectional data from the German diabetes and safety of atorvastatin in children and ado- Type 1 diabetes mellitus. Diabetes Nutr Metab documentation and quality management system lescents with familial hypercholesterolemia or 31 – 1999;12:27 29. Triolo TM, Armstrong TK, McFann K, et al. 225 (DPV). Diabetes Care 2006;29:218 – severe hyperlipidemia: a multicenter, random- 43.SinghTP,GroehnH,KazmersA.Vascular ized, placebo-controlled trial. J Pediatr 2003; Additional autoimmune disease found in 33% of function and carotid intimal-medial thickness 143:74 80 – patients at type 1 diabetes onset. Diabetes Care in children with insulin-dependent diabetes 55. Wiegman A, Hutten BA, de Groot E, et al. 1213 2011;34:1211 – mellitus. J Am Coll Cardiol 2003;41:661 – 665 cacy and safety of statin therapy in chil- fi Ef 30. Kordonouri O, Deiss D, Danne T, Dorow A, ̈ 44. Haller MJ, Stein J, Shuster J, et al. Peripheral dren with familial hypercholesterolemia: a Bassir C, Gr uters-Kieslich A. Predictivity of thy- artery tonometry demonstrates altered endo- randomized controlled trial. JAMA 2004;292: roid autoantibodies for the development of thy- thelial function in children with type 1 diabetes. 331 – 337 roid disorders in children and adolescents with – Pediatr Diabetes 2007;8:193 198 56. Scott LJ, Warram JH, Hanna LS, Laffel LM, type 1 diabetes. Diabet Med 2002;19:518 – 521 ̈ 45. Urbina EM, Wadwa RP, Davis C, et al. Prev- Ryan L, Krolewski AS. A nonlinear effect of hy- ohlich-Reiterer E, 31. Dost A, Rohrer TR, Fr alence of increased arterial stiffness in children perglycemia and current cigarette smoking are et al.; DPV Initiative and the German Compe- with type 1 diabetes mellitus differs by mea- major determinants of the onset of microalbu- tence Network Diabetes Mellitus. Hyperthy- surement site and sex: the SEARCH for Diabetes minuria in type 1 diabetes. Diabetes 2001;50: roidism in 276 children and adolescents with in Youth study. J Pediatr 2010;156:731 – 737.e1 – 2842 2849 type 1 diabetes from Germany and Austria. 46. Expert Panel on Integrated Guidelines for 57. Daniels M, DuBose SN, Maahs DM, et al.; Horm Res Paediatr 2015;84:190 – 198 Cardiovascular Health and Risk Reduction in Chil- T1D Exchange Clinic Network. Factors associ- 32. Mohn A, Di Michele S, Di Luzio R, Tumini S, dren and Adolescents; National Heart, Lung, and ated with microalbuminuria in 7,549 children Chiarelli F. The effect of subclinical hypothyroid- Blood Institute. Expert panel on integrated guide- and adolescents with type 1 diabetes in the ism on metabolic control in children and adoles- lines for cardiovascular health and risk reduction T1D Exchange clinic registry. Diabetes Care cents with type 1 diabetes mellitus. Diabet Med in children and adolescents: summary report. Pe- – 2645 2013;36:2639 – 73 2002;19:70 S256 – diatrics 2011;128(Suppl. 5):S213 58. Schwartz GJ, Work DF. Measurement and 33. Holmes GKT. Screening for coeliac disease 47. Daniels SR, Greer FR; Committee on Nutri- estimation of GFR in children and adolescents. in type 1 diabetes. Arch Dis Child 2002;87:495 – tion. Lipid screening and cardiovascular health 1843 – Clin J Am Soc Nephrol 2009;4:1832 498 in childhood. Pediatrics 2008;122:198 208 – 59. Marcovecchio ML,Woodside J, Jones T,et al.; 34. Rewers M, Liu E, Simmons J, Redondo MJ, 48. Kavey R-EW, Allada V, Daniels SR, et al. Car- AdDIT Investigators. Adolescent Type 1 Diabetes Hoffenberg EJ. 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Rubio-Tapia A, Hill ID, Kelly CP, Calderwood 2- to 5-yr duration of type 1 diabetes from 1990 Nursing, and the Kidney in Heart Disease; and AH, Murray JA; American College of Gastroen- – to 2006. Pediatr Diabetes 2011;12:682 689 61. Imperatore G, Boyle JP, Thompson TJ, et al.; the Interdisciplinary Working Group on Quality terology. ACG clinical guidelines: diagnosis and SEARCH for Diabetes in Youth Study Group. Pro- of Care and Outcomes Research: endorsed by management of celiac disease. Am J Gastroen- jections of type 1 and type 2 diabetes burden in the American Academy of Pe diatrics. Circulation – 676 terol 2013;108:656 ́ the U.S. population aged 20 years through , 37. Husby S, Koletzko S, Korponay-Szab oIR, – 2006;114:2710 2738 2050: dynamic modeling of incidence, mortal- et al.; ESPGHAN Working Group on Coeliac Dis- 49. Cadario F, Prodam F, Pasqualicchio S, et al. ity, and population growth. 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101 S94 Diabetes Care Volume 39, Supplement 1, January 2016 American Diabetes Association 12. Management of Diabetes in Pregnancy DOI: 10.2337/dc16-S015 | S98 – Diabetes Care 2016;39(Suppl. 1):S94 For guidelines related to the diagnosis of gestational diabetes mellitus, please refer ” to Section 2 fi cation and Diagnosis of Diabetes “ . Classi Recommendations Pregestational Diabetes Provide preconception counseling that addresses the importance of glycemic c control as close to normal as is safely possible, ideally A1C , 6.5% (48 mmol/mol), B to reduce the risk of congenital anomalies. Family planning should be discussed and effective contraception should be c prescribed and used until a woman is prepared and ready to become pregnant. A c Women with preexisting type 1 or type 2 diabetes who are planning pregnancy or who have become pregnant should be counseled on the risk of development and/or progression of diabetic retinopathy. Eye examinations should occur before pregnancy or in the fi rst trimester and then be monitored every tri- B mester and for 1 year postpartum as indicated by degree of retinopathy. Gestational Diabetes Mellitus Lifestyle change is an essential component of management of gestational di- c ce for treatment for many women. Medications abetes mellitus and may suf fi A should be added if needed to achieve glycemic targets. 12. MANAGEMENT OF DIABETES IN PREGNANCY Preferred medications in gestational diabetes mellitus are insulin and metformin; c glyburide may be used but may have a higher rate of neonatal hypoglycemia and macrosomia than insulin or metformin. Other agents have not been adequately A studied. Most oral agents cross the placenta, and all lack long-term safety data. General Principles for Management of Diabetes in Pregnancy c Potentially teratogenic medications (ACE inhibitors, statins, etc.) should be avoided in sexually active women of childbearing age who are not using reli- B able contraception. c Fasting, preprandial, and postprandial self-monitoring of blood glucose are recommended in both gestational diabetes mellitus and pregestational diabe- B tes in pregnancy to achieve glycemic control. er, A1C is lower in normal pregnancy Due to increased red blood cell turnov c 6.5% than in normal nonpregnant women. The A1C target in pregnancy is 6 – 48 mmol/mol); , 6% (42 mmol/mol) may be optimal if this can be achieved (42 – , 7% without signi fi cant hypoglycemia, but the t arget may be relaxed to B (53 mmol/mol) if necessary to prevent hypoglycemia. DIABETES IN PREGNANCY s been increasing in the U.S. The majority is The prevalence of diabetes in pregnancy ha remainder primarily pregestational type 1 gestational diabetes mellitus (GDM) with the diabetes and type 2 diabetes. The rise in GDM and pregestational type 2 diabetes in Suggested citation: American Diabetes Associa- parallel with obesity both in the U.S. and worldwide is of particular concern. Both pre- tion. Management of diabetes in pregnancy. Sec. cantly greater maternal and fi gestational type 1 diabetes an d type 2 diabetes confer signi d . 2016 12. In Standards of Medical Care in Diabetes fetal risk than GDM, with some differences ac cording to type as outlined below. In general, Diabetes Care 2016;39(Suppl. 1):S94 – S98 speci c risks of uncontrolled diabetes in pregnancy include spontaneous abortion, fetal fi © 2016 by the American Diabetes Association. anomalies, preeclampsia, intrauterine fetal demise, macrosomia, neonatal hypoglyce- Readers may use this article as long as the work mia, and neonatal hyperbilirubinemia, among others. In addition, diabetes in preg- is properly cited, the use is educational and not t, and the work is not altered. fi for pro nancy may increase the risk of obesity and type 2 diabetes in offspring later in life (1,2).

102 Management of Diabetes in Pregnancy S95 care.diabetesjournals.org Insulin Physiology PRECONCEPTION COUNSELING early in gestation (4,9 11). Clinical tri- – Early pregnancy is a time of insulin sen- als have not evaluated the risks and All women of childbearing age with di- sitivity, lower glucose levels, and lower bene fi ts of achieving these targets, and abetes should be counseled about the insulin requirements in women with type 1 treatment goals should account for the importance of near-normal glycemic con- diabetes. The situation rapidly reverses risk of maternal hypoglycemia in set- trol prior to conception. Observational as insulin resistance increases exponen- 6% ting an individualized target of , studies show an increased risk of diabetic tially during the second and early third 7% (53 mmol/mol). , (42 mmol/mol) to embryopathy, especially anencephaly, trimesters and levels off toward the end Due to physiological increases in red microcephaly, congenital heart disease, of the third trimester. In women with blood cell turnover, A1C levels fall during and caudal regression directly propor- normal pancreatic function, insulin pro- normal pregnancy (12). Additionally, as tional to elevations in A1C during the rst fi duction is suf cient to meet the challenge fi A1C represents an integrated measure of 10 weeks of pregnancy. Although obser- of this physiological insulin resistance glucose, it may not fully capture post- vational studies are confounded by the and to maintain normal glucose levels. prandial hyperglycemia, which drives association between elevated periconcep- However, in women with GDM and pre- macrosomia. Thus, while A1C may be tional A1C and other poorself-care behav- gestational type 2 diabetes, hyperglyce- useful, it should be used as a secondary iors, the quantity and consistency of data mia occurs if treatment is not adjusted measure, after self-monitoring of blood are convincing and support the rec- appropriately. glucose. ommendation to optimize glycemic con- In the second and third trimester, A1C 6.5% trol prior to conception, with A1C , Glucose Monitoring 6% (42 mmol/mol) has the lowest risk , (48 mmol/mol) associated with the low- ecting this physiology, preprandial fl Re of large-for-gestational-age infants, est risk of congenital anomalies (3,4). and postprandial monitoring of blood glu- whereas other adverse outcomes in- There are opportunities to educate all cose is recommended to achieve meta- crease with A1C $ 6.5% (48 mmol/mol). women and adolescents of reproductive bolic control in pregnant women with Taking all of this into account, a target of age with diabetes about the risks of un- diabetes. Postprandial monitoring is as- – – 6.5% (42 6 48 mmol/mol) is recom- planned pregnancies and the opportu- sociated with better glycemic control , 6% (42 mmol/mol) may mended but nities for improved maternal and fetal and lower risk of preeclampsia (7). There . be optimal as pregnancy progresses outcomes with pregnancy planning (5). are no adequately powered randomized These levels should be achieved without Effective preconception counseling trials comparing different fasting and hypoglycemia , which, in addition to the could avert substantial health and asso- postmeal glycemic targets in diabetes lae, may increase usual adverse seque ciated cost burden in offspring (6). Fam- in pregnancy. the risk of low birth weight. Given the ily planning should be discussed, and Nevertheless, the American College of alteration in red blood cell kinetics dur- effective contraception should be pre- Obstetricians and Gynecologists (ACOG) ing pregnancy and physiological scribed and used, until a woman is pre- (8) recommends the following targets changes in glycemic parameters, A1C pared and ready to become pregnant. for women with pregestational type 1 or levels may need to be monitored type 2 diabetes: Preconception Testing more frequently than usual (e.g., Preconception counseling visits should monthly). ○ 90 mg/dL (5.0 mmol/L) # Fasting address rubella, rapid plasma reagin, hep- ○ 130 – 140 # One-hour postprandial atitis B virus, and HIV testing as well as MANAGEMENT OF GESTATIONAL mg/dL (7.2 – 7.8 mmol/L) Pap smear, cervical cultures, blood typ- DIABETES MELLITUS ○ 120 mg/dL Two-hour postprandial # ing, prescription of prenatal vitamins GDM is characterized by increased risk (6.7 mmol/L) (with at least 400 m g of folic acid), and of macrosomia and birth complications smoking cessation counseling, if indi- and an increased risk of maternal diabe- These values represent optimal control c testing should cated. Diabetes-speci fi tes after pregnancy. The association of if they can be achieved safely. In practice, include A1C, thyroid-stimulating hor- macrosomia and birth complications it may be challenging for women with – mone, creatinine, and urinary albumin with oral glucose tolerance test (OGTT) type 1 diabetes to achieve these targets – creatinine ratio testing; review of the to results is continuous, with no clear in- without hypoglycemia, particularly women medication list for potentially teratogenic ection points (13). In other words, risks fl with a history of severe hypoglycemia or drugs (i.e., ACE inhibitors, statins); and increase with progre ssive hyperglyce- hypoglycemia unawareness. referral for a comprehensive eye exam. mia. Therefore, all women should be If women cannot achieve these tar- Clas- screened as outlined in Section 2 “ gets without signi cant hypoglycemia, fi GLYCEMIC TARGETS IN ” cation and Diagnosis of Diabetes. fi si Al- the American Diabetes Association PREGNANCY though there is some heterogeneity, (ADA) suggests less stringent targets Pregnancy in women with normal glucose many randomized controlled trials sug- based on clinical experience and individ- metabolism is character ized by fasting lev- gestthattheriskofGDMmaybere- . ualization of care els of blood glucose that are lower than in duced by diet, exercise, and lifestyle the nonpregnant state due to insulin- counseling (14,15). independent glucose uptake by the pla- A1C in Pregnancy Observational studies show the lowest centa and by postprandial hyperglycemia Lifestyle Management After diagnosis, treatment starts with rates of adverse fetal outcomes in associa- and carbohydrate intolerance as a result medical nutrition therapy, physical 6 – – 48 mmol/mol) tion with A1C , 6.5% (42 of diabetogenic placental hormones.

103 Volume 39, Supplement 1, January 2016 Diabetes Care S96 Management of Diabetes in Pregnancy activity, and weight management de- ces to insulin for maternal health if it suf fi pregnancy that may decrease hypoglyce- pending on pregestational weight, as 25); how- – control hyperglycemia (23 mia awareness. Hypoglycemia education outlined in the section on pregestational ever, metformin may slightly increase for patients and family members is impor- type 2 diabetes below, and glucose mon- the risk of prematurity. None of these tant before and during early pregnancy itoring aiming for the targets recom- studies or meta-analyses evaluated and throughout pregnancy to help to pre- mended by the Fifth International long-term outcomes in the offspring. vent and manage the risks of hypoglyce- Workshop-Conference on Gestational Thus, patients treated with oral agents mia. Insulin resistance drops rapidly with Diabetes Mellitus (16): should be informed that they cross the delivery of the placenta. Women become placenta and, while no adverse effects very insulin sensitive immediately follow- ○ Fasting # 95 mg/dL (5.3 mmol/L) and on the fetus have been demonstrated, ing delivery and may initially require either long-term studies are lacking. much less insulin than in the prepartum ○ One-hour postprandial # 140 mg/dL period. Insulin (7.8 mmol/L) or Pregnancy is a ketogenic state, and Insulin may be required to treat hyper- ○ # 120 mg/dL Two-hour postprandial women with type 1 diabetes, and to a glycemia, and its use should follow the (6.7 mmol/L) lesser extent those with type 2 diabetes, guidelines below. are at risk for diabetic ketoacidosis at Depending on the population, studies MANAGEMENT OF lower blood glucose levels than in the suggestthat70 – 85% of women diag- PREGESTATIONAL TYPE 1 nonpregnant state. All insulin-de cient fi DIABETES AND TYPE 2 DIABETES nosed with GDM under Carpenter- women need ketone strips at home and IN PREGNANCY Coustan or National Diabetes Data education on diabetic ketoacidosis pre- Group (NDDG) criteria can control vention and detection. In addition, rapid Insulin Use fi cation alone; GDM with lifestyle modi implementation of tight glycemic control Insulin is the preferred agent for man- it is anticipated that this proportion in the setting of retinopathy is associated agement of pregestational type 1 diabe- will increase using the lower Interna- with worsening of retinopathy (26). tes and type 2 diabetes that are not tional Association of the Diabetes and adequately controlled with diet, exer- Type 2 Diabetes Pregnancy Study Groups (IADPSG) (17) cise, and metformin. Pregestational type 2 diabetes is often diagnostic thresholds. The physiology of pregnancy requires associated with obesity. Recommended frequent titration of insulin to match Pharmacological Therapy weight gain during pregnancy for over- changing requirements. In the fi rst tri- Women with greater initial degrees of weight women is 15 – 25 lb and for obese mester, there is often a decrease in total hyperglycemia may require early initia- 20 lb. Glycemic control is – women is 10 daily insulin requirements, and women, tion of pharmacological therapy. Treat- often easier to achieve in type 2 diabe- particularly those with type 1 diabetes, ment has been demonstrated to tes than in type 1 diabetes but can re- may experience increased hypoglyce- improve perinatal outcomes in two quire much higher doses of insulin, mia. In the second trimester, rapidly large randomized studies as summa- sometimes necessitating concentrated increasing insulin resistance requires rized in a U.S. Preventive Services Task insulin formulations. As in type 1 diabetes, weekly or biweekly increases in insulin fi Force review (18). Insulin is the rst-line insulin requirements drop dramatically af- dose to achieve glycemic targets. In agent recommended for treatment of ter delivery. Associated hypertension and general, a smaller proportion of the total GDM in the U.S. Individual randomized other comorbidities often render preges- daily dose should be given as basal in- controlled trials support the ef fi cacy tational type 2 diabetes as high or higher 50%) and a greater proportion , sulin ( and short-term safety of metformin risk than pregestational type 1 diabetes, . 50%) as prandial insulin. In the late ( (19,20) (pregnancy category B) and gly- even if the diabetes is better controlled third trimester, there is often a leveling buride (21) (pregnancy category B) for and of shorter duration, with pregnancy off or small decrease in insulin require- the treatment of GDM. However, both loss appearing to be more prevalent in ments. Due to the complexity of insulin agents cross the placenta, and long- the third trimester in type 2 diabetes management in pregnancy, referral to a term safety data are not available for fi compared with the rst trimester in specialized center offering team-based either agent (22). type 1 diabetes (27,28). care (with team members including Sulfonylureas high-risk obstetrician, endocrinologist, POSTPARTUM CARE More recently, several meta-analyses dietitian, nurse, and social worker, as Postpartum care should include psychoso- and large observational studies examin- needed) is recommended if this resource cial assessment and support for self-care. ing maternal and fetal outcomes have is available. suggested that sulfonylureas, such as gly- All insulins are pregnancy category B Lactation buride, may be inferior to insulin and In light of the immediate nutritional and except for glargine, glulisine, and de- metformin due to increased risk of neo- fi ts of breastfeed- immunological bene gludec, which are labeled category C . natal hypoglycemia and macrosomia with ing for the baby, all women including this class. those with diabetes should be sup- Type 1 Diabetes Metformin Women with type 1 diabetes have an ported in attempts to breastfeed. Metformin, which is associated with a increased risk of hypoglycemia in the Breastfeeding may also confer longer- lower risk of hypoglycemia and potential fi rst trimester and, like all women, have fi ts to both mother term metabolic bene lower weight gain, may be preferable to altered counterregulatory response in (29) and offspring (30).

104 Management of Diabetes in Pregnancy S97 care.diabetesjournals.org Gestational Diabetes Mellitus restriction. Antihypertensive drugs by 35% and 40%, respectively, over 10 years Initial Testing known to be effective and safe in preg- compared with placebo (35). Because GDM may represent preexist- nancy include methyldopa, labetalol, Pregestational Type 1 and Type 2 ing undiagnosed type 2 or even type 1 diltiazem, clonidine, and prazosin. Diabetes diabetes, women with GDM should be Chronic diuretic use during pregnancy Insulin sensitivity increases with delivery tested for persistent diabetes or predia- is not recommended as it has been as- of the placenta and then returns to pre- 12 weeks postpartum with a – betes at 6 sociated with restricted maternal plasma 2 – pregnancy levels over the following 1 75-g OGTT using nonpregnancy criteria volume, which may reduce uteroplacental weeks. In women taking insulin, particu- as outlined in Section 2 fi Classi “ cation perfusion (37). lar attention is needed to hypoglycemia and Diagnosis of Diabetes. ” prevention in the setting of erratic sleep References Postpartum Follow-up and eating schedules. If the pregnancy 1. Holmes VA, Young IS, Patterson CC, et al.; The OGTT is recommended over A1C Diabetes and Pre-eclampsia Intervention Trial has motivated the adoption of a healthier Study Group. Optimal glycemic control, pre- at the 6- to 12-week postpartum visit diet, building on these gains to support onal hypertension in eclampsia, and gestati because A1C may be persistently im- weight loss is recommended in the post- womenwithtype1diabetesinthediabetes pacted (lowered) by the increased red partum period. and pre-eclampsia intervention trial. Diabetes blood cell turnover related to pregnancy Care 2011;34:1683 – 1688 Contraception 2. Dabelea D, Hanson RL, Lindsay RS, et al. In- or blood loss at delivery. Because GDM A major barrier to effective preconcep- trauterine exposure to diabetes conveys risks is associated with increased maternal tion care is the fact that the majority of for type 2 diabetes and obesity: a study of dis- risk for diabetes, women should also – cordant sibships. Diabetes 2000;49:2208 2211 pregnancies are unplanned. Planning – be tested every 1 3 years thereafter if 3. Guerin A, Nisenbaum R, Ray JG. Use of ma- pregnancy is critical in women with pre- 6- to 12-week 75-g OGTT is normal, with ternal GHb concentration to estimate the risk of gestational diabetes due to the need for congenital anomalies in the offspring of women frequency of screening depending on preconception glycemic control and with prepregnancy diabetes. Diabetes Care other risk factors including family his- preventive health services. Therefore, 1925 – 2007;30:1920 tory, prepregnancy BMI, and need for 4. Jensen DM, Korsholm L, Ovesen P, et al. Peri- all women with diabetes of childbearing insulin or oral glucose-lowering medica- conceptional A1C and risk of serious adverse age should have family planning options tion during pregnancy.Ongoing screening pregnancy outcome in 933 women with type 1 reviewed at regular intervals. This ap- diabetes. Diabetes Care 2009;32:1046 – 1048 may be performed with any recommended plies to women in the immediate post- 5. Charron-Prochownik D, Sereika SM, Becker D, glycemic test (e.g., hemoglobin A1C, fast- et al. Long-term effects of the booster-enhanced partum period. Women with diabetes ing plasma glucose, or 75-g OGTT using READY-Girls preconception counseling program have the same contraception options nonpregnant thresholds). on intentions and behaviors for family planning and recommendations as those without in teens with diabetes. Diabetes Care 2013;36: Gestational Diabetes Mellitus and Type 2 diabetes. The risk of an unplanned preg- 3870 3874 – Diabetes nancy outweighs the risk of any given 6. Peterson C, Grosse SD, Li R, et al. Preventable Women with a history of GDM have a health and cost burden of adverse birth out- contraception option. comes associated with pregestational diabetes greatly increased risk of conversion to in the United States. Am J Obstet Gynecol 2015; PREGNANCY AND type 2 diabetes over time and not solely 212:74.e1 – 74.e9 ANTIHYPERTENSIVE DRUGS within the 6- to 12-week postpartum 7. Manderson JG, Patterson CC, Hadden DR, time frame (31). In the prospective In normal pregnancy, blood pressure is Traub AI, Ennis C, McCance DR. Preprandial ver- Health Study II, subsequent di- ’ Nurses lower than in the nonpregnant state. sus postprandial blood glucose monitoring in type 1 diabetic pregnancy: a randomized con- abetes risk after a history of GDM was In a pregnancy complicated by diabetes trolled clinical trial. Am J Obstet Gynecol 2003; and chronic hypertension, target goals cantly lower in women who fol- fi signi 189:507 – 512 of systolic blood pressure 110 – 129 mmHg lowed healthy eating patterns (32). Ad- Obstetrics. – 8. Committee on Practice Bulletins – and diastolic blood pressure 65 79 mmHg justing for BMI moderately, but not Practice Bulletin No. 137: gestational diabetes are reasonable. Lower blood pressure completely, attenuated this association. – mellitus. Obstet Gynecol 2013;122:406 416 9. Nielsen GL, Møller M, Sørensen HT. HbA1c in levels may be associated with im- Interpregnancy or postpartum weight early diabetic pregnancy and pregnancy out- paired fetal growth. In a 2015 study gain is associated with increased risk of comes: a Danish population-based cohort study adverse pregnancy outcomes in subse- targeting diastolic blood pressure of of 573 pregnancies in women with type 1 dia- quent pregnancies (33) and earlier pro- 100 mmHg versus 85 mmHg in preg- betes. Diabetes Care 2006;29:2612 2616 – gression to type 2 diabetes. nant women, only 6% of whom had 10. Suhonen L, Hiilesmaa V, Teramo K. Glycae- mic control during early pregnancy and fetal Both metformin and intensive life- GDM at enrollment, there was no differ- malformations in women with type I diabetes style intervention prevent or delay pro- ence in pregnancy loss, neonatal care, or mellitus. Diabetologia 2000;43:79 – 82 other neonatal outcomes, although gression to diabetes in women with 11. Maresh MJA, Holmes VA, Patterson CC, et al.; women in the less intensive treatment prediabetes and a history of GDM. Of Diabetes and Pre-eclampsia Intervention Trial group had a higher rate of uncontrolled women with a history of GDM and im- Study Group. Glycemic targets in the second and third trimester of pregnancy for women with hypertension (36). paired glucose tolerance, only 5 – 6indi- – 42 type 1 diabetes. Diabetes Care 2015;38:34 During pregnancy, treatment with viduals need to be treated with either 12. Nielsen LR, Ekbom P, Damm P, et al. HbA1c ACE inhibitors and angiotensin receptor intervention to prevent one case of di- cantly lower in early and late levels are signi fi abetes over 3 years (34). In these blockers is contraindicated, because they pregnancy. Diabetes Care 2004;27:1200 – 1201 women, lifestyle intervention and met- may cause fetal renal dysplasia, oligo- 13. Metzger BE, Lowe LP, Dyer AR, et al.; HAPO formin reduced progression to diabetes Study Cooperative Research Group. Hyperglycemia hydramnios, and intrauterine growth

105 Volume 39, Supplement 1, January 2016 Diabetes Care S98 Management of Diabetes in Pregnancy ́ ujo RM. Does and adverse pregnancy outcomes. N Engl J Med 30. Pereira PF, Alfenas RdeCG, Ara and insulin in women with gestational diabetes 2008;358:1991 2002 – – mellitus. N Engl J Med 2000;343:1134 1138 uence the risk of developing fl breastfeeding in 22. Coustan DR. Pharmacological management 14. Bain E, Crane M, Tieu J, Han S, Crowther CA, diabetes mellitus in children? A review of cur- of gestational diabetes: an overview. Diabetes Middleton P. Diet and exercise interventions for – rent evidence. J Pediatr (Rio J) 2014;90:7 15 S208 Care 2007;30(Suppl. 2):S206 – preventing gestational diabetes mellitus. Co- 31. Kim C, Newton KM, Knopp RH. Gestational ́ ` ́ a-Patterson A, Sol a I, Roqu ı 23. Balsells M, Garc e chrane Database Syst Rev 2015;4:CD010443 diabetes and the incidence of type 2 diabetes: a M, Gich I, Corcoy R. Glibenclamide, metformin, ̈ ̈ on o K, Klemetti MM, et al. 15. Koivusalo SB, R systematic review. Diabetes Care 2002;25: and insulin for the treatment of gestational dia- Gestational diabetes mellitus can be prevented 1868 – 1862 betes: a systematic review and meta-analysis. by lifestyle intervention: the Finnish Gestational 32. Tobias DK, Hu FB, Chavarro J, Rosner B, BMJ 2015;350:h102 Diabetes Prevention Study (RADIEL): a random- Mozaffarian D, Zhang C. Healthful dietary pat- 24. JiangY-F,ChenX-Y,DingT,WangX-F,Zhu ized controlled trial. Diabetes Care 2016;39:24 30 – terns and type 2 diabetes mellitus risk among cacy and safety fi Z-N, Su S-W. Comparative ef 16. Metzger BE, Buchanan TA, Coustan DR, women with a history of gestational diabetes of OADs in management of GDM: network et al. Summary and recommendations of the mellitus. Arch Intern Med 2012;172:1566 – meta-analysis of randomized controlled tri- Fifth International Workshop-Conference on 1572 – als. J Clin Endocrinol Metab 2015;100:2071 Gestational Diabetes Mellitus. Diabetes Care 33. Villamor E, Cnattingius S. Interpregnancy 2080 S260 2007;30(Suppl. 2):S251 – weight change and risk of adverse pregnancy ̈ urmer T, 25. Camelo Castillo W, Boggess K, St 17. Mayo K, Melamed N, Vandenberghe H, Berger outcomes: a population-based study. Lancet Brookhart MA, Benjamin DK Jr, Jonsson Funk H. The impact of adoption of the International 1170 – 2006;368:1164 M. Association of adverse pregnancy outcomes Association of Diabetes in Pregnancy Study Group 34. Ratner RE, Christophi CA, Metzger BE, et al.; with glyburide vs insulin in women with gesta- criteria for the screening and diagnosis of gesta- Diabetes Prevention Program Research Group. – tional diabetes. JAMA Pediatr 2015;169:452 tional diabetes. Am J Obstet Gynecol 2015;212: Prevention of diabetes in women with a history 458 224.e1 – 224.e9 of gestational diabetes: effects of metformin 26. Chew EY, Mills JL, Metzger BE, et al.; Na- 18. Hartling L, Dryden DM, Guthrie A, Muise M, and lifestyle interventions. J Clin Endocrinol tional Institute of Child Health and Human De- ts and harms fi Vandermeer B, Donovan L. Bene Metab 2008;93:4774 4779 – velopment Diabetes in Early Pregnancy Study. of treating gestational diabetes mellitus: a sys- 35. Aroda VR, Christophi CA, Edelstein SL, et al.; Metabolic control and progression of retinopa- tematic review and meta-analysis for the U.S. Diabetes Prevention Program Research Group. thy: the Diabetes in Early Pregnancy Study. Di- Preventive Services Task Force and the National The effect of lifestyle intervention and metfor- abetes Care 1995;18:631 – 637 fi Institutes of Health Of ce of Medical Applica- min on preventing or delaying diabetes among 27. Clausen TD, Mathiesen E, Ekbom P, Hellmuth tions of Research. Ann Intern Med 2013;159: women with and without gestational diabetes: E, Mandrup-Poulsen T, Damm P. Poor pregnancy – 123 129 the Diabetes Prevention Program Outcomes outcome in women with type 2 diabetes. Diabe- 19. Rowan JA, Hague WM, Gao W, Battin MR, Study 10-year follow-up. J Clin Endocrinol 328 – tes Care 2005;28:323 Moore MP; MiG Trial Investigators. Metformin Metab 2015;100:1646 – 1653 28. Cundy T, Gamble G, Neale L, et al. Differing versus insulin for the treatment of gestational 36. Magee LA, von Dadelszen P, Rey E, et al. causes of pregnancy loss in type 1 and type 2 – diabetes. N Engl J Med 2008;358:2003 2015 Less-tight versus tight control of hypertension diabetes. Diabetes Care 2007;30:2603 – 2607 20. Gui J, Liu Q, Feng L. Metformin vs insulin in – in pregnancy. N Engl J Med 2015;372:407 417 29. Stuebe AM, Rich-Edwards JW, Willett WC, the management of gestational diabetes: a 37. Sibai BM. Treatment of hypertension in Manson JE, Michels KB. Duration of lactation meta-analysis. PLoS One 2013;8:e64585 pregnant women. N Engl J Med 1996;335: and incidence of type 2 diabetes. JAMA 2005; 21. Langer O, Conway DL, Berkus MD, Xenakis 2610 294:2601 – EM-J, Gonzales O. A comparison of glyburide 257 – 265

106 Diabetes Care Volume 39, Supplement 1, January 2016 S99 American Diabetes Association 13. Diabetes Care in the Hospital Diabetes Care 2016;39(Suppl. 1):S99 S104 | DOI: 10.2337/dc16-S016 – Recommendations c Consider performing an A1C on all patients with diabetes or hyperglycemia C admitted to the hospital if not performed in the prior 3 months. c Insulin therapy should be initiated for treatment of persistent hyperglycemia starting at a threshold $ 180 mg/dL (10.0 mmol/L). Once insulin therapy is started, a target glucose range of 140 – 180 mg/dL (7.8 – 10.0 mmol/L) is recom- C and noncritically ill patients. A mended for the majority of critically ill patients 7.8 mmol/L) may be ap- – c More stringent goals, such as 110 140 mg/dL (6.1 – propriate for selected critically ill patients, as long as this can be achieved 13. DIABETES CARE IN THE HOSPITAL C cant hypoglycemia. fi without signi Intravenous insulin infusions should be administered using validated written or c ned adjustments in the insulin computerized protocols that allow for prede fi infusion rate based on glycemic E uctuations and insulin dose. fl c A basal plus bolus correction insulin regimen is the preferred treatment for noncritically ill patients with poor oral intake or those who are taking nothing by mouth. An insulin regimen with basal, nutritional, and correction compo- nents is the preferred treatment for patients with good nutritional intake. A The sole use of sliding scale insulin in the inpatient hospital setting is strongly c discouraged. A A hypoglycemia management protocol should be adopted and implemented c by each hospital or hospital system. A plan for preventing and treating hypo- glycemia should be established for each patient. Episodes of hypoglycemia in E the hospital should be documented in the medical record and tracked. c The treatment regimen should be reviewed and changed if necessary to prevent , 70 mg/dL (3.9 mmol/L). C further hypoglycemia when a blood glucose value is B There should be a structured discharge plan tailored to the individual patient. c Both hyperglycemia and hypoglycemia are associated with adverse outcomes, in- cluding death (1,2). Therefore, hospital goals for the patient with diabetes include preventing both hyperglycemia and hypog lycemia, promoting the shortest safe hospital stay, and providing an effective transition out of the hospital that prevents complications and readmission. High-quality hospital care requires both hospital care delivery standards, often lity assurance standards for process assured by structured order sets, and qua improvement. HOSPITAL CARE DELIVERY STANDARDS Best practice ” protocols, reviews, and guidelines (2) are inconsistently imple- “ mented within hospitals. To correct this, hospitals have established protocols for structured patient care and structured order sets, which include computerized physician order entry (CPOE). Computerized Physician Order Entry In 2009, the federal Health Information Technology for Economic and Clinical Health Suggested citation: American Diabetes Associa- rement for stage 1 of the HITECH Act ’ s (HITECH) Act was enacted. A core requi tion. Diabetes care in the hospital. Sec. 13. In ” meaningful use “ included CPOE. The Institute of Medicine also recommends d Standards of Medical Care in Diabetes . 2016 ciency in medication fi CPOE to prevent medication-related errors and increase ef S104 – Diabetes Care 2016;39(Suppl. 1):S99 administration (3). A Cochrane review of randomized controlled trials using com- © 2016 by the American Diabetes Association. fi cant im- puterized advice to improve glucose control in the hospital found signi Readers may use this article as long as the work provement in percentage of time in target glucose range, lower mean blood glucose, is properly cited, the use is educational and not for pro fi t, and the work is not altered. “ and no increase in hypoglycemia (4). As hospitals move to comply with meaningful

107 Volume 39, Supplement 1, January 2016 Diabetes Care S100 Diabetes Care in the Hospital use, efforts should be made to ensure ” for glycemic fl uctuations and insulin dose insulin therapy is initiated, a glucose target that all components of structured insu- (2,12). – 10.0 mmol/L) is rec- – of 140 180 mg/dL (7.8 lin order sets are incorporated in the ommended for most critically ill patients Noncritical Care Setting orders (5). Thus, where feasible, there 140 (2). More stringent goals, such as 110 – Outside of critical care units, scheduled should be routine structured order sets mg/dL (6.1 7.8 mmol/L) may be appropri- – subcutaneous insulin injections should that produce computerized advice for ate for select patients, such as cardiac sur- align with meals and bedtime or every glucose control. gery patients (7), and patients with acute 4 – 6 h if no meals orif continuous enteral/ ischemic cardiac (9) or neurological events parenteral therapy is used (2). A basal CONSIDERATIONS ON ADMISSION provided the targets can be achieved plus correction insulin regimen is the cant hypoglycemia. fi without signi Initial orders should state that the pa- preferred treatment for patients with A glucose target between 140 and 180 tient has type 1 diabetes or type 2 diabe- poor oral intake or those who are taking mg/dL (between 7.8 and 10.0 mmol/L) is tes or no previous history of diabetes. If nothing by mouth (NPO) (13). An insulin recommended for most patients in non- the patient has diabetes, an order for an regimen with basal, nutritional, and critical care units (2). Patients with a prior A1C should be placed if none is available correction components (basal bolus) is – history of successful tight glycemic con- within the prior 3 months (2). In addition, the preferred treatment for patients trol in the outpatient setting who are clin- diabetes self-management education with good nutritional intake (10). In ically stable may be maintained with a should be ordered and should include such instances, point-of-care (POC) glu- glucose target below 140 mg/dL appropriate skills needed after dis- cose testing should be performed imme- (7.8 mmol/L). Conversely, higher glucose charge, such as taking glycemic medica- diately before meals. ranges may be acceptable in terminally ill tion, glucose monitoring, and coping with If oral intake is poor, a safer procedure patients, in patients with severe comor- hypoglycemia (2). is to administer the short-acting insulin bidities, and in in-patient care settings after the patient eats or to count the car- GLYCEMIC TARGETS IN where frequent glucose monitoring or bohydrates and cover the amount in- HOSPITALIZED PATIENTS close nursing supervision is not feasible. gested. A randomized controlled trial Clinical judgment combined with ongo- Standard De nition of Glucose fi has shown that basal – bolus treatment ’ s clinical ing assessment of the patient Abnormalities improved glycemic control and reduced status, including changes in the trajectory Hyperglycemia in hospitalized patients hospital complications compared with of glucose measures, illness severity, nu- fi has been de ned as blood glucose sliding scale insulin in general surgery tritional status, or concomitant medica- . 140 mg/dL (7.8 mmol/L). Blood glu- patients with type 2 diabetes (14). tions that might affect glucose levels fi cantly and cose levels that are signi Type 1 Diabetes (e.g., glucocorticoids), should be incorpo- persistently above this level require re- For patients with type 1 diabetes, dosing assessing treatment. An admission A1C rated into the day-to-day decisions re- insulin based solely on premeal glucose 6.5% (48 mmol/mol) suggests $ value garding insulin doses (2). levels does not account for basal insulin that diabetes preceded hospitalization requirements or calorie intake, increas- fi cation and Diag- (see Section 2 “ Classi ANTIHYPERGLYCEMIC AGENTS IN ing both hypoglycemia and hyperglyce- ). Hypoglycemia in nosis of Diabetes ” HOSPITALIZED PATIENTS mia risks and potentially leading to fi hospitalized patients has been de ned In most instances in the hospital setting, diabetic ketoacidosis (DKA). Typically , 70 mg/dL (3.9 mmol/L) as blood glucose insulin is the preferred treatment for basal insulin dosing schemes are based 40 mg/dL , and severe hypoglycemia as glycemic control (2). However, in certain on body weight, with some evidence (2.2 mmol/L) (6). circumstances, it may be appropriate to that patients with renal insuf ciency fi continue home regimens including oral should be treated with lower doses (15). Moderate Versus Tight Glycemic antihyperglycemic medications (10). If Control Transitioning Intravenous to oral medications are held in the hospi- Glycemic goals within the hospital set- Subcutaneous Insulin tal, there should be a protocol for re- ting have changed in the last 14 years. When discontinuing intravenous insulin, a – 2 days before discharge. suming them 1 – The initial target of 80 – 110 mg/dL (4.4 transition protocol is associated with 6.1 mmol/L) was based on a 42% relative less morbidity and lower costs of care Insulin Therapy reduction in intensive care unit mortal- (16) and is therefore recommended. A The sole use of sliding scale insulin in the ity in critically ill surgical patients (7). patient with type 1 or type 2 diabetes inpatient hospital setting is strongly dis- However, a meta-analysis of over 26 stud- being transitioned to outpatient subcu- couraged (2,11). ies, including the largest, Normoglycemia taneous insulin should receive sub- Critical Care Setting – Survival in Intensive Care Evaluation – cutaneous insulin 1 2hbeforethe In the critical care setting, continuous Using Glucose Algorithm Regulation intravenous insulin is discontinued. intravenous insulin infusion has been (NICE-SUGAR), showed increased rates 80% Converting to basal insulin at 60 – shown to be the best method for achiev- of severe hypoglycemia and mortality of the daily infusion dose has been ing glycemic targets. Intravenous insulin in tightly versus moderately controlled showntobeeffective(2,16,17). infusions should be administered based cohorts (8). This evidence established on validated written or computerized new standards: initiate insulin therapy Noninsulin Therapies fi protocols that allow for prede ned ad- The safety and ef fi cacy of noninsulin for persistent hyperglycemia greater antihyperglycemic therapies in the hospital justments in the infusion rate, accounting than 180 mg/dL (10.0 mmol/L). Once

108 Diabetes Care in the Hospital S101 care.diabetesjournals.org setting is an area of active research. A re- 2. Preoperative risk assessment for pa- any correctable underlying cause of cent randomized pilot trial in general tients at high risk for ischemic heart DKA, such as sepsis. Low-dose insulin, disease and those with autonomic given intravenously, intramuscularly, or medicine and surgery patients reported neuropathy or renal failure. subcutaneously, is safe and effective in that a dipeptidyl peptidase 4 inhibitor 3. The morning of surgery or proce- treating DKA (23). alone or in combination with basal insulin dure, hold any oral hypoglycemic Several studies have shown that in was well tolerated and resulted in similar agents and give half of NPH dose or uncomplicated mild-to-moderate DKA, glucose controland frequencyofhypogly- full doses of a long-acting analog or subcutaneous lispro (24) or aspart insu- bolus regi- – cemia compared with a basal pump basal insulin. lin (25) dosed every 1 – 2 h is as effective men (18). A report suggested that given 6h – 4. Monitor blood glucose every 4 and safe as intravenous regular insulin the serious consequences of hypoglyce- while NPO and dose with short- when used in conjunction with standard mia, incretin agents, which do not cause acting insulin as needed. intravenous fl uid and potassium replace- hypoglycemia, may substitute for insulin, ment protocols (23). If subcutaneous ad- sulfonylureas, or metformin (19). A re- A review found that tight peri- ministration is used, it is important, for view of several studies concluded that in- operative glycemic control did not im- safety reasons, to provide adequate nurs- cretins show promise; however, proof of prove outcomes and was associated ing training and care and frequent bed- fi safety and ef cacy compared with stan- with more hypoglycemia (22); there- side testing. However, in critically ill and dard therapies await the results of further fore, in general, tighter glycemic targets mentally obtunded patients, continuous randomized controlled trials (20). than mentioned above are not advised. intravenous insulin infusion is required. Several studies have shown that the use STANDARDS FOR SPECIAL Moderate Versus Tight Glycemic of bicarbonate in patients with DKA made SITUATIONS Control Targets no difference in resolution of acidosis or Enteral/Parenteral Feedings In general surgery (noncardiac) patients, time to discharge, and its use is generally For full enteral/parenteral feeding guid- basal insulin plus premeal regular or not recommended (26). ance, the reader is encouraged to consult bolus) cover- short-acting insulin (basal – review articles (2,21) and see Table 13.1 . Continuous Glucose Monitoring age has been associated with improved Continuous glucose monitoring (CGM) glycemic control and lower rates of peri- Glucocorticoid Therapy provides continuous estimates, direction, operative complications compared with The duration of glucocorticoid action and magnitude of glucose trends, which the traditional sliding scale regimen must be considered to prevent hyper- may have an advantage over POC glucose (regular or short-acting insulin coverage glycemia. Once-a-day short-acting ste- testing in detecting and reducing the in- only with no basal dosing) (13,14). roids such as prednisone peak in about cidence of hypoglycemia. Several studies 8 h, so coverage with intermediate- Diabetic Ketoacidosis and have shown that CGM use did not im- Hyperosmolar Hyperglycemic State fi acting insulin (NPH) may be suf cient. For prove glucose control, but detected a There is considerable variability in the long-acting steroids such as dexametha- greater number of hypoglycemic events presentation of DKA and hyperosmolar sone or multidose or continuous steroid than POC testing. A recent review has rec- hyperglycemic state, ranging from eu- use, long-acting insulin may be used ommended against using CGM in adults glycemia or mild hyperglycemia and (10,21). Whatever orders are started, in a hospital setting until more safety and acidosis to severe hyperglycemia, adjustments based on POC glucose test ef fi cacy data become available (27). dehydration, and coma; therefore, results are critical. TREATING AND PREVENTING treatment individualization based on a HYPOGLYCEMIA careful clinical and laboratory assess- Perioperative Care ment is needed (23). Standards for perioperative care include Patients with or without diabetes may Management goals include restora- the following: experience hypoglycemia in the hospital tion of circulatory volume and tissue setting. While increased mortality is as- 1. Target glucose range for the peri- perfusion, resolution of hyperglycemia, sociated with hypoglycemia, it may be a operative period should be 80 – 180 and correction of electrolyte imbalance marker of underlying disease rather mg/dL (4.4 – 10.0 mmol/L). and ketosis. It is also important to treat than the cause of increased mortality. However, until it is proven not to be Insulin dosing for enteral/parenteral feedings — Table 13.1 causal, it is prudent to avoid hypoglyce- mia. Despite the preventable nature of Situation Basal Bolus many inpatient episodes of hypoglyce- Glargine q.d. or SQ rapid-acting correction Continuous enteral feedings mia, institutions are more likely to have every 4 h NPH/detemir b.i.d. nursing protocols for hypoglycemia SQ rapid-acting insulin with Continue prior basal; Bolus enteral feedings treatment than for its prevention when each bolus feeding to cover if none, consider 10 units NPH or the bolus feeding and to both are needed. correct for hyperglycemia glargine insulin Triggering Events Regular insulin to Rapid-acting insulin SQ every Parenteral feedings Iatrogenic hypoglycemia triggers may in- TPN IV bottle 4 h to correct for hyperglycemia clude sudden reduction of corticosteroid IV, intravenous; SQ, subcutaneous; TPN, total parenteral nutrition. dose, altered ability of the patient to

109 Volume 39, Supplement 1, January 2016 Diabetes Care S102 Diabetes Care in the Hospital report symptoms, reduced oral intake, hypoglycemia protocol be adopted and Orders should also re ect that the meal fl emesis, new NPO status, inappropriate implemented in eac h hospital system, delivery and nutritional insulin coverage timing of short-acting insulin in relation and all episodes should be tracked in be matched, as their variability often to meals, reduced infusion rate of intrave- the medical records (2). creates the possibility of hyperglycemic nous dextrose, and unexpected interrup- and hypoglycemic events. SELF-MANAGEMENT IN THE tion of oral, enteral, or parenteral feedings. HOSPITAL TRANSITION FROM THE ACUTE Predictors of Hypoglycemia Diabetes self-management in the hos- CARE SETTING In one study, 84% of patients with an pital may be appropriate for select A Cochrane systematic review noted episode of severe hypoglycemia ( , 40 youth and adult patients. Candidates that a structured discharge plan tailored mg/dL [2.2 mmol/L]) had a prior episode include patients who successfully con- of hypoglycemia ( , 70 mg/dL [3.9 to the individual patient may reduce duct self-management of diabetes at mmol/L]) during the same admission length of hospital stay, readmission rates, home, have the cognitive and physical (28). In another study of hypoglycemic and increase patient satisfaction (33). skills needed to successfully self- episodes ( , 50 mg/dL [2.8 mmol/L]), Therefore, there should be a structured administer insulin, and perform self- 78% of patients were using basal insulin, discharge plan tailored to each patient. monitoring of blood glucose. In addition, with the incidence of hypoglycemia peak- Discharge planning should begin at ad- they should have adequate oral intake, A.M. Despite ing between midnight and 6 mission and be updated as patient needs fi cient in carbohydrate estima- be pro recognition of hypoglycemia, 75% of pa- change. tion, use multiple daily insulin injec- tients did not have their dose of basal in- Transition from the acute care setting tions or continuous subcutaneous sulin changed before the next insulin is a risky time for all patients. Inpatients insulin infusion (CSII) pump therapy, administration (29). may be discharged to varied settings, have stable insulin requirements, and including home (with or without visiting understand sick-day management. If Hypoglycemia Treatment nurse services), assisted living, rehabili- self-management is to be used, a pro- There should be a standardized hospital- tation, or skilled nursing facilities. For tocol should include a requirement wide, nurse-initiated hypoglycemia the patient who is discharged to assisted that the patient, nursing staff, and phy- treatment protocol to immediately ad- living or to home, the optimal program sician agree that patient self-management 70 mg/dL [3.9 dress hypoglycemia ( , will need to consider diabetes type and is appropriate. If CSII is to be used, hospital mmol/L]) (2). sillness ’ severity, effects of the patient policy and procedures delineating guide- s ’ on blood glucose levels, and the patient lines for CSII therapy are advised (31). Prevention capacities and desires. Common preventable sources of iatro- An outpatient follow-up visit with MEDICAL NUTRITION THERAPY IN genic hypoglycemi a are improper pre- the primary care provider, endocrinol- THE HOSPITAL scribing of hypoglycemic medications, ogist, or diabetes educator within 1 The goals of medical nutrition therapy are fi inappropriate management of the rst month of discharge is advised for all to optimize glycemic control, provide episode of hypoglycemia, and nutrition – patients having hyperglycemia in the to meet metabolic adequate calories insulin mismatch, often related to an hospital. If glycemic medications are demands, address personal food pre- unexpected interruption of nutrition. A changed or glucose control is not opti- ferences, and create a discharge plan. study of ” “ bundled preventative thera- mal at discharge, continuing contact The ADA does not endorse any single pies including proactive surveillance of may be needed to avoid hyperglycemia fi meal plan or speci ed percentages of glycemic outliers and an interdisciplinary and hypoglycemia. A recent discharge ADA “ macronutrients, and the term data-driven approach to glycemic man- algorithm for glycemic medication ad- ” diet should no longer be used. Current agement showed that hypoglycemic justment based on admission A1C nutrition recommendations advise indi- episodes in the hospital could be pre- found that the average A1C in patients vidualization based on treatment goals, vented. Compared with baseline, the with diabetes decreased from 8.7% (72 physiologicalparameters, andmedication study found that the relative risk of a se- mmol/mol) on admission to 7.3% (56 use. Consistent carbohydrate meal plans vere hypoglycemic event was 0.44 (95% mmol/mol) 3 months after discharge are preferred by many hospitals as they CI 0.34 0.58) in the postintervention pe- – (34). Therefore, if an A1C from the prior facilitate matching the prandial insulin riod (30). 3 months is unavailable, measuring the dose to the amount of carbohydrate con- A1C in all patients with diabetes or hy- sumed (32). Hospital Hypoglycemia Prevention perglycemia admitted to the hospital is When the nutritional issues in the and Treatment The Joint Commission recommends that hospital are complex, a registered dieti- recommended. all hypoglycemic episodes be evaluated tian, knowledgeable and skilled in med- Clear communication with outpatient for a root cause and the episodes be ical nutrition therapy, can serve as an providers either directly or via hospital aggregated and reviewed to address individual inpatient team member. discharge summaries facilitates safe systemic issues. An American Diabetes That person should be responsible for transitions to outpatient care. Providing Association (ADA) hypoglycemia con- integrating information about the pa- information regarding the cause of hy- sensus report suggested that the treat- tient ’ s clinical condition, meal planning, perglycemia (or the plan for determin- ment regimen be reviewed when a blood and lifestyle habits and for establishing ing the cause), related complications , glucose value is 70 mg/dL (3.9 mmol/L), a realistic treatment goals after discharge. and comorbidities, and recommended

110 Diabetes Care in the Hospital S103 care.diabetesjournals.org treatments can assist outpatient pro- with appropriate education at the time status should be con fi rmed through con- viders as they assume ongoing care. of discharge in order to avoid a poten- ventional laboratory glucose tests. The The Agency for Healthcare Research tially dangerous hiatus in care. FDA established a separate category for and Quality (AHRQ) recommends that POC glucose meters for use in health care Quality Assurance Standards at a minimum, discharge plans include settings and has released a draft on in- Even the best orders may not be carried the following (35): hospital use with stricter standards. Before outin a way that improves quality, norare ’ choosing a device, consider the device s they automatically updated when new approval status and accuracy. Medication Reconciliation evidence arises. To this end, the Joint ○ The patient s medications must be ’ Commissionhasan accreditation program References cross-checked to ensure that no for the hospital care of diabetes, and the 1. Clement S, Braithwaite SS, Magee MF, et al.; chronic medications were stopped Society of Hospital Medicine has a work- American Diabetes Association Diabetes in Hos- and to ensure the safety of new book for program development (36). pitals Writing Committee. Management of dia- prescriptions. betes and hyperglycemia in hospitals. Diabetes ○ Prescriptions for new or changed 591 Care 2004;27:553 – DIABETES CARE PROVIDERS 2. Moghissi ES, Korytkowski MT, DiNardo M, IN THE HOSPITAL lled and re- fi medication should be et al.; American Association of Clinical Endocri- viewed with the patient and family Appropriately trained specialists or spe- abetes Association. nologists; American Di at or before discharge. cialty teams may reduce length of stay, American Association of Clinical Endocrinolo- gists and American Diabetes Association con- improve glycemic control, and improve Structured Discharge Communication sensus statement on inpatient glycemic outcomes, but the studies are few. A ○ control. Diabetes Care 2009;32:1119 1131 – Information on medication changes, call to action outlined the studies needed 3. Institute of Medicine. Preventing Medication pending tests and studies, and to evaluate these outcomes (11). Details Errors . Aspden P, Wolcott J, Bootman JL, follow-up needs must be accurately of team formation are available from the Cronenwett LR, Eds. Washington, DC, The and promptly communicated to National Academies Press, 2007 Society ofHospital Medicine and the Joint outpatient physicians. 4. Gillaizeau F, Chan E, Trinquart L, et al. Com- Commission standards for programs. ○ puterized advice on drug dosage to improve Discharge summaries should be prescribing practice. Cochrane Database Syst transmitted to the primary physician BEDSIDE BLOOD GLUCOSE Rev 2013;11:CD002894 as soon as possible after discharge. MONITORING 5. Wexler DJ, Shrader P, Burns SM, Cagliero E. ○ Appointment-keeping behavior is Effectiveness of a computerized insulin order Indications enhanced when the inpatient template in general medical inpatients with Bedside POC blood glucose monitoring type 2 diabetes: a cluster randomized trial. Di- team schedules outpatient medi- guides insulin dosing. In the patient re- abetes Care 2010;33:2181 – 2183 cal follow-up prior to discharge. ceiving nutrition, glucose monitoring 6. Seaquist ER, Anderson J, Childs B, et al. Hy- should be performed before meals to poglycemia and diabetes: a report of a work- It is recommended that the following group of the American Diabetes Association match food ingestion. In the patient areas of knowledge be reviewed and ad- and the Endocrine Society. Diabetes Care not receiving nutrition, glucose moni- – 2013;36:1384 1395 dressed prior to hospital discharge: toring is advised every 4 6h(2).More – 7. van den Berghe G, Wouters P, Weekers F, frequent blood glucose testing ranging et al. Intensive insulin therapy in critically ill ○ Identifythehealthcareprovider from every 30 min to every 2 h is re- patients. N Engl J Med 2001;345:1359 1367 – who will provide diabetes care 8. Finfer S, Chittock DR, Su SY-S, et al.; NICE- quired for patients receiving intrave- after discharge. SUGAR Study Investigators. Intensive versus nous insulin. Safety standards should ○ conventional glucose control in critically ill pa- Level of understanding related to the be established for blood glucose moni- 1297 – tients. N Engl J Med 2009;360:1283 diabetes diagnosis, self-monitoring nger- toring that prohibit the sharing of fi 9. Steg PG, James SK, Atar D, et al.; Task Force of blood glucose, and explanation stick lancing devices, lancets, needles, onthemanagementofST-segmentelevation of home blood glucose goals. acute myocardial infarction of the European So- and pens to reduce the risk of transmis- ○ De fi nition, recognition, treatment, ciety of Cardiology (ESC). ESC Guidelines for the sion of blood-borne diseases. management of acute myocardial infarction in and prevention of hyperglycemia patients presenting with ST-segment elevation. Limitations in the Hospital Setting and hypoglycemia. 2619 – Eur Heart J 2012;33:2569 ○ POC meters have limitations for measur- Information on consistent nutri- 10. Maynard G, Wesorick DH, O ’ Malley C, ing blood glucose. Although the U.S. Food tion habits. Inzucchi SE; Society of Hospital Medicine Glyce- ○ and Drug Administration (FDA) has stan- If relevant, when and how to take mic Control Task Force. Subcutaneous insulin dards for blood glucose meters used by lowering medica- – blood glucose order sets and protocols: effective design and implementation strategies. J Hosp Med 2008;3 lay persons, there have been questions tions, including insulin administra- 41 – (Suppl.):29 about the appropriateness of these crite- tion. 11. Draznin B, Gilden J, Golden SH, et al.; PRIDE ○ ria, especially inthe hospital andforlower Sick-day management. Investigators. Pathways to quality inpatient man- ○ cant blood glucose readings (37). Signi fi Proper use and disposal of needles agement of hyperglycemia and diabetes: a call to discrepancies between capillary, venous, and syringes. action. Diabetes Care 2013;36:1807 – 1814 12. Umpierrez G, Cardona S, Pasquel F, et al. and arterial plasma samples have been Randomized controlled trial of intensive versus It is important that patients be pro- observed in patients with low or high he- conservative glucose control in patients under- vided with appropriate durable medical moglobin concentrations and with hypo- going coronary artery bypass graft surgery: equipment, medications, supplies (e.g., perfusion. Any glucose result that does GLUCO-CABG trial. Diabetes Care 2015;38: insulin pens), and prescriptions along ’ not correlate with the patient s clinical 1665 – 1672

111 Volume 39, Supplement 1, January 2016 Diabetes Care S104 Diabetes Care in the Hospital 13. Umpierrez GE, Smiley D, Hermayer K, et al. proven itself and is considered the mainstay of during hospitalization. Endocr Pract 2015;21: Randomized study comparing a basal-bolus 2117 – treatment. Diabetes Care 2013;36:2112 507 – 501 with a basal plus correction insulin regimen 21. Corsino L, Dhatariya K, Umpierrez G. 30. Maynard G, Kulasa K, Ramos P, et al. Impact for the hospital management of medical and Management of Diabetes and Hyperglycemia of a hypoglycemia reduction bundle and a sys- surgical patients with type 2 diabetes: basal in Hospitalized Patients , 2000 [Internet]. tems approach to inpatient glycemic manage- – plus trial. Diabetes Care 2013;36:2169 2174 Available from http://www.ncbi.nlm.nih – ment. Endocr Pract 2015;21:355 367 14. Umpierrez GE, Smiley D, Jacobs S, et al. Ran- .gov/books/NBK279093/. Accessed 6 October 31. Houlden RL, Moore S. In-hospital manage- domized study of basal-bolus insulin therapy in 2015 ment of adults using insulin pump therapy. Can J ́ the inpatient management of patients with ı 22. Buchleitner AM, Mart nez-Alonso M, 133 – Diabetes 2014;38:126 ́ ` type 2 diabetes undergoing general surgery andez M, Sol a I, Mauricio D. Perioperative Hern 32. Curll M, Dinardo M, Noschese M, (RABBIT 2 surgery). Diabetes Care 2011;34: glycaemic control for diabetic patients undergo- Korytkowski MT. Menu selection, glycaemic – 256 261 ing surgery. Cochrane Database Syst Rev 2012; control and satisfaction with standard and patient- 15. Baldwin D, Zander J, Munoz C, et al. A ran- 9:CD007315 controlled consistent carbohydrate meal plans domized trial of two weight-based doses of in- 23.KitabchiAE,UmpierrezGE,MilesJM, in hospitalised patients with diabetes. Qual Saf sulin glargine and glulisine in hospitalized Fisher JN. Hyperglycemic crises in adult pa- – 359 Health Care 2010;19:355 - subjects with type 2 diabetes and renal insuf fi tients with diabetes. Diabetes Care 2009;32: 33. Shepperd S, Lannin NA, Clemson LM, 1974 ciency. Diabetes Care 2012;35:1970 – 1335 – 1343 McCluskey A, Cameron ID, Barras SL. Discharge 16. Schmeltz LR, DeSantis AJ, Thiyagarajan V, 24. Umpierrez GE, Latif K, Stoever J, et al. Ef fi - planning from hospital to home. Cochrane et al. Reduction of surgical mortality and mor- cacy of subcutaneous insulin lispro versus con- Database Syst Rev 2013;1:CD000313 bidity in diabetic patients undergoing cardiac tinuous intravenous regular insulin for the 34. Umpierrez GE, Reyes D, Smiley D, et al. Hos- surgery with a combined intravenous and sub- treatment of patients with diabetic ketoacidosis. pital discharge algorithm based on admission for the management of patients with cutaneous insulin glucose management strat- Am J Med 2004;117:291 – 296 HbA 1c type 2 diabetes. Diabetes Care 2014;37:2934 – egy. Diabetes Care 2007;30:823 828 – 25. Umpierrez GE, Cuervo R, Karabell A, Latif K, 2939 17. Shomali ME, Herr DL, Hill PC, Pehlivanova Freire AX, Kitabchi AE. Treatment of diabetic 35. Agency for Healthcare Research and Qual- M, Sharretts JM, Magee MF. Conversion from ketoacidosis with subcutaneous insulin aspart. ity. Adverse events after hospital discharge [In- intravenous insulin to subcutaneous insulin af- 1878 – Diabetes Care 2004;27:1873 ternet], 2014. Available from http://psnet.ahrq ter cardiovascular surgery: transition to target 26. Duhon B, Attridge RL, Franco-Martinez AC, .gov/primer.aspx?primerID 5 11. Accessed 1 – 126 study. Diabetes Technol Ther 2011;13:121 Maxwell PR, Hughes DW. Intravenous sodium October 2015 18. Umpierrez GE, Gianchandani R, Smiley D, bicarbonate therapy in severely acidotic dia- 36. Society of Hospital Medicine. Clinical et al. Safety and ef fi cacy of sitagliptin therapy betic ketoacidosis. Ann Pharmacother 2013; Tools: Glycemic Control Implementation Tool- for the inpatient management of general med- 975 47:970 – kit [Internet]. Available from http://www icine and surgery patients with type 2 diabetes: 27. Gomez AM, Umpierrez GE. Continuous glu- .hospitalmedicine.org/Web/Quality_Innovation/ a pilot, randomized, controlled study. Diabetes cose monitoring in insulin-treated patients in s/Glycemic_Control/Web/ Implementation_Toolkit Care 2013;36:3430 – 3435 non-ICU settings. J Diabetes Sci Technol 2014; Quality___Innovation/Implementation_ 19. Schwartz SS, DeFronzo RA, Umpierrez GE. 936 8:930 – ools/Clinical_Tools.aspx. Toolkit/Glycemic/Clinical_T Practical implementation of incretin-based 28. Dendy JA, Chockalingam V, Tirumalasetty Accessed 25 August 2015 therapy in hospitalized patients with type 2 di- NN, et al. Identifying risk factors for severe hy- fi 37. Boyd JC, Bruns DE. Quality speci cations for 257 abetes. Postgrad Med 2015;127:251 – poglycemia in hospitalized patients with diabe- glucose meters: assessment by simulation mod- 20. Umpierrez GE, Korytkowski M. Is incretin- 1056 – tes. Endocr Pract 2014;20:1051 eling of errors in insulin dose. Clin Chem 2001; based therapy ready for the care of hospitalized 29. Ulmer BJ, Kara A, Mariash CN. Temporal oc- – 214 47:209 patients with type 2 diabetes? Insulin therapy has currencesandrecurrencepatternsofhypoglycemia

112 Diabetes Care Volume 39, Supplement 1, January 2016 S105 American Diabetes Association 14. Diabetes Advocacy Diabetes Care 2016;39(Suppl. 1):S105 S106 | DOI: 10.2337/dc16-S017 – Managing the daily health demands of diabetes can be challenging. People living with diabetes should not have to face additional dis crimination due to diabetes. By advocating ls, the American Diabetes Association (ADA) for the rights of those with diabetes at all leve can help to ensure that they live a healthy and productive life. A strategic goal of the ADA is that more children and adults with diabetes live free from the burden of discrimination. sStandardsof One tactic for achieving this goal is to implement the ADA ’ Medical Care through advocacy-oriented position statements. The ADA publishes evidence-based, peer-reviewed statements on topics such as diabetes and em- ployment, diabetes and driving, and dia betes management in certain settings rrectional institutions. In addition to such as schools, child care programs, and co 14. DIABETES ADVOCACY advocacy position statements are im- s clinical position statements, these ’ ADA portant tools in educating schools, employers, licensing agencies, policymakers, and others about the intersection o f diabetes medicine and the law. ADVOCACY POSITION STATEMENTS rst fi Partial list, with most recent publications appearing Diabetes Care in the School Setting (1) First publication: 1998 (revised 2015) A sizeable portion of a child ’ s day is spent in school, so close communication with and cooperation of school personnel are essential to optimize diabetes manage- Diabe- “ ment, safety, and academic opportunities. See the ADA position statement ” tes Care in the School Setting (http://care.diabetesjournals.org/content/38/10/ 1958.full.pdf 1 html). Care of Young Children With Diabetes in the Child Care Setting (2) First publication: 2014 , Very young children (aged 6 years) with diabetes have legal protections and can rs with appropriate training, access to be safely cared for by child care provide resources, and a system of communication with parents and the child s diabetes ’ “ provider. See the ADA position statement Care of Young Children With Diabetes in (http://care.diabetesjournals.org/content/37/10/2834). the Child Care Setting ” Diabetes and Driving (3) First publication: 2012 Peoplewithdiabeteswhowishtooperatemotorvehiclesaresubjecttoagreatvarietyof and federal jurisdictions, which may lead to licensing requirements applied by both state loss of employment or signi cant restrictions on a person ’ s license. Presence of a medical fi cantly impaired consciousness or cognition may lead to condition that can lead to signi fi tness to drive. People with diabetes should be individually fi drivers being evaluated for dgeable in diabetes if license restrictions assessed by a health care professional knowle are being considered, and patients should b e counseled about detecting and avoiding hypoglycemia while driving. See the ADA position statement ” Diabetes and Driving “ (http://care.diabetesjournals.org /content/37/Supplement_1/S97). Suggested citation: American Diabetes Associa- Diabetes and Employment (4) tion. Diabetes advocacy. Sec. 14. In Standards of First publication: 1984 (revised 2009) Medical Care in Diabetes d 2016 . Diabetes Care Any person with diabetes, whether insulin trea ted or noninsulin treated, should be eligible 2016;39(Suppl. 1):S105 S106 – for any employment for which he or she is otherwise quali fi ed. Employment decisions © 2016 by the American Diabetes Association. should never bebased on generalizationsorstereotypesregardingtheeffectsof diabetes. Readers may use this article as long as the work tness of a person with diabetes for a particular fi When questions arise about the medical is properly cited, the use is educational and not for pro t, and the work is not altered. fi tise in treating diabetes should perform job, a health care professional with exper

113 Volume 39, Supplement 1, January 2016 Diabetes Care S106 Diabetes Advocacy – Association. Diabetes Care 2015;38:1958 an individualized assessment. See the have written polic ies and procedures 1963 Diabetes and Em- “ ADA position statement for the management of diabetes and ’ 2. Siminerio LM, Albanese-O Neill A, Chiang JL, ployment (http://care.diabetesjournals ” for training of medical and correctional et al. Care of young children with diabetes in the .org/content/37/Supplement_1/S112). staff in diabetes care practices. See the child care setting: a position statement of the ADA position statement “ Diabetes Man- American Diabetes Association. Diabetes Care Diabetes Management in Correctional – 2842 2014;37:2834 ” agement in Correctional Institutions Institutions (5) 3. American Diabetes Asso ciation. Diabetes and (http://care.diabetesjournals.org/content/ driving. Diabetes Care 2014;37:(Suppl. 1):S97 S103 – First publication: 1989 (revised 2008) t_1/S104). 37/Supplemen 4. American Diabetes Association. Diabetes and People with diabetes in correctional fa- employment. Diabetes Care 2014;37(Suppl. 1): cilities should receive care that meets References S112 S117 – national standards. Because it is estimated Neill A, Butler KL, 1. Jackson CC, Albanese-O ’ 5. American Diabetes As sociation. Diabetes that nearly 80,000 inmates have diabe- et al. Diabetes care in the school setting: a management in correctional institutions. Diabe- tes Care 2014;37(Suppl. 1):S104 – S111 position statement of the American Diabetes tes, correctional institutions should

114 PROFESSIONAL PRACTICE COMMITTEE S107 Volume 39, Supplement 1, January 2016 Diabetes Care Professional Practice Committee Standards of Medical Care for the 2016 d in Diabetes DOI: 10.2337/dc16-S018 | Diabetes Care 2016;39(Suppl. 1):S107 S108 – fl icts of interest covering the period of 12 months before fi Committee members disclosed the following nancial or other con December 2015 Otherresearch Industry-sponsored support Member Employment research grant William H. Herman, MD, MPH None None (Chair) University of Michigan, Ann Arbor, MI None Novo Nordisk*# Johns Hopkins University School of Medicine, Thomas W. Donner, MD Baltimore, MD R. James Dudl, MD None Kaiser Permanente, Bonita, CA None None Hermes J. Florez, MD, PhD, MPH University of Miami and GRECC-Miami VA None Healthcare System, Miami, FL National Institutes of Health, Bethesda, MD Judith E. Fradkin, MD None None 2 None Nutrition and Fitness None Private practices: (NF) Charlotte A. Hayes, MMSc, MS, Consulting, Atlanta, GA RD, CDE, ACSM CCEP Rita Rastogi Kalyani, MD, MHS, FACP Johns Hopkins University, Baltimore, MD None None None University of California, San Francisco, San Suneil Koliwad, MD, PhD None Francisco, CA None Monroe Plan for Medical Care, Pittsford, NY; None Joseph A. Stankaitis, MD, MPH YourCare Health Plan, Buffalo, NY None Tracey H. Taveira, PharmD, None UniversityofRhodeIslandCollegeofPharmacy, CDOE, CVDOE Kingston, RI; Providence VA Medical Center, Warren Alpert Medical School of Brown University, Providence, RI Deborah J. Wexler, MD, MSc Massachusetts General Hospital, Boston, MA U01DK098246 d None GRADE REAL R18DK102737 d HEALTH-Diabetes Joseph Wolfsdorf, MB, BCh None Boston Children ’ s Hospital, Boston, MA None None Jane L. Chiang, MD (Staff) American Diabetes Association, Alexandria, VA None Erika Gebel Berg, PhD (Staff) American Diabetes Association, Alexandria, VA None None Allison T. McElvaine, PhD (Staff) None None American Diabetes Association, Alexandria, VA DSMB, Data and Safety Monitoring Board; GRECC, Geriatric Research Education and Clinical Center; MEDCAC, Medicare Evidence Development & Coverage Advisory Committee. $10,000 per year from company to individual. * $ #Grant or contract is to university or other employer.

115 Volume 39, Supplement 1, January 2016 Diabetes Care S108 Professional Practice Committee ’ bureau/ Speakers Consultant/advisory board Other Member honoraria Ownership interest Merck Sharp & Dohme None National Committee for Quality Assurance W.H.H. None (Chair, DSMB),* Lexicon (Chair, Diabetes Panel), Centers for Medicare & Medicaid Services (member, MEDCAC), Pharmaceuticals (Editor for the Americas), (Chair, DSMB) Diabetic Medicine (ad hoc Editor in Chief) Diabetes Care None T.W.D. None None None R.J.D. None None None None None None None H.J.F. None J.E.F. None None None None None C.A.H. Receives royalties from the American Scherer Clinical Emory University: Emory at Grady Diabetes Course Communications Diabetes Association, Academy of Nutrition and Dietetics (Chair, Legislative and Public Policy Committee) None R.R.K. (Editorial Board) None AstraZeneca (Advisory Diabetes Care Group member) None None S.K. None Yes Health None National Committee for Quality Assurance J.A.S. None None (physician surveyor and member of the Reconsideration Committee), New York State Department of Health Medicaid Redesign t Review Team ’ fi s Evidence-Based Bene Workgroup, Board member for St. Ann ’ s fi Community, Rochester, NY, a nonpro t senior living/long-term care organization None T.H.T. None None None Diabetes Care (Editorial Board), None None D.J.W. None PracticeUpdate: Diabetes (Editorial Board) J.W. Diabetes Care , Hormone Research in None None None Pediatric Diabetes Paediatrics ,and (Editorial Board); UpToDate (Section Editor) None None None None J.L.C. None None E.G.B. None None None None None None A.T.M.

116 Diabetes Care Volume 39, Supplement 1, January 2016 S109 Index A1C smoking in, S29, S89 body mass index (BMI), S17 age in diagnosis, S14 statins in, S89 bromocriptine, S55 CGM effects on, S39, S40, S101 thyroid disease in, S88 in children, S18, S41 S90 type 1 diabetes in, S86 – calcium channel blockers, S74 in children, adolescents, S87 S91 type 2 diabetes in, S90 – canagli fl ozin, S53, S54, S56, S58 – S43 CVD outcomes and, S42 vaccination schedule, S29 cancer, S31 diagnostic criteria, S13 – S14 chlorthalidone, S63 capsaicin, S77 epidemiology, S7 Chronic Care Model, S7, S23 carbamazepine, S77 goals, S41 chronic kidney disease, S27, S72 S74 – carbohydrates, S27, S37 S10 – hyperglycemia and, S9 Chronic Kidney Disease Epidemiology cardiac autonomic neuropathy, S77 limitations, S41 Collaboration (CKD-EPI) equation, S73 cardiac testing, S67 cation, S13 fi mean glucose levels for speci fi ed A1C level, classi cardiovascular disease clinical evaluation, S23, S24 S41 antiplatelet agents, S4 – S5, S66 – S67, S75 clopidogrel, S66 microvascular complications, S42 – S89 in children, adolescents, S88 clozapine, S49 older adults, S83 heart failure, S68 S32, – cognitive dysfunction, S9 S10, S26, S31 – pregnancy levels, S95 hypertension/blood pressure S44, S82 race/ethnicity differences, S14, S41 S89 – – control, S60 S63, S81, S88 cognitive function, statin use and, S66 recommendations, S40, S41 insulin regimens, S43 colesevelam, S55 testing, S40 S41 – LDL cholesterol, S64, S65, S68 complications acarbose, S55 lifestyle modi S37, S47, – cation, S7, S36 fi A1C, microvascular, S42 – S9 access to health care, S8 – S64, S68 S48, S62 epidemiology, S8 ACCORD trial, S10, S31 – S32, S42 – S44, S61, S62 S66 – lipid management, S63 prevention of, S7, S27 ACE inhibitors, S61 – S63, S68, S72 – S74, S89, outcomes, S42 – S43, S73 risk factors, S14, S29 S97 overview, S4, S60 consensus reports, S1 ADAG study, S41, S44 pharmacological interventions, S62 S63 – continuous glucose monitoring (CGM), S39, S40, adherence, S8 prevention, S26, S27, S37 S101 ADVANCE trial, S42 – S44, S61 risk calculator tool, S64 Contrave (naltrexone/bupropion), S50 S106 – advocacy, S6, S105 as risk factor, S16, S60 coronary artery calcium screening, S67 – S68 African Americans, S14, S15, S27 risk factors for, S15, S17, S29, S31, S60, – coronary heart disease, S8, S67 S68 AIM-HIGH trial, S65 S66 – S64, S74 correctional facilities, S106 albiglutide, S50, S53, S54, S56, S58 smoking and, S29, S89 cultural differences, S8 – albuminuria, S29, S72 S74, S90 care improvement strategies fi cystic brosis, S18 alcohol, S26, S65 adherence, S8 related diabetes, S20 – brosis fi cystic – S55, S68 alogliptin, S53 – S106 advocacy, S6, S105 amlodipine, S63 Chronic Care Model, S7 amputation, S78 delivery systems, S7 dapagli fl ozin, S53, S54, S56, S58 amylin mimetics, S53, S56 demographics, S6 S32, S82 – dementia, S9, S31 anemia, S14 institutional changes, S7 S8 – depression, S10, S30 angiotensin receptor blockers, S61, S62, S68, intermediate outcomes, S8 Diabetes Control and Complications Trial S72 S74, S89, S97 – – objectives, S7 S8 (DCCT), S42, S44, S52, S87 antidepressants, S49 outcomes, S8 diabetes distress, S30 antihyperglycemic agents, S100 – S101 patient-centered, S6 Diabetes Prevention Program (DPP), S36, S37 antihypertensive agents, S63, S97 processes of care, S8 Diabetes Prevention Program Outcomes Study antiplatelet agents, S4 S67, S75 – – S5, S66 recommendations, S6, S9, S10 (DPPOS), S36 antipsychotics, S49 team building, S7 Recognition Program Diabetes Prevention antiretroviral agents, S10 treatment intensi fi cation, S8 (DPRP), S37 (ATT) metanalysis, S66 Antithrombotic Trialists ’ S87, S105 – child care, school, S86 diabetes self-management education, support antivascular endothelial growth factor, S75, S76 children, adolescents S9, S24 (DSME, DSMS), S7, S8 – S25, S36, – Asian Americans, S8, S15, S17, S47 A1C levels in, S18, S41 S37, S86, S102 ASPIRE trial, S40 – S88 autoimmune diseases in, S87 S17, S45, – diabetic ketoacidosis (DKA), S13, S16 aspirin resistance, S67 celiac disease in, S88 S58, S90, S101 aspirin therapy, S4 – S5, S66 – S67, S75 diabetes management, S87 diabetic kidney disease, S27, S29, S72 – S74 atherosclerotic cardiovascular disease. see S25, S36, DSME, DSMS, S7, S8 – S9, S24 – Diabetic Retinopathy Study, S76 cardiovascular disease S37, S86 diagnosis atorvastatin, S64 dyslipidemia management, S89 A1C ( A1C) see – autonomic neuropathy, S29, S76 S78 exercise for, S28 anemia, S14 a -glucosidase inhibitors, S37, S55 glycemic control, S87, S89 S18 – community screening, S17 hypertension, S88 – S89 comorbidities, S31 S32 – hypoglycemia in, S44, S87 con fi rmation of, S14 – S51, S58 bariatric surgery, S49 INDEX S90 nephropathy, S27, S29, S72 – S74, S89 – fasting test, S13, S14 b -blockers, S74 S29, S76 – S78, S90 – neuropathy, S28 hemoglobinopathies, S14 Belviq (lorcaserin), S50 pediatric to adult care transition, S91 S20 – monogenic syndromes, S19 benazepril, S63 psychosocial issues, S87 one-step strategy, S18 – S20 bile acid sequestrants, S55 S76, S90 retinopathy, S28, S73 – plasma glucose criteria, S13 bipolar disorder, S10 school, child care, S86 S87, S105 – – S17, S36 prediabetes, S14 see blood glucose control. glycemic control screening, S87 red blood cell turnover, S14 S63, S81, S88 S89 blood pressure control, S60 – –

117 Volume 39, Supplement 1, January 2016 Diabetes Care S110 Index S102 – treatment, S9, S44, S101 intercurrent illness, S45 referrals, S30 S45 – type 1 diabetes, S44 – S74 kidney disease treatment, S73 2-hour plasma glucose, S13, S14 hypoglycemia unawareness, S44 neurocognitive function, S82 two-step strategy, S19, S20 neuropathy treatment, S77 see type 1 type 1 diabetes ( older adults, S82, S83 diabetes) immune-mediated type 1 diabetes, S15 omega-3 fatty acids, S27 see type 2 type 2 diabetes ( – immunizations, S29 S30 physical activity in, S28 diabetes) IMPROVE-IT trial, S65 pregnancy, S95 diastolic blood pressure, S62 incident diabetes, statin use and, S66 recommendations, S39, S43, S44 diuretics, S61 S63, S74, S97 – incretin-based therapies, S53 self-monitoring of blood glucose (SMBG), dopamine-2 agonists, S55 S63 – perindopril, S62 – indapamide – S55, S58, S68, S101 DPP-4 inhibitors, S53 S40 – S39 infections, S79 driving, S105 targets, S43 – S44 in fl uenza, S29 dulaglutide, S50, S53, S54, S56, S58 GRADE study, S54 insulin, insulin secretagogues duloxetine, S77 S2 – grading system, S1 basal, S40, S54, S57 S58 – dyslipidemia, S65, S83, S89 bolus, S58 carbohydrate counting, S27 S9 – health care access, S8 Early Treatment Diabetic Retinopathy characterization, S56 health disparities, S8 Study, S76 in children, adolescents, S90 hearing impairment, S31 eating patterns, S26 continuous subcutaneous infusion, S58 heart failure, S68 e-cigarettes, S29 CVD targeting, S43 hemoglobinopathies, S14 empagli ozin, S53, S54, S56, S58, S68 fl hospital care, S99, S100 hepatitis B, S30 EMPA-REG OUTCOME study, S56, S68 hypoglycemia unawareness, S44 herbal supplements, S26 employment, S105 – S106 inhaled, S58 S100 – HITECH Act, S99 S85 – end-of-life treatment, S82 neurocognitive function, S82 HIV patients, diabetes care in, S10 energy balance, S26 older adults, S83 homelessness, S9 erectile dysfunction, S77 – S78 S58 oral agents, S40, S57 – hospital care ethnic differences, S8, S14, S17, S41 physical activity, S28 admission considerations, S100 euthyroid sick syndrome, S88 physiology in pregnancy, S95, S96 antihyperglycemic therapies, evaluation, S23, S24, S31 self-monitoring of blood glucose (SMBG), S100 S101 – EXAMINE trial, S68 bedside glucose monitoring, S103 S39 – S40 exenatide, S50, S53, S54, S56, S58 CGM, S39, S40, S101 type 1 diabetes, S52 – S53 S29, S37, S48 exercise, S27 – computerized physician order entry, insurance, S9 ezetimibe, S64, S65 islet cell transplantation, S53 S100 – S99 critical care setting, S100 fasting test, S13, S14 diabetes self-management, S102 Japanese Americans, S17 lipid management fats, S26, S27. see also diabetic ketoacidosis (DKA), S13, S16 – S17, fatty liver disease, S31 S45, S58, S90, S101 Kumamoto Study, S42 fi brate/statin therapy, S65 discharge plan, S102 – S103 receptor agonists, S50 5-HT enteral/parenteral feeding, S101 2C laser photocoagulation therapy, S75, S76 uvastatin, S64 fl glucocorticoids, S101 LDL cholesterol, S64, S65, S68 food insecurity, S9 glycemic control, S100, S101 fi cation, S7, S36 – lifestyle modi S37, S47, S48, foot care, S78 – S79 hyperglycemia in, S100 – S64, S68 S62 foundations of care, S23 hyperosmolar hyperglycemic state, linagliptin, S53 – S55 fractures, S31 S101 lipase inhibitors, S37, S50 S102 – hypoglycemia, S99 S66. – lipid management, S63 fats see also insulin therapy, S99, S100 gabapentin, S77 lipid pro fi les, S65 medical nutrition therapy, gastrointestinal neuropathies, S77 liraglutide, S50, S53, S54, S56, S58 S27, S102 – S25 gastroparesis, S77 liraglutide (Saxenda), S50 perioperative care, S101 genitourinary neuropathies, S77 fi ciencies, S9 literacy de recommendations, S99 – gestational diabetes mellitus, S18 S20, S37, lixisenatide, S50, S53, S54, S56, S58 S101 – target glucose ranges, S99 S94 S97 – Look AHEAD, S47, S68 type 1 diabetes, S100 glibenclamide, S55 lorcaserin (Belviq), S50 HOT trial, S62 gliclazide, S55 loss of protective sensation, S78 hydrochlorothiazide, S63 glimepiride, S55 lovastatin, S64 – hyperglycemia, S9 S10, S42, S45, S96, glipizide, S55 S99 – S101 fi glomerular ltration rate estimation, S73 macular edema, S75, S76 Hyperglycemia and Adverse Pregnancy GLP-1 receptor agonists, S50, S53, S54, S56, S58, MAO inhibitors, S49 Outcome (HAPO) study, S18 S83 maturity-onset diabetes of the young (MODY), S63, S81, S88 – S89 – hypertension, S60 glucagon, S44 S20 S13, S19 – hypertriglyceridemia, S65 glucocorticoids, S101 medical evaluation, S31 hypoglycemia glucose, S44. glycemic control see also see – medical nutrition therapy, S25 S27, S102. in children, adolescents, S44, S87 glyburide, S55, S83, S96 glycemic control, S27, S28, S40 also nutrition glycemic control – hospital care, S99 S102 Medicare, S8, S25 see A1C ( A1C) maternal, S95 see also under medications, S10, S17, S49, S103. carbohydrate counting, S27 nutrition in control of, S27 children, adolescents, S87, S89 c conditions fi speci in older adults, S82, S84 continuous glucose monitoring (CGM), Mediterranean diet, S10, S27, S37 physical activity in control of, S28 S39, S40, S101 meglitinides, S54, S55 predictors of, S102 hospital care, S100, S101 mental illness, S10 prevention, S9, S27, S28, hyperglycemia, S9 S10, S42, S45, S96, – metformin S101 S102 – S101 S99 – cardiovascular disease, S67, S68 symptoms, S10 hypoglycemia) see hypoglycemia ( children, adolescents, S90

118 Index S111 care.diabetesjournals.org effectiveness of, S36, S37 scienti c evidence grading, S1 – S2 fi pancreatic transplantation, S53 hospital care, S101 c statements, S1 scienti fi Patient-Centered Medical Home, S7 older adults, S83 SEARCH study, S89 PCSK9 inhibitors, S65 in pregnancy, S96 self-monitoring of blood glucose (SMBG), percent of days covered (PDC), S8 – therapy generally, S53 S55 – – indapamide, S62 perindopril S63 – S39 S40 metoclopramide, S77 periodontal disease, S31 sex differences, S8, S66 S67 – miglitol, S55 peripheral arterial disease (PAD), S78 SGLT2 inhibitors, S53, S54, S56, S58, S83 mineralocorticoid receptor blockers, S74 S78 peripheral neuropathy, S28 – S29, S76 – simvastatin, S64 fi cation of Diet in Renal Disease (MDRD) Modi phentermine/topiramate combination, S50 sitagliptin, S53 – S55, S68 study, S73 photocoagulation therapy, S75 smoking cessation, S29, S89 S29, S37, S48 – physical activity, S27 socioeconomic differences, S8 pioglitazone, S37, S54, S55 sodium, S26, S27 naltrexone/bupropion (Contrave), S50 pitavastatin, S64 spironolactone, S74 nateglinide, S54, S55 plasma glucose criteria, S13 S62 SPRINT trial, S61 – neonatal diabetes, S19 pneumococcal pneumonia, S29 – S30 SSRIs, S49 nephrologist, referrals to, S74 pneumococcal polysaccharide vaccine 23 (PPSV23), Standards of Care, S1 S90 – S74, S89 – nephropathy, S27, S29, S72 – S29 S30 statins S78, S90 – neuropathy, S28 – S29, S76 POC meters, S103 in CHD management, S68 NHANES, S7, S14, S31 position statements, S1 children, adolescents, S89 niacin/statin therapy, S65 – S66 pramlintide, S53, S56 cognitive function and, S66 NICE-SUGAR study, S100 pravastatin, S64 dementia and, S10 nonketotic hyperosmolar state, S45 – prediabetes, S14 S17, S36 S66 – in lipid management, S64 nucleoside reverse transcriptase inhibitors (NRTIs), S10 pregabalin, S77 – S65 type 1 diabetes, S64 fi numeracy de ciencies, S9 S96 – pregestational diabetes, S94 S66 – type 2 diabetes, S63 nutrition pregnancy sulfonylureas, S54, S55, S58, S83, S96, S101 alcohol, S26, S65 A1C levels, S95 sympathomimetic amine anorectic/antiepileptic carbohydrates, S27, S37 antihypertensive medications in, combination, S50 cognitive dysfunction and, S10 S63, S97 systolic blood pressure, S62 in diabetes prevention, S37 blood pressure targets, S61 eating patterns, S26 contraception, S97 energy balance, S26 tapentadol, S77 gestational diabetes mellitus, fats, S26, S27 TECOS trial, S68 S20, S37, S94 – S97 – S18 herbal supplements, S26 testosterone levels, S31 glucose monitoring, S95 kidney disease treatment, S73 thiazolidinediones, S37, S54, S55, S67, S83 glycemic control, S95 macronutrient distribution, S26 thyroid disease, S88 hyperglycemia, S96 micronutrients, S26 tobacco, S29, S89 insulin physiology, S95, S96 older adults, S84 TODAY study, S90 S97 lactation, S96 – protein, S26, S27 tramadol, S77 pharmacological therapy, S96, S97 sodium, S26, S27 Translating Research Into Action for Diabetes – S97 postpartum care, S96 (TRIAD) study, S8 preconception counseling, testing, S95 c therapies fi see also speci treatment. obesity S96 pregestational diabetes, S94 – adherence, S8 assessment, S47 recommendations, S94 S25 – DSME, DSMS, S7, S8 S9, S24 – bariatric surgery, S49 – S51, S58 retinopathy, S75 – S76 exercise, S27 – S29, S37, S48 concomitant medications, S49 – S97 type 1 diabetes, S96 foundations of care, S23 see also nutrition) diet, S48 ( type 2 diabetes, S96 S97 – glucose, S44 S37, S47, fi cation, S7, S36 – lifestyle modi Professional Practice Committee, S3, S107 – S108 hypoglycemia, S44 S64, S68 S48, S62 – proliferative diabetic retinopathy, S75, S76 immunizations, S29 – S30 S50 – pharmacotherapy, S48 protease inhibitors, S10 S24 initial care basis, S23 – physical activity, S27 – S29, S37, S48 protein, S26, S27 intensi fi cation, S8 recommendations, S48 psychosocial issues, S30, S87 cation, S7, S36 lifestyle modi – S37, S47, fi treatment, S47, S48 P2Y12 receptor antagonists, S67 – S64, S68 S48, S62 – weight management, S25 S27, S68 medical nutrition therapy, S25 S27, S102 – obstructive sleep apnea, S31 red blood cell turnover test, S14 ongoing care, S24 olanzapine, S49 referrals, S24, S30, S74, S75 patient engagement, S23 older adults reimbursement, DSME/DSMS, S25 end-of-life treatment, S82 S85 – pharmacological, S36, S37 renal function assessment, S72 – S73 geriatric syndromes screening, S81 psychosocial issues, S30 repaglinide, S54, S55 hypertension, S81 referrals, S24 resistance training, S27 hypoglycemia, S82, S84 smoking cessation, S29, S89 retinal photography, S75 S9 – tailoring, S8 long-term care facilities, S81, S84 retinopathy, S28, S73 – S76, S90 technology in, S37 neurocognitive function, S82 revisions summary, S4 – S5 S53 – type 1 diabetes, S52 nutrition, S84 Reye syndrome, S67 – S58 type 2 diabetes, S53 S82 – overview, S81 risperidone, S49 S27, S68 – weight management, S25 – S63, S81 palliative care, S60 rosiglitazone, S37, S54, S55 tricyclic antidepressants, S49, S77 – S84 pharmacological therapy, S83 rosuvastatin, S64 2-hour plasma glucose, S13, S14 recommendations, S81 type 1 diabetes S83 treatment, S82 – A1C microvascular complications, S42 SAVOR-TIMI 53 trial, S68 omega-3 fatty acids, S27 carbohydrate counting, S27 saxagliptin, S53 S55, S68 – ophthalmologist, referrals to, S75 S90 – in children, adolescents, S86 Saxenda (liraglutide), S50 opioid antagonist/aminoketone antidepressant classi cation, S13 fi schizoaffective disorder, S10 combination, S50 CVD outcomes and, S42 schizophrenia, S10 orlistat, S37, S50 demographics, S6 – S87, S105 school, child care, S86 orthostatic hypotension, S77

119 Volume 39, Supplement 1, January 2016 Diabetes Care S112 Index diagnosis, S15 S16 – BMI, ethnicity factors, S17 S58 – pharmacological therapy, S53 differential diagnosis, S18 carbohydrate counting, S27 pregnancy, S96 – S97 epidemiology, S8 children, adolescents, S18, S19 – prevention, delay, S36 S37 glycemic control, S39 S91 in children, adolescents, S90 – resistance training, S27 hospital care, S100 cation, S13 fi classi retinopathy, S75 hypoglycemia, S9, S44 – S45 combination therapy, S53 S57 – risk factors, S17 idiopathic, S15 S16 – S43 – CVD outcomes and, S42 statin therapy, S63 – S66 immune-mediated, S15 demographics, S6, S8 – pharmacological therapy, S52 S53 S19 diagnosis, S16 – UK Prospective Diabetes Study (UKPDS), S42, S29 – physical activity, S27 differential diagnosis, S18, S19 S67, S74 S97 pregnancy, S96 – – exercise, S27 S29 retinopathy, S75 glycemic control, S40 venlafaxine, S77 risk factors, S16 S10 – hyperglycemia in, S9 S43 – Veterans Affairs Diabetes Trial (VADT), S42 – S65 statin therapy, S64 hypoglycemia, S9 vildagliptin, S53 – S55 type 2 diabetes hypoglycemia in, S10 A1C microvascular complications, S42 mental illness in, S10 S51, S58 bariatric surgery, S49 – obesity in, S48 S27, S68 – weight management, S25

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