American Diabetes Association Standards of Medical Care in Diabetesd2019

Home , 920s, Derek LeRoith, Diabetes management, Diabetes medication, Direct Group, Glucose test

January 2019 Volume 42, Supplement 1

[T]he simple word Care may sufﬁce to express [the journal’s] philosophical 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 Diabetes Care as a reafﬁrmation of Francis Weld Peabody’s contention that “the secret of the care of the patient is in caring for the patient.” —Norbert Freinkel, Diabetes Care, January-February 1978

EDITOR IN CHIEF Matthew rel="tag">C. Riddle, MD

ASSOCIATE EDITORS EDITORIAL BOARD George Bakris, MD Andrew J. Ahmann, MD Philip Home, DM, DPhil Lawrence Blonde, MD, FACP Vanita R. Aroda, MD George S. Jeha, MD Andrew J.M. Boulton, MD Linda A. Barbour, MD, MSPH Lee M. Kaplan, MD, PhD David D’Alessio, MD Roy W. Beck, MD, PhD M. Sue Kirkman, MD Eddie L. Greene, MD Gianni Bellomo, MD Ildiko Lingvay, MD, MPH, MSCS Korey K. Hood, PhD Geremia Bolli, MD Maureen Monaghan, PhD, CDE Frank B. Hu, MD, MPH, PhD John B. Buse, MD, PhD Kristen J. Nadeau, MD, MS Steven E. Kahn, MB, ChB Sonia Caprio, MD Gregory A. Nichols, PhD, MBA Sanjay Kaul, MD, FACC, FAHA Jessica R. Castle, MD Kwame Osei, MD Derek LeRoith, MD, PhD Robert J. Chilton, DO, FACC, FAHA Kevin A. Peterson, MD, MPH, FRCS(Ed), Robert G. Moses, MD Kenneth Cusi, MD, FACP, FACE FAAFP Stephen Rich, PhD J. Hans DeVries, MD, PhD Ravi Retnakaran, MD, MSc, FRCPC Julio Rosenstock, MD Ele Ferrannini, MD Elizabeth Seaquist, MD Judith Wylie-Rosett, EdD, RD Thomas W. Gardner, MD, MS Guntram Schernthaner, MD Jennifer Green, MD Jan S. Ulbrecht, MB, BS Meredith A. Hawkins, MD, MS Ram Weiss, MD, PhD Petr Heneberg, RNDr, PhD Deborah Wexler, MD, MSc Norbert Hermanns, PhD, MSc Vincent C. Woo, MD, FRCPC Irl B. Hirsch, MD, MACP Bernard Zinman, CM, MD, FRCPC, FACP Reinhard W. Holl, MD, PhD

AMERICAN DIABETES ASSOCIATION OFFICERS CHAIR OF THE BOARD PRESIDENT-ELECT, MEDICINE & SCIENCE Karen Talmadge, PhD Louis Philipson, MD PRESIDENT, MEDICINE & SCIENCE PRESIDENT-ELECT, HEALTH CARE & Jane Reusch, MD EDUCATION Gretchen Youssef, MS, RD, CDE PRESIDENT, HEALTH CARE & EDUCATION SECRETARY/TREASURER-ELECT Felicia Hill-Briggs, PhD, ABPP Brian Bertha, JD, MBA SECRETARY/TREASURER CHIEF EXECUTIVE OFFICER Michael Ching, CPA Tracey D. Brown, MBA, BChE CHAIR OF THE BOARD-ELECT CHIEF SCIENTIFIC, MEDICAL & MISSION OFFICER David J. Herrick, MBA William T. Cefalu, MD

The mission of the American Diabetes Association is to prevent and cure diabetes and to improve the lives of all people affected by diabetes. 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.

Copyright © 2018 by the American Diabetes Association, Inc. All rights reserved. Printed in 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. Single issues of Diabetes Care can be ordered by calling toll-free (800) 232-3472, 8:30 A.M. 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 Periodicals postage paid at Arlington, VA, and additional mailing ofﬁces.

AMERICAN DIABETES ASSOCIATION PERSONNEL AND CONTACTS

ASSOCIATE PUBLISHER, EDITORIAL CONTENT MANAGER ADVERTISING REPRESENTATIVES SCHOLARLY JOURNALS Nancy C. Baldino Christian S. Kohler American Diabetes Association Paul Nalbandian Associate Publisher, Advertising & TECHNICAL EDITORS Sponsorships EDITORIAL OFFICE DIRECTOR Theresa Cooper Lyn Reynolds [email protected] Donna J. Reynolds (703) 549-1500, ext. 4806 Tina Auletta PEER REVIEW MANAGER Senior Account Executive Shannon Potts DIRECTOR, MEMBERSHIP/SUBSCRIPTION SERVICES [email protected] Donald Crowl (703) 549-1500, ext. 4809 ASSOCIATE MANAGER, PEER REVIEW PHARMACEUTICAL/DEVICE DIGITAL ADVERTISING Larissa M. Pouch The Walchli Tauber Group SENIOR ADVERTISING MANAGER Maura Paoletti Julie DeVoss Graff National Sales Manager DIRECTOR, SCHOLARLY JOURNALS [email protected] [email protected] Heather Norton Blackburn (703) 299-5511 (443) 512-8899, ext. 110 January 2019 Volume 42, Supplement 1

Standards of Medical Care in Diabetes—2019

S1 Introduction S90 9. Pharmacologic Approaches to Glycemic Treatment S3 Professional Practice Committee Pharmacologic Therapy for Type 1 Diabetes S4 Summary of Revisions: Standards of Medical Care in Diabetes—2019 Surgical Treatment for Type 1 Diabetes Pharmacologic Therapy for Type 2 Diabetes S7 1. Improving Care and Promoting Health in S103 10. Cardiovascular Disease and Risk Populations Management Diabetes and Population Health Hypertension/Blood Pressure Control Tailoring Treatment for Social Context Lipid Management 2. Classiﬁcation and Diagnosis of Diabetes Antiplatelet Agents S13 Cardiovascular Disease Classiﬁcation Diagnostic Tests for Diabetes S124 11. Microvascular Complications and Foot Care A1C Chronic Kidney Disease Type 1 Diabetes Diabetic Retinopathy Prediabetes and Type 2 Diabetes Neuropathy Gestational Diabetes Mellitus Foot Care – Cystic Fibrosis Related Diabetes 12. Older Adults Posttransplantation Diabetes Mellitus S139 Monogenic Diabetes Syndromes Neurocognitive Function Hypoglycemia S29 3. Prevention or Delay of Type 2 Diabetes Treatment Goals Lifestyle Interventions Lifestyle Management Pharmacologic Interventions Pharmacologic Therapy Prevention of Cardiovascular Disease Treatment in Skilled Nursing Facilities Diabetes Self-management Education and Support and Nursing Homes End-of-Life Care S34 4. Comprehensive Medical Evaluation and 13. Children and Adolescents Assessment of Comorbidities S148 Type 1 Diabetes Patient-Centered Collaborative Care Type 2 Diabetes Comprehensive Medical Evaluation Transition From Pediatric to Adult Care Assessment of Comorbidities S165 14. Management of Diabetes in Pregnancy S46 5. Lifestyle Management Diabetes in Pregnancy Diabetes Self-management Education and Support Preconception Counseling Nutrition Therapy Glycemic Targets in Pregnancy Physical Activity Management of Gestational Diabetes Mellitus Smoking Cessation: Tobacco and e-Cigarettes Management of Preexisting Type 1 Diabetes Psychosocial Issues and Type 2 Diabetes in Pregnancy S61 6. Glycemic Targets Pregnancy and Drug Considerations Postpartum Care Assessment of Glycemic Control A1C Goals S173 15. Diabetes Care in the Hospital Hypoglycemia Hospital Care Delivery Standards Intercurrent Illness Glycemic Targets in Hospitalized Patients 7. Diabetes Technology Bedside Blood Glucose Monitoring S71 Antihyperglycemic Agents in Hospitalized Patients Insulin Delivery Hypoglycemia Self-monitoring of Blood Glucose Medical Nutrition Therapy in the Hospital Continuous Glucose Monitors Self-management in the Hospital Automated Insulin Delivery Standards for Special Situations Transition From the Acute Care Setting S81 8. Obesity Management for the Treatment of Type 2 Diabetes Preventing Admissions and Readmissions Assessment S182 16. Diabetes Advocacy Diet, Physical Activity, and Behavioral Therapy Advocacy Statements Pharmacotherapy Disclosures Medical Devices for Weight Loss S184 Metabolic Surgery S187 Index

This issue is freely accessible online at care.diabetesjournals.org/content/42/Supplement_1.

Keep up with the latest information for Diabetes Care and other ADA titles via Facebook (/ADAJournals) and Twitter (@ADA_Journals).

Diabetes Care Volume 42, Supplement 1, January 2019 S1

Introduction: Standards of Medical Care in Diabetesd2019 Diabetes Care 2019;42(Suppl. 1):S1–S2 | https://doi.org/10.2337/dc19-SINT01

Diabetes is a complex, chronic illness The ADA strives to improve and update updates the Standards of Care annually. requiring continuous medical care with the Standards of Care to ensure that However, the Standards of Care is a multifactorial risk-reduction strategies clinicians, health plans, and policy makers “living” document, where notable up- beyond glycemic control. Ongoing pa- can continue to rely on them as the most dates are incorporated online should tient self-management education and authoritative and current guidelines for the PPC determine that new evidence or support are critical to preventing acute diabetes care. To improve access, the regulatory changes (e.g., drug approvals, complications and reducing the risk of Standards of Care is now available label changes) merit immediate inclusion. long-term complications. Significant ev- through ADA’s new interactive app, along More information on the “living Standards” INTRODUCTION idence exists that supports a range of with tools and calculators that can help can be found on DiabetesPro at profes- interventions to improve diabetes out- guidepatientcare.To download the app, sional.diabetes.org/content-page/living- comes. please visit professional.diabetes.org/ standards. The Standards of Care The American Diabetes Association’s SOCapp.Readerswhowishtocom- supersedes all previous ADA position (ADA’s) “Standards of Medical Care in ment on the 2019 Standards of Care statementsdand the recommendations Diabetes,” referred to as the Standards of are invited to do so at professional. thereindon clinical topics within the Care, is intended to provide clinicians, diabetes.org/SOC. purview of the Standards of Care; ADA patients, researchers, payers, and other position statements, while still con- interested individuals with the compo- ADA STANDARDS, STATEMENTS, taining valuable analysis, should not be nents of diabetes care, general treat- REPORTS, and REVIEWS considered the ADA’s current position. ment goals, and tools to evaluate the The ADA has been actively involved in the The Standards of Care receives annual quality of care. The Standards of Care development and dissemination of di- review and approval by the ADA Board recommendations are not intended to abetes care standards, guidelines, and of Directors. preclude clinical judgment and must be related documents for over 25 years. The ADA Statement applied in the context of excellent ADA’s clinical practice recommendations An ADA statement is an official ADA clinical care, with adjustments for in- are viewed as important resources for point of view or belief that does not dividual preferences, comorbidities, health care professionals who care for contain clinical practice recommenda- and other patient factors. For more people with diabetes. tions and may be issued on advocacy, detailed information about manage- policy, economic, or medical issues re- ment of diabetes, please refer to Med- Standards of Care lated to diabetes. ical Management of Type 1 Diabetes This document is an official ADA posi- ADA statements undergo a formal (1) and Medical Management of Type 2 tion, is authored by the ADA, and pro- review process, including a review by Diabetes (2). vides all of the ADA’s current clinical the appropriate national committee, The recommendations include screen- practice recommendations. ADA mission staff, and the ADA Board ing, diagnostic, and therapeutic act- To update the Standards of Care, the of Directors. ions that are known or believed to ADA’s Professional Practice Committee favorably affect health outcomes of (PPC) performs an extensive clinical di- Consensus Report patients with diabetes. Many of these abetes literature search, supple- A consensus report of a particular topic interventions have also been shown to mented with input from ADA staff and contains a comprehensive examination be cost-effective (3). the medical community at large. The PPC and is authored by an expert panel (i.e.,

“Standards of Medical Care in Diabetes” was originally approved in 1988. Most recent review/revision: December 2018. © 2018 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 proﬁt, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license. S2 Introduction Diabetes Care Volume 42, Supplement 1, January 2019

Table 1—ADA evidence-grading system for “Standards of Medical Care in Diabetes” that forms the basis for the recommen- Level of evidence Description dations. ADA recommendations are assigned ratings of A, B,orC, depending on A Clear evidence from well-conducted, generalizable randomized controlled the quality of evidence. Expert opinion trials that are adequately powered, including E is a separate category for recommen- c Evidence from a well-conducted multicenter trial dations in which there is no evidence c Evidence from a meta-analysis that incorporated quality ratings in the analysis from clinical trials, in which clinical trials Compelling nonexperimental evidence, i.e., “all or none” rule developed by may be impractical, or in which there the Centre for Evidence-Based Medicine at the University of Oxford is conflicting evidence. Recommenda- Supportive evidence from well-conducted randomized controlled trials that tions with an A rating are based on large are adequately powered, including well-designed clinical trials or well-done c Evidence from a well-conducted trial at one or more institutions meta-analyses. Generally, these recom- c Evidence from a meta-analysis that incorporated quality ratings in the mendations have the best chance of analysis improving outcomes when applied to B Supportive evidence from well-conducted cohort studies the population to which they are ap- c Evidence from a well-conducted prospective cohort study or registry propriate. Recommendations with lower c Evidence from a well-conducted meta-analysis of cohort studies levels of evidence may be equally im- Supportive evidence from a well-conducted case-control study portant but are not as well supported. C Supportive evidence from poorly controlled or uncontrolled studies Of course, evidence is only one com- c Evidencefromrandomizedclinicaltrialswithoneormoremajororthree ponent of clinical decision making. Clini- or more minor methodological flaws that could invalidate the results cians care for patients, not populations; c Evidencefromobservational studieswith highpotentialforbias (suchas case series with comparison with historical controls) guidelines must always be interpreted c Evidence from case series or case reports with the individual patient in mind. In- Conflicting evidence with the weight of evidence supporting the dividual circumstances, suchas comorbid recommendation and coexisting diseases, age, education, E Expert consensus or clinical experience disability, and, above all, patients’ values and preferences, must be considered and may lead to different treatment targets and strategies. Furthermore, con- consensus panel) and represents the by invited experts. The scientific review ventional evidence hierarchies, such as panel’s collective analysis, evaluation, may provide a scientific rationale for the one adapted by the ADA, may miss and opinion. clinical practice recommendations in the nuances important in diabetes care. For The need for a consensus report arises Standards of Care. The category may also example, although there is excellent when clinicians, scientists, regulators, include task force and expert committee evidence from clinical trials supporting and/or policy makers desire guidance reports. the importance of achieving multiple and/or clarity on a medical or scientific risk factor control, the optimal way to issue related to diabetes for which the GRADING OF SCIENTIFIC EVIDENCE achieve this result is less clear. It is dif- evidence is contradictory, emerging, or fi Since the ADA first began publishing cult to assess each component of such incomplete. Consensus reports may also practice guidelines, there has been con- a complex intervention. highlight gaps in evidence and propose siderable evolution in the evaluation of areas of future research to address these scientific evidence and in the develop- References gaps. A consensus report is not an ADA ment of evidence-based guidelines. In 1. American Diabetes Association. Medical position and represents expert opinion 2002, the ADA developed a classification Management of Type 1 Diabetes.7thed. only but is produced under the auspices system to grade the quality of scientific Wang CC, Shah AC, Eds. Alexandria, VA, American of the Association by invited experts. Diabetes Association, 2017 evidence supporting ADA recommen- A consensus report may be developed 2. American Diabetes Association. Medical dations. A 2015 analysis of the evi- after an ADA Clinical Conference or Re- Management of Type 2 Diabetes.7thed. dence cited in the Standards of Care Burant CF, Young LA, Eds. Alexandria, VA, search Symposium. found steady improvement in quality American Diabetes Association, 2012 fi over the previous 10 years, with the 3. Li R, Zhang P, Barker LE, Chowdhury FM, Scienti c Review Zhang X. Cost-effectiveness of interventions to A scientific review is a balanced review 2014 Standards of Care for the first prevent and control diabetes mellitus: a sys- and analysis of the literature on a scien- time having the majority of bulleted tematic review. Diabetes Care 2010;33:1872– tific or medical topic related to diabetes. recommendations supported by A-or 1894 A scientific review is not an ADA po- B-level evidence (4). A grading system 4. Grant RW, Kirkman MS. Trends in the ev- Table 1 idence level for the American Diabetes As- sition and does not contain clinical prac- ( ) developed by the ADA and sociation’s “Standards of Medical Care in tice recommendations but is produced modeled after existing methods was Diabetes” from 2005 to 2014. Diabetes Care under the auspices of the Association used to clarify and codify the evidence 2015;38:6–8 Diabetes Care Volume 42, Supplement 1, January 2019 S3

Professional Practice Committee: Standards of Medical Care in Diabetesd2019 Diabetes Care 2019;42(Suppl. 1):S3| https://doi.org/10.2337/dc19-SPPC01

The Professional Practice Committee For the current revision, PPC mem- Members of the PPC (PPC) of the American Diabetes Associ- bers systematically searched MEDLINE Joshua J. Neumiller, PharmD, CDE, FASCP* ation (ADA) is responsible for the “Stan- for human studies related to each section (Chair) ” dards of Medical Care in Diabetes, and published since 15 October 2017. Christopher P. Cannon, MD COMMITTEE PRACTICE PROFESSIONAL referred to as the Standards of Care. Recommendations were revised based Jill Crandall, MD The PPC is a multidisciplinary expert on new evidence or, in some cases, to David D’Alessio, MD committee comprised of physicians, clarify the prior recommendation or Ian H. de Boer, MD, MS* diabetes educators, and others who match the strength of the wording to Mary de Groot, PhD have expertise in a range of areas, the strength of the evidence. A table Judith Fradkin, MD including adult and pediatric endocri- linking the changes in recommendations Kathryn Evans Kreider, DNP, APRN, nology, epidemiology, public health, to new evidence can be reviewed at FNP-BC, BC-ADM lipid research, hypertension, precon- professional.diabetes.org/SOC. The Stan- David Maahs, MD, PhD ception planning, and pregnancy care. dards of Care was approved by ADA’s Nisa Maruthur, MD, MHS Appointment to the PPC is based on Board of Directors, which includes health Medha N. Munshi, MD* excellence in clinical practice and re- care professionals, scientists, and lay people. Maria Jose Redondo, MD, PhD, MPH search. Although the primary role of Feedback from the larger clinical com- Guillermo E. Umpierrez, MD, CDE, FACE, the PPC is to review and update the munity was valuable for the 2018 revision FACP* Standards of Care, it may also be in- of the Standards of Care. Readers who Jennifer Wyckoff, MD volved in ADA statements, reports, and wish to comment on the 2019 Standards *Subgroup leaders reviews. of Care are invited to do so at professional The ADA adheres to the National .diabetes.org/SOC. ADA Nutrition Consensus Report Academy of Medicine Standards for De- The PPC would like to thank the fol- Writing GroupdLiaison veloping Trustworthy Clinical Practice lowing individuals who provided their Melinda Maryniuk, MEd, RDN, CDE Guidelines. All members of the PPC expertise in reviewing and/or consulting are required to disclose potential con- with the committee: Ann Albright, PhD, RD; American College of ﬂicts of interest with industry and/or Pamela Allweiss, MD, MPH; Barbara J. CardiologydDesignated other relevant organizations. These dis- Anderson, PhD; George Bakris, MD; Richard Representatives (Section 10) closures are discussed at the onset of Bergenstal, MD; Stuart Brink, MD; Donald Sandeep Das, MD, MPH, FACC each Standards of Care revision meeting. R. Coustan, MD; Ellen D. Davis, MS, RN, Mikhail Kosiborod, MD, FACC Members of the committee, their em- CDE, FAADE; Jesse Dinh, PharmD; Steven ployers, and their disclosed conﬂicts of Edelman, MD; Barry H. Ginsberg, MD, PhD; ADA Staff interest are listed in the “Disclosures: Irl B. Hirsch, MD; Scott Kahan, MD, MPH; Erika Gebel Berg, PhD Standards of Medical Care in Diabetesd David Klonoff, MD; Joyce Lee, MD, MPH; (corresponding author: [email protected]) 2019” table (see pp. S184–S186). The Randie Little, PhD; Alexandra Migdal, MD; Mindy Saraco, MHA ADA funds development of the Stand- Anne Peters, MD; Amy Rothberg, MD; Matthew P. Petersen ards of Care out of its general revenues Jennifer Sherr, MD, PhD; Hood Thabit, Sacha Uelmen, RDN, CDE and does not use industry support for MB, BCh, MD, PhD; Stuart Alan Weinzimer, Shamera Robinson, MPH, RDN this purpose. MD; and Neil White, MD. William T. Cefalu, MD

© 2018 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 proﬁt, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license. S4 Diabetes Care Volume 42, Supplement 1, January 2019

Summary of Revisions: Standards of Medical Care in Diabetesd2019 Diabetes Care 2019;42(Suppl. 1):S4–S6 | https://doi.org/10.2337/dc19-srev01

GENERAL CHANGES Because telemedicine is a growing professional audiences in an informative, The field of diabetes care is rapidly field that may increase access to care empowering, and educational style. changing as new research, technology, forpatients withdiabetes, discussionwas A new figure from the ADA-European and treatments that can improve the added on its use to facilitate remote Association for the Study of Diabetes health and well-being of people with delivery of health-related services and (EASD) consensus report about the di- diabetes continue to emerge. With an- clinical information. abetes care decision cycle was added to nual updates since 1989, the American emphasize the need for ongoing assess- fi Diabetes Association (ADA) has long Section 2. Classi cation and Diagnosis ment and shared decision making to been a leader in producing guidelines of Diabetes achieve the goals of health care and Based on new data, the criteria for the that capture the most current state of avoid clinical inertia. diagnosis of diabetes was changed to the field. To that end, the “Standards A new recommendation was added to include two abnormal test results from of Medical Care in Diabetes” (Standards explicitly call out the importance of the the same sample (i.e., fasting plasma of Care) now includes a dedicated section diabetes care team and to list the pro- glucose and A1C from same sample). on Diabetes Technology, which contains fessionals that make up the team. The section was reorganized to im- preexisting material that was previously The table listing the components of a prove flow and reduce redundancy. in other sections that has been consol- comprehensive medical evaluation was SUMMARY OF REVISIONS Additional conditions were identified idated, as well as new recommendations. revised, and the section on assessment that may affect A1C test accuracy including Another general change is that each rec- and planning was used to create a new the postpartum period. ommendation is now associated with a table (Table 4.2). A new table was added listing factors number (i.e., the second recommendation Section 3. Prevention or Delay of in Section 7 is now recommendation 7.2). that increase risk of treatment-associated Type 2 Diabetes Table 4.3 Finally, the order of the prevention section This section was moved (previously it was hypoglycemia ( ). was changed (from Section 5 to Section 3) Section 5) and is now located before the A recommendation was added to in- to follow a more logical progression. Lifestyle Management section to better clude the 10-year atherosclerotic cardio- Although levels of evidence for several reflect the progression of type 2 diabetes. vascular disease (ASCVD) risk as part of recommendations have been updated, The nutrition section was updated to overall risk assessment. these changes are not addressed below highlight the importance of weight loss The fatty liver disease section was as the clinical recommendations have for those at high risk for developing revised to include updated text and a remained the same. Changes in evidence type 2 diabetes who have overweight new recommendation regarding when level from, for example, E to C are not or obesity. to test for liver disease. noted below. The 2019 Standards of Care Because smoking may increase the risk contains, in addition to many minor of type 2 diabetes, a section on tobacco Section 5. Lifestyle Management changes that clarify recommendations use and cessation was added. Evidence continues to suggest that there or reflect new evidence, the following is not an ideal percentage of calories from more substantive revisions. Section 4. Comprehensive Medical carbohydrate, protein, and fat for all Evaluation and Assessment of people with diabetes. Therefore, more SECTION CHANGES Comorbidities discussion was added about the im- Section 1. Improving Care and On the basis of a new consensus report portance of macronutrient distribution Promoting Health in Populations on diabetes and language, new text was based on an individualized assessment of Additional information was included on added to guide health care professionals’ current eating patterns, preferences, and the financial costs of diabetes to individ- use of language to communicate about metabolic goals. Additional considera- uals and society. diabetes with people with diabetes and tions were added to the eating

patterns, macronutrient distribution, and intermittently scanned [“flash”]), and au- abbreviated, as these are not generally meal planning sections to better iden- tomated insulin delivery devices. recommended. tify candidates for meal plans, specifically The recommendation to use self- for low-carbohydrate eating patterns monitoring of blood glucose in people Section 10. Cardiovascular Disease and people who are pregnant or lactat- who are not using insulin was changed and Risk Management ing, who have or are at risk for disor- to acknowledge that routine glucose For the first time, this section is endorsed dered eating, who have renal disease, monitoring is of limited additional clin- by the American College of Cardiology. and who are taking sodium–glucose co- ical benefit in this population. Additional text was added to acknowl- transporter 2 inhibitors. There is not edge heart failure as an important type a one-size-fits-all eating pattern for in- of cardiovascular disease in people with dividuals with diabetes, and meal plan- Section 8. Obesity Management for diabetes for consideration when deter- ning should be individualized. the Treatment of Type 2 Diabetes fi mining optimal diabetes care. A recommendation was modified to A recommendation was modi ed to fi The blood pressure recommenda- encourage people with diabetes to de- acknowledge the bene ts of tracking tions were modified to emphasize the crease consumption of both sugar weight, activity, etc., in the context of importance of individualization of targets sweetened and nonnutritive-sweetened achieving and maintaining a healthy based on cardiovascular risk. beverages and use other alternatives, weight. A discussion of the appropriate use of with an emphasis on water intake. A brief section was added on medical the ASCVD risk calculator was included, The sodium consumption recommen- devices for weight loss, which are not and recommendations were modified dation was modified to eliminate the currently recommended due to limited to include assessment of 10-year ASCVD further restriction that was potentially data in people with diabetes. risk as part of overall risk assessment indicated for those with both diabetes The recommendations for metabolic fi and in determining optimal treatment and hypertension. surgery were modi ed to align with re- approaches. Additional discussion was added to the cent guidelines, citing the importance of The recommendation and text regard- physical activity section to include the ben- considering comorbidities beyond dia- ing the use of aspirin in primary pre- efit of a variety of leisure-time physical ac- betes when contemplating the ap- vention was updated with new data. tivities and flexibility and balance exercises. propriateness of metabolic surgery for For alignment with the ADA-EASD The discussion about e-cigarettes was a given patient. consensus report, two recommendations expanded to include more on public were added for the use of medications perception and how their use to aide Section 9. Pharmacologic Approaches that have provencardiovascular benefitin smoking cessation was not more effec- to Glycemic Treatment people with ASCVD, with and without tive than “usual care.” The section on the pharmacologic treat- heart failure. ment of type 2 diabetes was significantly changed to align, as per the Section 6. Glycemic Targets living Standards update in October Section 11. Microvascular This section now begins with a discussion 2018, with the ADA-EASD consensus Complications and Foot Care of A1C tests to highlight the centrality of report on this topic, summarized in To align with the ADA-EASD consensus A1C testing in glycemic management. the new Figs. 9.1 and 9.2. This includes report, a recommendation was added for The self-monitoring of blood glucose consideration of key patient factors: people with type 2 diabetes and chronic and continuous glucose monitoring text a) important comorbidities such as kidney disease to consider agents with and recommendations were moved to ASCVD, chronic kidney disease, and proven benefit with regard to renal out- the new Diabetes Technology section. heart failure, b) hypoglycemia risk, c) comes. To emphasize that the risks and ben- effects on body weight, d)sideeffects, The recommendation on the use of fi e ts of glycemic targets can change as e) costs, and f) patient preferences. telemedicine in retinal screening was diabetes progresses and patients age, To align with the ADA-EASD con- modified to acknowledge the utility of a recommendation was added to reeval- sensus report, the approach to inject- this approach, so long as appropriate uate glycemic targets over time. able medication therapy was revised referrals are made for a comprehensive fi The section was modi ed to align (Fig. 9.2). A recommendation that, for eye examination. with the living Standards updates made most patients who need the greater Gabapentin was added to the list of in April 2018 regarding the consensus efficacy of an injectable medication, a agents to be considered for the treat- fi de nition of hypoglycemia. glucagon-like peptide 1 receptor ago- ment of neuropathic pain in people with nist should be the first choice, ahead diabetes based on data on efficacy and Section 7. Diabetes Technology of insulin. the potential for cost savings. This new section includes new recommen- A new section was added on insulin The gastroparesis section includes a dations, the self-monitoring of blood glu- injection technique, emphasizing the im- discussion of a few additional treatment cose section formerly included in Section portance of technique for appropriate modalities. 6 “Glycemic Targets,” and a discussion of insulin dosing and the avoidance of com- The recommendation for patients with insulin delivery devices (syringes, pens, and plications (lipodystrophy, etc.). diabetes to have their feet inspected at insulin pumps), blood glucose meters, con- The section on noninsulin pharmaco- every visit was modified to only include tinuous glucose monitors (real-time and logic treatments for type 1 diabetes was those at high risk for ulceration. Annual S6 Summary of Revisions Diabetes Care Volume 42, Supplement 1, January 2019

examinations remain recommended for screening in youth with type 1 diabetes Greater emphasis has been placed on everyone. beginning at 10–12 years of age. the use of insulin as the preferred med- Based on new evidence, a recom- ication for treating hyperglycemia in Section 12. Older Adults mendation was added discouraging gestational diabetes mellitus as it does A new section and recommendation on e-cigarette use in youth. not cross the placenta to a measurable lifestyle management was added to address The discussion of type 2 diabetes in extent and how metformin and gly- the unique nutritional and physical activity children and adolescents was significantly buride should not be used as first- needs and considerations for older adults. expanded, with new recommendations line agents as both cross the placenta Within the pharmacologic therapy in a number of areas, including screen- to the fetus. discussion, deintensification of insulin re- ing and diagnosis, lifestyle management, gimes was introduced to help simplify pharmacologic management, and transi- Section 15. Diabetes Care in the insulin regimen to match individual’s tion of care to adult providers. New Hospital self-management abilities. A new figure sections and/or recommendations for Because of their ability to improve hos- was added (Fig. 12.1) that provides a path type 2 diabetes in children and adoles- pital readmission rates and cost of care, for simplification. A new table was also cents were added for glycemic targets, a new recommendation was added call- added (Table 12.2) to help guide providers metabolic surgery, nephropathy, neurop- ing for providers to consider consulting considering medication regimen simplifi- athy, retinopathy, nonalcoholic fatty liver with a specialized diabetes or glucose cation and deintensification/deprescrib- disease, obstructive sleep apnea, poly- management team where possible ing in older adults with diabetes. cystic ovary syndrome, cardiovascular when caring for hospitalized patients disease, dyslipidemia, cardiac function with diabetes. Section 13. Children and Adolescents testing, and psychosocial factors. Figure Introductory language was added to the 13.1 wasaddedtoprovideguidance Section 16. Diabetes Advocacy beginning of this section reminding the The “Insulin Access and Affordability on the management of diabetes in reader that the epidemiology, patho- Working Group: Conclusions and overweight youth. physiology, developmental consider- Recommendations” ADA statement was ations, and response to therapy in added to this section. Published in 2018, pediatric-onset diabetes are different Section 14. Management of Diabetes this statement compiled public informa- from adult diabetes, and that there in Pregnancy tion and convened a series of meetings are also differences in recommended Women with preexisting diabetes are with stakeholders throughout the in- care for children and adolescents with now recommended to have their care sulin supply chain to learn how each type 1 as opposed to type 2 diabetes. managed in a multidisciplinary clinic to entity affects the cost of insulin for the A recommendation was added to em- improve diabetes and pregnancy out- consumer, an important topic for the phasize the need for disordered eating comes. ADA and people living with diabetes. Diabetes Care Volume 42, Supplement 1, January 2019 S7

1. Improving Care and Promoting American Diabetes Association Health in Populations: Standards of Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S7–S12 | https://doi.org/10.2337/dc19-S001 .IPOIGCR N RMTN HEALTH PROMOTING AND CARE IMPROVING 1.

DIABETES AND POPULATION HEALTH

Recommendations 1.1 Ensure treatment decisions are timely, rely on evidence-based guidelines, and are made collaboratively with patients based on individual preferences, prog- noses, and comorbidities. B 1.2 Align approaches to diabetes management with the Chronic Care Model, emphasizing productive interactions between a prepared proactive care team and an informed activated patient. A 1.3 Care systems should facilitate team-based care, patient registries, decision support tools, and community involvement to meet patient needs. B 1.4 Efforts to assess the quality of diabetes care and create quality improvement strategies should incorporate reliable data metrics, to promote improved pro- cesses of care and health outcomes, with simultaneous emphasis on costs. E

Population health is defined as “the health outcomes of a group of individuals, including the distribution of health outcomes within the group”; these outcomes can bemeasured in termsof health outcomes(mortality, morbidity, health, and functional status), disease burden (incidence and prevalence), and behavioral and metabolic Suggested citation: American Diabetes Associa- factors (exercise, diet, A1C, etc.) (1). Clinical practice recommendations for health care tion. 1. Improving care and promoting health providers are tools that can ultimately improve health across populations; however, in populations: Standards of Medical Care in for optimal outcomes, diabetes care must also be individualized for each patient. Thus, Diabetesd2019. Diabetes Care 2019;42(Suppl. 1): efforts to improve population health will require a combination of system-level and S7–S12 patient-level approaches. With such an integrated approach in mind, the American © 2018 by the American Diabetes Association. Diabetes Association (ADA) highlights the importance of patient-centered care, Readers may use this article as long as the work fi is properly cited, the use is educational and not de ned as care that is respectful of and responsive to individual patient preferences, for profit, and the work is not altered. More infor- needs, and values and that ensures that patient values guide all clinical decisions (2). mation is available at http://www.diabetesjournals Clinical practice recommendations, whether based on evidence or expert opinion, are .org/content/license. S8 Improving Care and Promoting Health Diabetes Care Volume 42, Supplement 1, January 2019

intended to guide an overall approach to health strategies are needed in order to suboptimal (3). Efforts to increase the care. The science and art of medicine reduce costs and provide optimized care. quality of diabetes care include provid- come together when the clinician is faced ing care that is concordant with with making treatment recommenda- Chronic Care Model evidence-based guidelines (16); expand- tions for a patient who may not meet Numerous interventions to improve ad- ing the role of teams to implement more the eligibility criteria used in the studies herence to the recommended standards intensive disease management strate- on which guidelines are based. Recog- have been implemented. However, a gies (7,17,18); tracking medication- nizing that one size does not fit all, the major barrier to optimal care is a delivery taking behavior at a systems level (19); standards presented here provide guid- system that is often fragmented, lacks redesigning the organization of the care ance for when and how to adapt rec- clinical information capabilities, dupli- process (20); implementing electronic ommendations for an individual. cates services, and is poorly designed health record tools (21,22); empowering for the coordinated delivery of chronic and educating patients (23,24); removing Care Delivery Systems care. The Chronic Care Model (CCM) financial barriers and reducing patient The proportion of patients with diabetes takes these factors into consideration out-of-pocket costs for diabetes educa- who achieve recommended A1C, blood and is an effective framework for im- tion, eye exams, diabetes technology, and pressure, and LDL cholesterol levels has proving the quality of diabetes care (9). necessary medications (7); assessing and increased in recent years (3). The mean addressing psychosocial issues (25,26); Six Core Elements. The CCM includes six A1C nationally among people with diabe- core elements to optimize the care of and identifying, developing, and engaging tes declined from 7.6% (60 mmol/mol) patients with chronic disease: community resources and public policies in 1999–2002 to 7.2% (55 mmol/mol) that support healthy lifestyles (27). The – in 2007 2010 based on the National 1. Delivery system design (moving from National Diabetes Education Program Health and Nutrition Examination Survey a reactive to a proactive care delivery maintains an online resource (www (NHANES), with younger adults less likely system where planned visits are .betterdiabetescare.nih.gov) to help health to meet treatment targets than older coordinated through a team-based care professionals design and implement adults (3). This has been accompanied approach) more effective healthcare delivery systems by improvements in cardiovascular out- 2. Self-management support for those with diabetes. comesandhasledtosubstantialre- 3. Decision support (basing care on The care team, which centers around ductions in end-stage microvascular evidence-based, effective care the patient, should avoid therapeutic complications. guidelines) inertia and prioritize timely and appro- – fi Nevertheless, 33 49% of patients still 4. Clinical information systems (using priate intensi cation of lifestyle and/or did not meet general targets for glyce- registries that can provide patient- pharmacologic therapy for patients who mic, blood pressure, or cholesterol con- specific and population-based sup- have not achieved the recommended – trol, and only 14% met targets for all port to the care team) metabolic targets (28 30). Strategies three measures while also avoiding smok- 5. Community resources and policies shown to improve care team behavior ing (3). Evidence suggests that progress in (identifying or developing resources and thereby catalyze reductions in A1C, cardiovascular risk factor control (partic- to support healthy lifestyles) blood pressure, and/or LDL cholesterol ularly tobacco use) may be slowing (3,4). 6. Health systems (to create a quality- include engaging in explicit and collab- Certain segments of the population, such oriented culture) orative goal setting with patients (31,32); as young adults andpatients with complex identifying and addressing language, fi comorbidities, nancial or other social Redefining the roles of the health care numeracy, or cultural barriers to care – hardships, and/or limited English pro- delivery team and empowering patient (33 35); integrating evidence-based guide- fi ciency, face particular challenges to self-management are fundamental to lines and clinical information tools – goal-based care (5 7). Even after adjust- the successful implementation of the into the process of care (16,36,37); ing for these patient factors, the persis- CCM (10). Collaborative, multidisciplinary soliciting performance feedback, setting tent variability in the quality of diabetes teams are best suited to provide care reminders, and providing structured care care across providers and practice set- for people with chronic conditions such (e.g., guidelines, formal case manage- tings indicates that substantial system- as diabetes and to facilitate patients’ ment, and patient education resources) level improvements are still needed. self-management (11–13). (7); and incorporating care management Diabetes poses a significant financial teams including nurses, dietitians, phar- burden to individuals and society. It is Strategies for System-Level Improvement macists, and other providers (17,38). estimated that the annual cost of di- Optimal diabetes management requires Initiatives such as the Patient-Centered agnosed diabetes in 2017 was $327 an organized, systematic approach and Medical Home show promise for im- billion, including $237 billion in direct the involvement of a coordinated team of proving health outcomes by fostering medical costs and $90 billion in reduced dedicated health care professionals work- comprehensive primary care and offer- productivity. After adjusting for inflation, ing in an environment where patient- ing new opportunities for team-based economic costs of diabetes increased centered high-quality care is a priority chronic disease management (39). by 26% from 2012 to 2017 (8). This is (7,14,15). While many diabetes pro- Telemedicine is a growing field that attributed to the increased prevalence cesses of care have improved nationally may increase access to care for patients of diabetes and the increased cost per in the past decade, the overall quality of with diabetes. Telemedicine is defined person with diabetes. Ongoing population care for patients with diabetes remains as the use of telecommunications to care.diabetesjournals.org Improving Care and Promoting Health S9

facilitate remote delivery of health-re- barriers to medication taking may be accommodate personalized care goals lated services and clinical information achieved if the patient and provider (7,57). (40). A growing body of evidence sug- agree on a targeted approach for a spe- gests that various telemedicine modali- cific barrier (12). TAILORING TREATMENT FOR ties may be effective at reducing A1C in The Affordable Care Act has resulted SOCIAL CONTEXT patients with type 2 diabetes compared in increased access to care for many Recommendations with usual care or in addition to usual individuals with diabetes with an empha- 1.5 Providers should assess social care (41). For rural populations or those sis on the protection of people with context, including potential with limited physical access to health preexisting conditions, health promotion, food insecurity, housing stabil- care, telemedicine has a growing body of anddiseaseprevention(45).Infact,health ity, and financial barriers, and evidence for its effectiveness, particularly insurance coverage increased from apply that information to treat- with regard to glycemic control as mea- 84.7% in 2009 to 90.1% in 2016 for ment decisions. A sured by A1C (42–44). Interactive strat- adults with diabetes aged 18–64 years. 1.6 Refer patients to local commu- egies that facilitate communication Coverage for those $65 years remained nity resources when available. B between providers and patients, including near universal (46). Patients who have 1.7 Provide patients with self- the use of web-based portals or text either private or public insurance coverage management support from lay messaging and those that incorporate are more likely to meet quality indicators health coaches, navigators, or medication adjustment, appear more for diabetes care (47). As mandated community health workers effective. There is limited data avail- by the Affordable Care Act, the Agency when available. A able on the cost-effectiveness of these for Healthcare Research and Quality strategies. developed a National Quality Strategy Successful diabetes care also requires based on the triple aims that include Health inequities related to diabetes a systematic approach to supporting improving the health of a population, and its complications are well docu- patients’ behavior change efforts. overall quality and patient experience of mented and are heavily influenced by High-quality diabetes self-management care, and per capita cost (48,49). As social determinants of health (58–62). education and support (DSMES) has health care systems and practices adapt Social determinants of health are defined been shown to improve patient self- to the changing landscape of health as the economic, environmental, politi- management, satisfaction, and glucose care, it will be important to integrate cal, and social conditions in which people outcomes. National DSMES standards traditional disease-specific metrics with live and are responsible for a major part call for an integrated approach that in- measures of patient experience, as well of health inequality worldwide (63). The cludes clinical content and skills, behav- as cost, in assessing the quality of diabe- ADA recognizes the association between ioral strategies (goal setting, problem tes care (50,51). Information and guid- social and environmental factors and the solving), and engagement with psycho- ance specific to quality improvement and prevention and treatment of diabetes social concerns (26). For more informa- practice transformation for diabetes care and has issued a call for research that tion on DSMES, see Section 5 “Lifestyle is available from the National Diabetes seeks to better understand how these Management.” Education Program practice transforma- social determinants influence behaviors In devising approaches to support tion website and the National Institute of and how the relationships between these disease self-management, it is notable Diabetes and Digestive and Kidney Dis- variables might be modified for the pre- that in 23% of cases, uncontrolled A1C, eases report on diabetes care and quality vention and management of diabetes blood pressure, or lipids were associated (52,53). Using patient registries and elec- (64). While a comprehensive strategy to with poor medication-taking behaviors tronic health records, health systems reduce diabetes-related health inequi- (“medication adherence”) (19). At a sys- can evaluate the quality of diabetes care ties in populations has not been for- tem level, “adequate” medication taking being delivered and perform interven- mally studied, general recommendations is defined as 80% (calculated as the tion cycles as part of quality improve- from other chronic disease models can number of pills taken by the patient ment strategies (54). Critical to these be drawn upon to inform systems-level in a given time period divided by the efforts is provider adherence to clinical strategies in diabetes. For example, the number of pills prescribed by the physi- practice recommendations and accu- National Academy of Medicine has cian in that same time period) (19). rate, reliable data metrics that include published a framework for educating If medication taking is 80% or above sociodemographic variables to examine health care professionals on the impor- and treatment goals are not met, then health equity within and across popula- tance of social determinants of health treatment intensification should be tions (55). (65). Furthermore, there are resources considered (e.g., uptitration). Barriers In addition to quality improvement available for the inclusion of standard- to medication taking may include efforts, other strategies that simulta- ized sociodemographic variables in elec- patient factors (financial limitations, neously improve the quality of care tronic medical records to facilitate the remembering to obtain or take medica- and potentially reduce costs are gaining measurement of health inequities as tions, fear, depression, or health beliefs), momentum and include reimbursement well as the impact of interventions de- medication factors (complexity, multiple structures that, in contrast to visit-based signed to reduce those inequities (66–68). daily dosing, cost, or side effects), and billing, reward the provision of appro- Social determinants of health are not system factors (inadequate follow- priate and high-quality care to achieve always recognized and often go undis- up or support). Success in overcoming metabolic goals (56) and incentives that cussed in the clinical encounter (61). A S10 Improving Care and Promoting Health Diabetes Care Volume 42, Supplement 1, January 2019

study by Piette et al. (69) found that to get more.” An affirmative response Standards for Culturally and Linguisti- among patients with chronic illnesses, to either statement had a sensitivity of cally Appropriate Services in Health two-thirds of those who reported not 97% and specificity of 83%. and Health Care provide guidance on taking medications as prescribed due to Treatment Considerations how health care providers can reduce cost never shared this with their physi- In those with diabetes and FI, the priority language barriers by improving their cian. In a more recent study using data is mitigating the increased risk for un- cultural competency, addressing health from the National Health Interview controlled hyperglycemia and severe hy- literacy, and ensuring communication Survey (NHIS), Patel et al. (61) found poglycemia. Reasons for the increased with language assistance (76). The site that half of adults with diabetes reported risk of hyperglycemia include the steady offers a number of resources and materi- fi fi nancial stress and one- fth reported consumption of inexpensive carbohy- als that can be used to improve the quality – food insecurity (FI). One population in drate-rich processed foods, binge eat- of care delivery to non-English speaking which such issues must be considered is ing, financial constraints to the filling patients. fi older adults, where social dif culties may of diabetes medication prescriptions, impair their quality of life and increase Community Support and anxiety/depression leading to poor Identification or development of com- their risk of functional dependency (70) diabetes self-care behaviors. Hypoglyce- munity resources to support healthy (see Section 12 “Older Adults” for a de- mia can occur as a result of inadequate lifestyles is a core element of the CCM tailed discussion of social considerations or erratic carbohydrate consumption (9). Health care community linkages in older adults). Creating systems-level following the administration of sul- are receiving increasing attention from mechanisms to screen for social deter- fonylureas or insulin. See Table 9.1 for the American Medical Association, the minants of health may help overcome drug-specific and patient factors, includ- Agency for Healthcare Research and structural barriers and communication ing cost and risk of hypoglycemia, for Quality, and others as a means of pro- gaps between patients and providers treatment options for adults with FI and moting translation of clinical recommen- (61). In addition, brief, validated screen- type 2 diabetes. Providers should con- dations for lifestyle modification in real- ing tools for some social determinants of sider these factors when making treat- world settings (77). Community health health exist and could facilitate discus- ment decisions in people with FI and workers (CHWs) (78), peer supporters sion around factors that significantly seek local resources that might help (79–81), and lay leaders (82) may assist impact treatment during the clinical en- patients with diabetes and their family in the delivery of DSMES services (66), counter. Below is a discussion of assess- members to more regularly obtain particularly in underserved communi- ment and treatment considerations in nutritious food (74). ties. A CHW is defined by the American the context of FI, homelessness, and Public Health Association as a “frontline limitedEnglishproficiency/low literacy. Homelessness public health worker who is a trusted Homelessness often accompanies many member of and/or has an unusually close Food Insecurity additional barriers to diabetes self- understanding of the community served” FI is the unreliable availability of nutri- management, including FI, literacy and (83). CHWs can be part of a cost-effective, tious food and the inability to consis- fi numeracy de ciencies, lack of insurance, evidence-based strategy to improve tently obtain food without resorting to cognitive dysfunction, and mental health the management of diabetes and car- socially unacceptable practices. Over issues. Additionally, patients with diabe- diovascular risk factors in underserved 14% (or one of every seven people) tes who are homeless need secure places communities and health care systems of the U.S. population is food insecure. to keep their diabetes supplies and re- (84). The rate is higher in some racial/ethnic frigerator access to properly store their minority groups, including African insulin and take it on a regular schedule. American and Latino populations, in Risk for homelessness can be ascertained References low-income households, and in homes 1. Kindig D, Stoddart G. What is population using a brief risk assessment tool de- health? Am J Public Health 2003;93:380–383 headed by a single mother. The risk for veloped and validated for use among 2. Institute of Medicine Committee on Quality type 2 diabetes is increased twofold in veterans (75). Given the potential chal- of Health Care in America. Crossing the quality those with FI (64) and has been associ- lenges, providers who care for homeless chasm: a new health system for the 21st century ated with low adherence to taking medi- individuals should be familiar with re- [Internet], 2001. Washington, DC, The National cations appropriately and recommended Academies Press. Available from http://www sources or have access to social workers .nap.edu/catalog/10027. Accessed 22 October self-care behaviors, depression, diabe- that can facilitate temporary housing 2018 tes distress, and worse glycemic control for their patients as a way to improve 3. Ali MK, Bullard KM, Saaddine JB, Cowie CC, when compared with individuals who diabetes care. Imperatore G, Gregg EW. Achievement of goals are food secure (71,72). Risk for FI can in U.S. diabetes care, 1999-2010. N Engl J Med – be assessed with a validated two-item 2013;368:1613 1624 Language Barriers 4. Wang J, Geiss LS, Cheng YJ, et al. Long-term screening tool (73) that includes the Providers who care for non-English and recent progress in blood pressure levels statements: 1) “Within the past 12 speakers should develop or offer educa- among U.S. adults with diagnosed diabetes, months we worried whether our food tional programs and materials in multiple 1988-2008. Diabetes Care 2011;34:1579–1581 would run out before we got money languages with the specific goals of pre- 5. Kerr EA, Heisler M, Krein SL, et al. Beyond ” “ comorbidity counts: how do comorbidity type to buy more and 2) Within the past venting diabetes and building diabetes and severity influence diabetes patients’ treat- 12 months the food we bought just awareness in people who cannot easily ment priorities and self-management? J Gen didn’t last and we didn’thavemoney read or write in English. The National Intern Med 2007;22:1635–1640 care.diabetesjournals.org Improving Care and Promoting Health S11

6. Fernandez A, Schillinger D, Warton EM, et al. 23. Battersby M, Von Korff M, Schaefer J, et al. 38. Stone RA, Rao RH, Sevick MA, et al. Active Language barriers, physician-patient language Twelve evidence-based principles for imple- care management supported by home tele- concordance, and glycemic control among in- menting self-management support in primary monitoring in veterans with type 2 diabetes: sured Latinos with diabetes: the Diabetes Study care. Jt Comm J Qual Patient Saf 2010;36:561– the DiaTel randomized controlled trial. Diabetes of Northern California (DISTANCE). J Gen Intern 570 Care 2010;33:478–484 Med 2011;26:170–176 24. Grant RW, Wald JS, Schnipper JL, et al. 39. Bojadzievski T, Gabbay RA. Patient-centered 7. TRIAD Study Group. Health systems, patients Practice-linked online personal health records medical home and diabetes. Diabetes Care 2011; factors, and quality of care for diabetes: a syn- for type 2 diabetes mellitus: a randomized con- 34:1047–1053 thesis of findings from the TRIAD study. Diabetes trolled trial. Arch Intern Med 2008;168:1776– 40. American Telemedicine Association. About Care 2010;33:940–947 1782 telemedicine [Internet]. Available from http:// 8. American Diabetes Association. Economic 25. Young-Hyman D, de Groot M, Hill-Briggs F, www.americantelemed.org/main/about/about- costs of diabetes in the U.S. in 2017. Diabetes Gonzalez JS, Hood K, Peyrot M. Psychosocial care telemedicine/telemedicine-faqs. Accessed 2 Care 2018;41:917–928 for people with diabetes: a position statement October 2018 9. Stellefson M, Dipnarine K, Stopka C. The of the American Diabetes Association. Diabetes 41. Lee SWH, Chan CKY, Chua SS, Chaiyakunapruk Chronic Care Model and diabetes management Care 2016;39:2126–2140 N. Comparative effectiveness of telemedicine in US primary care settings: a systematic review. 26. Beck J, Greenwood DA, Blanton L, et al.; strategies on type 2 diabetes management: Prev Chronic Dis 2013;10:E26 2017 Standards Revision Task Force. 2017 Na- a systematic review and network meta-analysis. 10. Coleman K, Austin BT, Brach C, Wagner EH. tional standards for diabetes self-management Sci Rep 2017;7:12680 Evidence on the Chronic Care Model in the new education and support. Diabetes Care 2017; 42. Faruque LI, Wiebe N, Ehteshami-Afshar A, millennium. Health Aff (Millwood) 2009;28:75–85 40:1409–1419 et al.; Alberta Kidney Disease Network. Effect of 11. Piatt GA, Anderson RM, Brooks MM, et al. 27. Pullen-Smith B, Carter-Edwards L, Leathers telemedicine on glycated hemoglobin in diabe- 3-year follow-up of clinical and behavioral im- KH. Community health ambassadors: a model for tes: a systematic review and meta-analysis of provements following a multifaceted diabetes engaging community leaders to promote better randomized trials. CMAJ 2017;189:E341–E364 care intervention: results of a randomized con- health in North Carolina. J Public Health Manag 43. Marcolino MS, Maia JX, Alkmim MBM, trolled trial. Diabetes Educ 2010;36:301–309 Pract 2008;14(Suppl.):S73–S81 Boersma E, Ribeiro AL. Telemedicine application 12. Katon WJ, Lin EHB, Von Korff M, et al. 28. Davidson MB. How our current medical care in the care of diabetes patients: systematic review Collaborative care for patients with depression system fails people with diabetes: lack of timely, and meta-analysis. PLoS One 2013;8:e79246 and chronic illnesses. N Engl J Med 2010;363: appropriate clinical decisions. Diabetes Care 44. Heitkemper EM, Mamykina L, Travers J, 2611–2620 2009;32:370–372 Smaldone A. Do health information technology 13. Parchman ML, Zeber JE, Romero RR, Pugh JA. 29. Selby JV, Uratsu CS, Fireman B, et al. Treat- self-management interventions improve glyce- Risk of coronary artery disease in type 2 diabetes ment intensification and risk factor control: to- mic control in medically underserved adults with and the delivery of care consistent with the ward more clinically relevant quality measures. diabetes? A systematic review and meta-analysis. chronic care model in primary care settings: Med Care 2009;47:395–402 J Am Med Inform Assoc 2017;24:1024–1035 a STARNet study. Med Care 2007;45:1129–1134 30. Raebel MA, Ellis JL, Schroeder EB, et al. 45. Myerson R, Laiteerapong N. The Affordable 14. Tricco AC, Ivers NM, Grimshaw JM, et al. Intensification of antihyperglycemic ther- Care Act and diabetes diagnosis and care: ex- Effectiveness of quality improvement strategies on apy among patients with incident diabetes: ploring the potential impacts. Curr Diab Rep the management of diabetes: a systematic review a Surveillance Prevention and Management 2016;16:27 and meta-analysis. Lancet 2012;379:2252–2261 of Diabetes Mellitus (SUPREME-DM) study. 46. Casagrande SS, McEwen LN, Herman WH. 15. Schmittdiel JA, Gopalan A, Lin MW, Banerjee Pharmacoepidemiol Drug Saf 2014;23:699– Changes in health insurance coverage under the S, Chau CV, Adams AS. Population health man- 710 Affordable Care Act: a national sample of U.S. agement for diabetes: health care system-level 31. Grant RW, Pabon-Nau L, Ross KM, Youatt EJ, adults with diabetes, 2009 and 2016. Diabetes approaches for improving quality and addressing Pandiscio JC, Park ER. Diabetes oral medication Care 2018;41:956–962 disparities. Curr Diab Rep 2017;17:31 initiation and intensification: patient views com- 47. Doucette ED, Salas J, Scherrer JF. Insurance 16. O’Connor PJ, Bodkin NL, Fradkin J, et al. pared with current treatment guidelines. Diabe- coverage and diabetes quality indicators among Diabetes performance measures: current status tes Educ 2011;37:78–84 patients in NHANES. Am J Manag Care 2016;22: and future directions. Diabetes Care 2011;34: 32. Tamhane S, Rodriguez-Gutierrez R, Hargraves 484–490 1651–1659 I, Montori VM. Shared decision-making in diabe- 48. Stiefel M, Nolan K. Measuring the triple aim: 17. Jaffe MG, Lee GA, Young JD, Sidney S, Go AS. tes care. Curr Diab Rep 2015;15:112 a call for action. Popul Health Manag 2013;16: Improved blood pressure control associated 33. Schillinger D, Piette J, Grumbach K, et al. 219–220 with a large-scale hypertension program. JAMA Closing the loop: physician communication with 49. Agency for Healthcare Research and Quality. 2013;310:699–705 diabetic patients who have low health literacy. About the National Quality Strategy [Internet], 18. Peikes D, Chen A, Schore J, Brown R. Effects Arch Intern Med 2003;163:83–90 2017. Available from https://www.ahrq.gov/ of care coordination on hospitalization, quality of 34. Rosal MC, Ockene IS, Restrepo A, et al. workingforquality/about/index.html. Accessed care, and health care expenditures among Medi- Randomized trial of a literacy-sensitive, 22 October 2018 care beneficiaries: 15 randomized trials. JAMA culturally tailored diabetes self-management 50. National Quality Forum. Home page [Internet], 2009;301:603–618 intervention for low-income Latinos: Lati- 2017. Available from http://www.qualityforum 19. Raebel MA, Schmittdiel J, Karter AJ, nos en control. Diabetes Care 2011;34:838– .org/home.aspx. Accessed 22 October 2018 Konieczny JL, Steiner JF. Standardizing terminol- 844 51. Burstin H, Johnson K. Getting to better care ogy and definitions of medication adherence 35. Osborn CY, Cavanaugh K, Wallston KA, et al. and outcomes for diabetes through measure- and persistence in research employing electronic Health literacy explains racial disparities in di- ment [article online], 2016. Available from databases. Med Care 2013;51(Suppl. 3):S11–S21 abetes medication adherence. J Health Commun http://www.ajmc.com/journals/evidence-based- 20. Feifer C, Nemeth L, Nietert PJ, et al. Different 2011;16(Suppl. 3):268–278 diabetes-management/2016/march-2016/getting- paths to high-quality care: three archetypes of 36. Garg AX, Adhikari NKJ, McDonald H, et al. to-better-care-and-outcomes-for-diabetes-through- top-performing practice sites. Ann Fam Med Effects of computerized clinical decision support measurement. Accessed 22 October 2018 2007;5:233–241 systemson practitionerperformance and patient 52. National Institute of Diabetes and Diges- 21. Reed M, Huang J, Graetz I, et al. Outpatient outcomes: a systematic review. JAMA 2005;293: tive and Kidney Diseases. Practice transformation electronic health records and the clinical care 1223–1238 for physicians & health care teams [Internet]. and outcomes of patients with diabetes mellitus. 37. Smith SA, Shah ND, Bryant SC, et al.; Evidens Available from https://www.niddk.nih.gov/ Ann Intern Med 2012;157:482–489 Research Group. Chronic care model and shared health-information/health-communication- 22. Cebul RD, Love TE, Jain AK, Hebert CJ. carein diabetes: randomized trial of an electronic programs/ndep/health-care-professionals/ Electronic health records and quality of diabetes decision support system. Mayo Clin Proc 2008; practice-transformation/Pages/resourcedetail care. N Engl J Med 2011;365:825–833 83:747–757 .aspx. Accessed 22 October 2018 S12 Improving Care and Promoting Health Diabetes Care Volume 42, Supplement 1, January 2019

53. National Institute of Diabetes and Digestive 64. Hill JO, Galloway JM, Goley A, et al. Socio- 74. Seligman HK, Schillinger D. Hunger and and Kidney Diseases. Diabetes care and quality: ecological determinants of prediabetes and socioeconomic disparities in chronic disease. past,present,andfuture[Internet].Availablefrom type 2 diabetes. Diabetes Care 2013;36:2430– N Engl J Med 2010;363:6–9 https://www.niddk.nih.gov/health-information/ 2439 75. Montgomery AE, Fargo JD, Kane V, Culhane health-communication-programs/ndep/health- 65. National Academies of Sciences, Engineer- DP. Development and validation of an instrument care-professionals/practice-transformation/ ing, and Medicine. A Framework to Address to assess imminent risk of homelessness among defining-quality-care/diabetes-care-quality/Pages/ the Social Determinants of Health [Internet], veterans. Public Health Rep 2014;129:428–436 default.aspx. Accessed 22 October 2018 2016. Washington, DC, The National Academies 76. U.S. Department of Health and Human Ser- 54. O’Connor PJ, Sperl-Hillen JM, Fazio CJ, Press. Available from https://www.nap.edu/ vices. Think cultural health [Internet]. Available Averbeck BM, Rank BH, Margolis KL. Outpatient catalog/21923/a-framework-for-educating-health- from https://www.thinkculturalhealth.hhs.gov/. diabetes clinical decision support: current status and professionals-to-address-the-social-determinants- Accessed 22 October 2018 future directions. Diabet Med 2016;33:734–741 of-health. Accessed 22 October 2018 77. Agency for Healthcare Research and Quality. 55. Centers for Medicare & Medicaid Services. 66. Institute of Medicine. Capturing social and Clinical-community linkages [Internet]. Avail- CMS Equity Plan for Medicare [Internet]. Avail- behavioral domains and measures in electronic able from http://www.ahrq.gov/professionals/ able from https://www.cms.gov/About-CMS/ health records: phase 2 [Internet], 2014. Wash- prevention-chronic-care/improve/community/ Agency-Information/OMH/equity-initiatives/ ington, DC, The National Academies Press. Avail- index.html. Accessed 22 October 2018 equity-plan.html. Accessed 22 October 2018 able from https://www.nap.edu/catalog/18951/ 78. Shah M, Kaselitz E, Heisler M. The role of 56. Rosenthal MB, Cutler DM, Feder J. The ACO capturing-social-and-behavioral-domains-and- community health workers in diabetes: update on rules–striking the balance between participation and measures-in-electronic-health-records. Accessed currentliterature.CurrDiabRep2013;13:163–171 transformative potential. N Engl J Med 2011;365:e6 22 October 2018 79. Heisler M, Vijan S, Makki F, Piette JD. Di- 57. Washington AE, Lipstein SH. The Patient- 67. Chin MH, Clarke AR, Nocon RS, et al. A abetes control with reciprocal peer support Centered Outcomes Research Institute–promoting roadmap and best practices for organizations versus nurse care management: a randomized better information, decisions, and health. N Engl J to reduce racial and ethnic disparities in health trial. Ann Intern Med 2010;153:507–515 Med 2011;365:e31 care. J Gen Intern Med 2012;27:992–1000 80. Long JA, Jahnle EC, Richardson DM, 58. Hutchinson RN, Shin S. Systematic review of 68. National Quality Forum. National voluntary Loewenstein G, Volpp KG. Peer mentoring health disparities for cardiovascular diseases and consensus standards for ambulatory cared and financial incentives to improve glucose associated factors among American Indian and measuring healthcare disparities [Internet], 2008. control in African American veterans: a random- Alaska Native populations. PLoS One 2014;9: Available from https://www.qualityforum.org/ ized trial. Ann Intern Med 2012;156:416–424 e80973 Publications/2008/03/National_Voluntary_ 81. Fisher EB, Boothroyd RI, Elstad EA, et al. Peer 59. Borschuk AP, Everhart RS. Health disparities Consensus_Standards_for_Ambulatory_Care% support of complex health behaviors in preven- among youth with type 1 diabetes: a systematic E2%80%94Measuring_Healthcare_Disparities tion and disease management with special ref- review of the current literature. Fam Syst Health .aspx. Accessed 22 October 2018 erence to diabetes: systematic reviews. Clin 2015;33:297–313 69. Piette JD, Heisler M, Wagner TH. Cost- Diabetes Endocrinol 2017;3:4 60. Walker RJ, Strom Williams J, Egede LE. In- related medication underuse among chronically 82. Foster G, Taylor SJC, Eldridge SE, Ramsay J, fluence of race, ethnicity and social determinants ill adults: the treatments people forgo, how Griffiths CJ. Self-management education proof health on diabetes outcomes. Am J Med Sci often, and who is at risk. Am J Public Health grammes by lay leaders for people with chronic 2016;351:366–373 2004;94:1782–1787 conditions. Cochrane Database Syst Rev 2007;4: 61. Patel MR, Piette JD, Resnicow K, Kowalski- 70. Laiteerapong N, Karter AJ, Liu JY, et al. CD005108 Dobson T, Heisler M. Social determinants of Correlates of quality of life in older adults 83. Rosenthal EL, Rush CH, Allen CG; Project on health, cost-related nonadherence, and cost- with diabetes: the Diabetes & Aging Study. Di- CHW Policy & Practice. Understanding scope reducing behaviors among adults with diabetes: abetes Care 2011;34:1749–1753 and competencies: a contemporary look at the findings from the National Health Interview 71. Heerman WJ, Wallston KA, Osborn CY, et al. United States community health worker field: Survey. Med Care 2016;54:796–803 Food insecurity is associated with diabetes self- progress report of the Community Health Worker 62. Steve SL, Tung EL, Schlichtman JJ, Peek ME. care behaviours and glycaemic control. Diabet (CHW) Core Consensus (C3) Project: building Social disorder in adults with type 2 diabetes: Med 2016;33:844–850 national consensus on CHW core roles, skills, building on race, place, and poverty. Curr Diab 72. Silverman J, Krieger J, Kiefer M, Hebert P, and qualities [Internet], 2016. Available from Rep 2016;16:72 Robinson J, Nelson K. The relationship between http://files.ctctcdn.com/a907c850501/1c1289f0- 63. World Health Organization Commission on food insecurity and depression, diabetes distress 88cc-49c3-a238-66def942c147.pdf. Accessed Social Determinants of Health. Closing the gap and medication adherence among low-income 22 October 2018 in a generation: health equity through action patients with poorly-controlled diabetes. J Gen 84. U.S. Department of Health and Human Ser- on the social determinants of health [Internet], Intern Med 2015;30:1476–1480 vices. Community health workers help patients 2008. Geneva, Switzerland, World Health Organiza- 73. Hager ER, Quigg AM, Black MM, et al. De- manage diabetes [Internet]. Available from tion. Available from http://www.who.int/social_ velopment and validity of a 2-item screen to https://www.thecommunityguide.org/content/ determinants/final_report/csdh_finalreport_2008 identify families at risk for food insecurity. Pe- community-health-workers-help-patients-manage- .pdf. Accessed 22 October 2018 diatrics 2010;126:e26–e32 diabetes. Accessed 22 October 2018 Diabetes Care Volume 42, Supplement 1, January 2019 S13

2. Classiﬁcation and Diagnosis of American Diabetes Association Diabetes: Standards of Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S13–S28 | https://doi.org/10.2337/dc19-S002 .CASFCTO N IGOI FDIABETES OF DIAGNOSIS AND CLASSIFICATION 2.

CLASSIFICATION Diabetes can be classiﬁed into the following general categories:

1. Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to absolute insulin deficiency) 2. Type 2 diabetes (due to a progressive loss of b-cell insulin secretion frequently on the background of insulin resistance) 3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation) 4. Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young [MODY]), diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), and drug- or 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 statement “Diagnosis and Classification of Diabetes Mellitus” (1). Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical Suggested citation: American Diabetes Associa- presentation and disease progression may vary considerably. Classification is im- tion. 2. Classification and diagnosis of diabetes: portant for determining therapy, but some individuals cannot be clearly classified as Standards of Medical Care in Diabetesd2019. having type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms of Diabetes Care 2019;42(Suppl. 1):S13–S28 type 2 diabetes occurring only in adults and type 1 diabetes only in children are no © 2018 by the American Diabetes Association. longer accurate, as both diseases occur in both age-groups. Children with type 1 Readers may use this article as long as the work is properly cited, the use is educational and not diabetes typically present with the hallmark symptoms of polyuria/polydipsia, and for profit, and the work is not altered. More infor- approximately one-third present with diabetic ketoacidosis (DKA) (2). The onset of mation is available at http://www.diabetesjournals type 1 diabetes may be more variable in adults, and they may not present with the .org/content/license. S14 Classification and Diagnosis of Diabetes Diabetes Care Volume 42, Supplement 1, January 2019

classic symptoms seen in children. Oc- of subtypes of this heterogeneous dis- Fasting and 2-Hour Plasma Glucose casionally, patients with type 2 diabetes order have been developed and vali- The FPG and 2-h PG may be used to may present with DKA, particularly ethnic datedinScandinavianandNorthern diagnose diabetes (Table 2.2). The con- minorities (3). Although difficulties in European populations but have not cordance between the FPG and 2-h PG distinguishing diabetes type may occur in been confirmed in other ethnic and racial tests is imperfect, as is the concordance all age-groups at onset, the true diag- groups. Type 2 diabetes is primarily as- between A1C and either glucose-based nosis becomes more obvious over sociated with insulin secretory defects test.ComparedwithFPGandA1Ccut time. related to inflammation and metabolic points, the 2-h PG value diagnoses more In both type 1 and type 2 diabetes, stress among other contributors, includ- people with prediabetes and diabetes (9). various genetic and environmental fac- ing genetic factors. Future classification tors can result in the progressive loss of schemes for diabetes will likely focus A1C b-cell mass and/or function that mani- on the pathophysiology of the underly- Recommendations fests clinically as hyperglycemia. Once ing b-cell dysfunction and the stage of 2.1 To avoid misdiagnosis or missed hyperglycemia occurs, patients with all disease as indicated by glucose status diagnosis, the A1C test should be forms of diabetes are at risk for devel- (normal, impaired, or diabetes) (4). performed using a method that is oping the same chronic complications, certified by the NGSP and stan- although rates of progression may differ. DIAGNOSTIC TESTS FOR DIABETES dardized to the Diabetes Control The identification of individualized ther- Diabetes may be diagnosed based on and Complications Trial (DCCT) apies for diabetes in the future will re- plasma glucose criteria, either the fasting assay. B quire better characterization of the many plasma glucose (FPG) value or the 2-h 2.2 Marked discordance between mea- paths to b-cell demise or dysfunction (4). plasma glucose (2-h PG) value during a sured A1C and plasma glucose Characterization of the underlying 75-g oral glucose tolerance test (OGTT), levels should raise the possibility pathophysiology is more developed in or A1C criteria (6) (Table 2.2). of A1C assay interference due to type 1 diabetes than in type 2 diabetes. It Generally, FPG, 2-h PG during 75-g hemoglobin variants (i.e., hemo- is now clear from studies of first-degree OGTT, and A1C are equally appropriate globinopathies) and consider- relatives of patients with type 1 diabetes for diagnostic testing. It should be noted ation of using an assay without that the persistent presence of two or that the tests do not necessarily detect interference or plasma blood glu- more autoantibodies is an almost certain diabetes in the same individuals. The cose criteria to diagnose diabe- predictor of clinical hyperglycemia and efficacy of interventions for primary pre- tes. B diabetes. The rate of progression is de- vention of type 2 diabetes (7,8) has 2.3 In conditions associated with an pendent on the age at first detection primarily been demonstrated among in- altered relationship between A1C of antibody, number of antibodies, anti- dividuals who have impaired glucose and glycemia, such as sickle cell body specificity, and antibody titer. Glu- tolerance (IGT) with or without elevated disease, pregnancy (second and cose and A1C levels rise well before the fasting glucose, not for individuals with third trimesters and the postpar- clinical onset of diabetes, making diag- isolated impaired fasting glucose (IFG) or tum period), glucose-6-phosphate nosis feasible well before the onset of for those with prediabetes defined by dehydrogenase deficiency, HIV, DKA. Three distinct stages of type 1 di- A1C criteria. hemodialysis, recent blood loss or abetes can be identified (Table 2.1) and The same tests may be used to screen transfusion, or erythropoietin ther- serve as a framework for future research for and diagnose diabetes and to detect apy, only plasma blood glucose cri- and regulatory decision making (4,5). individuals with prediabetes. Diabetes teria should be used to diagnose The paths to b-cell demise and dys- may be identified anywhere along the diabetes. B function are less well defined in type 2 spectrum of clinical scenarios: in seem- diabetes, but deficient b-cell insulin ingly low-risk individuals who happen to The A1C test should be performed using a secretion, frequently in the setting of have glucose testing, in individuals tested method that is certified by the NGSP insulin resistance, appears to be the based on diabetes risk assessment, and (www.ngsp.org) and standardized or common denominator. Characterization in symptomatic patients. traceable to the Diabetes Control and

Table 2.1—Staging of type 1 diabetes (4,5) Stage 1 Stage 2 Stage 3 Characteristics c Autoimmunity c Autoimmunity c New-onset hyperglycemia c Normoglycemia c Dysglycemia c Symptomatic c Presymptomatic c Presymptomatic Diagnostic criteria c Multiple autoantibodies c Multiple autoantibodies c Clinical symptoms c No IGT or IFG c Dysglycemia: IFG and/or IGT c Diabetes by standard criteria c FPG 100–125 mg/dL (5.6–6.9 mmol/L) c 2-h PG 140–199 mg/dL (7.8–11.0 mmol/L) c A1C 5.7–6.4% (39–47 mmol/mol) or $10% increase in A1C care.diabetesjournals.org Classiﬁcation and Diagnosis of Diabetes S15

Table 2.2—Criteria for the diagnosis of diabetes FPG $126 mg/dL (7.0 mmol/L). Fasting is deﬁned as no caloric intake for at least 8 h.* OR 2-h PG $200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water.* OR A1C $6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is NGSP certiﬁed and standardized to the DCCT assay.* OR In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose $200 mg/dL (11.1 mmol/L). *In the absence of unequivocal hyperglycemia, diagnosis requires two abnormal test results from the same sample or in two separate test samples.

Complications Trial (DCCT) reference clinical guidance concluded that A1C, Americans may also have higher levels of assay. Although point-of-care A1C assays FPG, or 2-h PG can be used to test for fructosamine and glycated albumin and may be NGSP certified or U.S. Food and prediabetes or type 2 diabetes in chil- lower levels of 1,5-anhydroglucitol, suggest- Drug Administration approved for diag- dren and adolescents. (see p. S20 SCREEN- ing that their glycemic burden (particularly nosis, proficiency testing is not always ING AND TESTING FOR PREDIABETES AND TYPE 2 postprandially) may be higher (21,22). The mandated for performing the test. There- DIABETES IN CHILDREN AND ADOLESCENTS for ad- association of A1C with risk for complica- fore, point-of-care assays approved for ditional information) (13). tions appears to be similar in African Amer- diagnostic purposes should only be con- icans and non-Hispanic whites (23,24). sideredinsettingslicensedtoperform Race/Ethnicity/Hemoglobinopathies moderate-to-high complexity tests. As Hemoglobin variants can interfere with Other Conditions Altering the Relationship discussed in Section 6 “Glycemic Targets,” the measurement of A1C, although most of A1C and Glycemia point-of-care A1C assays may be more assays in use in the U.S. are unaffected by In conditions associated with increased generally applied for glucose monitoring. the most common variants. Marked dis- red blood cell turnover, such as sickle cell The A1C has several advantages com- crepancies between measured A1C and disease, pregnancy (second and third pared with the FPG and OGTT, including plasma glucose levels should prompt trimesters), glucose-6-phosphate dehy- fi greater convenience (fasting not re- consideration that the A1C assay may drogenase de ciency (25,26), hemodialy- quired), greater preanalytical stability, not be reliable for that individual. For sis, recent blood loss or transfusion, or and less day-to-day perturbations during patients with a hemoglobin variant but erythropoietin therapy, only plasma blood stress and illness. However, these ad- normal red blood cell turnover, such as glucose criteria should be used to diagnose vantages may be offset by the lower those with the sickle cell trait, an A1C diabetes (27). A1C is less reliable than sensitivity of A1C at the designated cut assay without interference from hemo- blood glucose measurement in other con- – point, greater cost, limited availability of globin variants should be used. An up- ditions such as postpartum (28 30), HIV A1C testing in certain regions of the de- dated list of A1C assays with interferences treated with certain drugs (11), and iron- fi veloping world, and the imperfect corre- is available at www.ngsp.org/interf.asp. de cient anemia (31). lation between A1C and average glucose African Americans heterozygous for in certain individuals. The A1C test, with the common hemoglobin variant HbS Confirming the Diagnosis a diagnostic threshold of $6.5% (48 may have, for any given level of mean Unless there is a clear clinical diagnosis mmol/mol), diagnoses only 30% of the glycemia, lower A1C by about 0.3% than (e.g., patient in a hyperglycemic crisis diabetes cases identified collectively those without the trait (14). Another ge- or with classic symptoms of hyperglyce- using A1C, FPG, or 2-h PG, according netic variant, X-linked glucose-6-phosphate mia and a random plasma glucose $200 to National Health and Nutrition Exam- dehydrogenase G202A, carried by 11% mg/dL [11.1 mmol/L]), diagnosis requires ination Survey (NHANES) data (10). of African Americans, was associated two abnormal test results from the When using A1C to diagnose diabetes, with a decrease in A1C of about 0.8% same sample (32) or in two separate it is important to recognize that A1C is an in homozygous men and 0.7% in homo- test samples. If using two separate test indirect measure of average blood glu- zygous women compared with those samples, it is recommended that the cose levels and to take other factors into without the variant (15). second test, which may either be a repeat consideration that may impact hemoglo- Even in the absence of hemoglobin of the initial test or a different test, be bin glycation independently of glycemia variants, A1C levels may vary with race/ performed without delay. For example, if including HIV treatment (11,12), age, race/ ethnicity independently of glycemia the A1C is 7.0% (53 mmol/mol) and a ethnicity, pregnancy status, genetic back- (16–18). For example, African Americans repeat result is 6.8% (51 mmol/mol), the ground, and anemia/hemoglobinopathies. may have higher A1C levels than non- diagnosis of diabetes is confirmed. If two Hispanic whites with similar fasting and different tests (such as A1C and FPG) are Age postglucose load glucose levels (19), and both above the diagnostic threshold The epidemiological studies that formed A1C levels may be higher for a given mean when analyzed from the same sample the basis for recommending A1C to di- glucose concentration when measured or in two different test samples, this also agnose diabetes included only adult pop- with continuous glucose monitoring (20). confirms the diagnosis. On the other ulations (10). However, a recent ADA Though conflicting data exists, African hand, if a patient has discordant results S16 Classification and Diagnosis of Diabetes Diabetes Care Volume 42, Supplement 1, January 2019

from two different tests, then the test determine how long a patient has had permanent insulinopenia and are prone result that is above the diagnostic cut hyperglycemia. The criteria to diagnose to DKA, but have no evidence of b-cell point should be repeated, with consider- diabetes are listed in Table 2.2. autoimmunity. Although only a minority ation of the possibility of A1C assay in- of patients with type 1 diabetes fall into terference. The diagnosis is made on the Immune-Mediated Diabetes this category, of those who do, most are of basis of the confirmed test. For example, This form, previously called “insulin- African or Asian ancestry. Individuals with if a patient meets the diabetes criterion dependent diabetes” or “juvenile-onset this form of diabetes suffer from episodic of the A1C (two results $6.5% [48 diabetes,” accounts for 5–10% of diabetes DKA and exhibit varying degrees of insulin mmol/mol]) but not FPG (,126 mg/dL and is due to cellular-mediated auto- deficiency between episodes. This form [7.0 mmol/L]), that person should never- immune destruction of the pancreatic of diabetes is strongly inherited and is theless be considered to have diabetes. b-cells. Autoimmune markers include islet not HLA associated. An absolute require- Since all the tests have preanalytic and cell autoantibodies and autoantibodies to ment for insulin replacement therapy in analytic variability, it is possible that an GAD (GAD65), insulin, the tyrosine phos- affected patients may be intermittent. abnormal result (i.e., above the diagnostic phatases IA-2 and IA-2b, and ZnT8. Type 1 threshold), when repeated, will produce diabetes is defined by the presence of Screening for Type 1 Diabetes Risk a value below the diagnostic cut point. one or more of these autoimmune The incidence and prevalence of type 1 This scenario is likely for FPG and 2-h PG if markers. The disease has strong HLA diabetes is increasing (33). Patients with the glucose samples remain at room tem- associations, with linkage to the DQA type 1 diabetes often present with acute peratureandarenotcentrifuged promptly. and DQB genes. These HLA-DR/DQ alleles symptoms of diabetes and markedly Because of the potential for preanalytic can be either predisposing or protective. elevated blood glucose levels, and ap- variability, it is critical that samples for The rate of b-cell destruction is quite proximately one-third are diagnosed plasma glucose be spun and separated variable, being rapid in some individuals with life-threatening DKA (2). Several immediately after they are drawn. If pa- (mainly infants and children) and slow in studies indicate that measuring islet tients have test results nearthemarginsof others (mainly adults). Children and ado- autoantibodies in relatives of those the diagnostic threshold, the health care lescents may present with DKA as the with type 1 diabetes may identify indi- professional should follow the patient first manifestation of the disease. Others viduals who are at risk for developing closely and repeat the test in 3–6months. have modest fasting hyperglycemia type 1 diabetes (5). Such testing, coupled that can rapidly change to severe hyper- with education about diabetes symp- TYPE 1 DIABETES glycemia and/or DKA with infection or toms and close follow-up, may enable other stress. Adults may retain sufficient earlier identification of type 1 diabetes Recommendations b-cell function to prevent DKA for many onset. A study reported the risk of pro- 2.4 Plasma blood glucose rather than years; such individuals eventually be- gression to type 1 diabetes from the time A1C should be used to diagnose come dependent on insulin for survival of seroconversion to autoantibody pos- the acute onset of type 1 diabetes and are at risk for DKA. At this latter stage itivity in three pediatric cohorts from in individuals with symptoms of of the disease, there is little or no insulin Finland, Germany, and the U.S. Of the hyperglycemia. E secretion, as manifested by low or un- 585 children who developed more than 2.5 Screening for type 1 diabetes risk detectable levels of plasma C-peptide. two autoantibodies, nearly 70% devel- with a panel of autoantibodies is Immune-mediated diabetes commonly oped type 1 diabetes within 10 years and currently recommended only in occurs in childhood and adolescence, 84% within 15 years (34). These findings the setting of a research trial or in but it can occur at any age, even in are highly significant because while the first-degree family members of a the 8th and 9th decades of life. German group was recruited from off- proband with type 1 diabetes. B Autoimmune destruction of b-cells spring of parents with type 1 diabetes, 2.6 Persistence of two or more auto- has multiple genetic predispositions the Finnish and American groups were antibodies predicts clinical diabe- and is also related to environmental recruited from the general population. tes and may serve as an indication factors that are still poorly defined. Al- Remarkably, the findings in all three for intervention in the setting of though patients are not typically obese groups were the same, suggesting that a clinical trial. B when they present with type 1 diabetes, the same sequence of events led to obesity should not preclude the diagno- clinical disease in both “sporadic” and Diagnosis sis. People with type 1 diabetes are also familial cases of type 1 diabetes. Indeed, In a patient with classic symptoms, mea- prone to other autoimmune disorders the risk of type 1 diabetes increases as surement of plasma glucose is sufficient such as Hashimoto thyroiditis, Graves dis- the number of relevant autoantibodies to diagnose diabetes (symptoms of hy- ease, Addison disease, celiac disease, vit- detected increases (35–37). perglycemia or hyperglycemic crisis plus iligo, autoimmune hepatitis, myasthenia Although there is currently a lack of a random plasma glucose $200 mg/dL gravis, and pernicious anemia (see Section accepted screening programs, one should [11.1 mmol/L]). In these cases, knowing 4 “Comprehensive Medical Evaluation consider referring relatives of those with the plasma glucose level is critical be- and Assessment of Comorbidities”). type 1 diabetes for antibody testing for cause, in addition to confirming that risk assessment in the setting of a clini- symptoms are due to diabetes, it will in- Idiopathic Type 1 Diabetes cal research study (www.diabetestrialnet form management decisions. Some pro- Some forms of type 1 diabetes have no .org). Widespread clinical testing of asymp- viders may also want to know the A1C to known etiologies. These patients have tomatic low-risk individuals is not currently care.diabetesjournals.org Classification and Diagnosis of Diabetes S17

recommended due to lack of approved World Health Organization (WHO) and appropriate, treat other cardio- therapeutic interventions. Individuals numerous other diabetes organizations vascular disease risk factors. B who test positive should be counseled define the IFG cutoff at 110 mg/dL 2.13 Risk-based screening for pre- about the risk of developing diabetes, (6.1 mmol/L). diabetes and/or type 2 diabetes diabetes symptoms, and DKA preven- As with the glucose measures, several should be considered after the tion. Numerous clinical studies are be- prospective studies that used A1C to onset of puberty or after 10 years ing conducted to test various methods predict the progression to diabetes as of age, whichever occurs earlier, of preventing type 1 diabetes in those defined by A1C criteria demonstrated a in children and adolescents who with evidence of autoimmunity (www. strong, continuous association between are overweight (BMI $85th per- clinicaltrials.gov). A1C and subsequent diabetes. In a sys- centile) or obese (BMI $95th tematic review of 44,203 individuals percentile) and who have addi- PREDIABETES AND TYPE from 16 cohort studies with a follow-up tional risk factors for diabe- 2 DIABETES interval averaging 5.6 years (range 2.8– tes. (See Table 2.4 for evidence 12 years), those with A1C between 5.5 Recommendations grading of risk factors.) and 6.0% (between 37 and 42 mmol/mol) 2.7 Screening for prediabetes and had a substantiallyincreasedriskof type 2 diabetes with an infor- diabetes (5-year incidence from 9 to mal assessment of risk factors Prediabetes 25%). Those with an A1C range of or validated tools should be “ ” Prediabetes is the term used for indi- 6.0–6.5% (42–48 mmol/mol) had a considered in asymptomatic viduals whose glucose levels do not meet 5-year risk of developing diabetes be- adults. B the criteria for diabetes but are too high tween 25 and 50% and a relative risk 2.8 Testing for prediabetes and/or to be considered normal (23,24). Pa- 20 times higher compared with A1C of type 2 diabetes in asymptomatic fi tients with prediabetes are de ned by 5.0% (31 mmol/mol) (41). In a commu- people should be considered in the presence of IFG and/or IGT and/or nity-based study of African American adults of any age who are over- – – Table A1C 5.7 6.4% (39 47 mmol/mol) ( and non-Hispanic white adults without weightorobese(BMI$25 kg/m2 2.5 ). Prediabetes should not be viewed diabetes, baseline A1C was a stronger or $23 kg/m2 in Asian Ameri- as a clinical entity in its own right but predictor of subsequent diabetes and cans) and who have one or more rather as an increased risk for diabetes cardiovascular events than fasting glu- additional risk factors for diabe- and cardiovascular disease (CVD). Crite- cose (42). Other analyses suggest that A1C tes (Table 2.3). B ria for testing for diabetes or prediabe- of 5.7% (39 mmol/mol) or higher is asso- 2.9 For all people, testing should betes in asymptomatic adults is outlined ciated with a diabetes risk similar to that of gin at age 45 years. B Table 2.3 in . Prediabetes is associated the high-risk participants in the Diabetes 2.10 If tests are normal, repeat testing with obesity (especially abdominal or Prevention Program (DPP) (43), and A1C at carried out at a minimum of visceral obesity), dyslipidemia with high baseline was a strong predictor of the 3-year intervals is reasonable. C triglycerides and/or low HDL choles- development of glucose-defined diabe- 2.11 To test for prediabetes and terol, and hypertension. tes during the DPP and its follow-up (44). type 2 diabetes, fasting plasma Diagnosis Hence, it is reasonable to consider glucose, 2-h plasma glucose IFG is defined as FPG levels between an A1C range of 5.7–6.4% (39–47 during 75-g oral glucose toler- 100 and 125 mg/dL (between 5.6 and mmol/mol) as identifying individuals with ance test, and A1C are equally 6.9 mmol/L) (38,39) and IGT as 2-h PG prediabetes. Similar to those with IFG appropriate. B during 75-g OGTT levels between 140 and/or IGT, individuals with A1C of 5.7– 2.12 In patients with prediabetes and and 199 mg/dL (between 7.8 and 11.0 6.4% (39–47 mmol/mol) should be in- type 2 diabetes, identify and, if mmol/L) (40). It should be noted that the formed of their increased risk for diabetes

Table 2.3—Criteria for testing for diabetes or prediabetes in asymptomatic adults 1. Testing should be considered in overweight or obese (BMI $25 kg/m2 or $23 kg/m2 in Asian Americans) adults who have one or more of the following risk factors: c First-degree relative with diabetes c High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Paciﬁc Islander) c History of CVD c Hypertension ($140/90 mmHg or on therapy for hypertension) c HDL cholesterol level ,35 mg/dL (0.90 mmol/L) and/or a triglyceride level .250 mg/dL (2.82 mmol/L) c Women with polycystic ovary syndrome c Physical inactivity c Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans) 2. Patients with prediabetes (A1C $5.7% [39 mmol/mol], IGT, or IFG) should be tested yearly. 3. Women who were diagnosed with GDM should have lifelong testing at least every 3 years. 4. For all other patients, testing should begin at age 45 years. 5. If results are normal, testing should be repeated at a minimum of 3-year intervals, with consideration of more frequent testing depending on initial results and risk status. S18 Classiﬁcation and Diagnosis of Diabetes Diabetes Care Volume 42, Supplement 1, January 2019

Table 2.4—Risk-based screening for type 2 diabetes or prediabetes in asymptomatic children and adolescents in a clinical setting Testing should be considered in youth* who are overweight ($85% percentile) or obese ($95 percentile) A and who have one or more additional risk factors based on the strength of their association with diabetes: c Maternal history of diabetes or GDM during the child’s gestation A c Family history of type 2 diabetes in ﬁrst- or second-degree relative A c Race/ethnicity (Native American, African American, Latino, Asian American, Paciﬁc Islander) A c Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth weight) B *After the onset of puberty or after 10 years of age, whichever occurs earlier. If tests are normal, repeat testing at a minimum of 3-year intervals, or more frequently if BMI is increasing, is recommended.

and CVD and counseled about effective are not known, autoimmune destruction Insulin resistance may improve with strategies to lower their risks (see Section 3 of b-cells does not occur and patients do weight reduction and/or pharmacologic “Prevention or Delay of Type 2 Diabetes”). not have any of the other known causes treatment of hyperglycemia but is sel- Similar to glucose measurements, the con- of diabetes. Most but not all patients dom restored to normal. tinuum of risk is curvilinear, so as A1C rises, with type 2 diabetes are overweight or The risk of developing type 2 diabetes the diabetes risk rises disproportionately obese. Excess weight itself causes some increases with age, obesity, and lack of (41). Aggressive interventions and vig- degree of insulin resistance. Patients physical activity. It occurs more fre- ilant follow-up should be pursued for who are not obese or overweight by quently in women with prior GDM, in those considered at very high risk (e.g., traditional weight criteria may have an those with hypertension or dyslipidemia, those with A1C .6.0% [42 mmol/mol]). increased percentage of body fat distrib- and in certain racial/ethnic subgroups Table 2.5 summarizes the categories uted predominantly in the abdominal (African American, American Indian, of prediabetes and Table 2.3 the criteria region. Hispanic/Latino, and Asian American). It for prediabetes testing. The ADA dia- DKA seldom occurs spontaneously in is often associated with a strong genetic betes risk test is an additional option type 2 diabetes; when seen, it usually predisposition or family history in first- for assessment to determine the ap- arises in association with the stress degree relatives, more so than type 1 propriateness of testing for diabetes of another illness such as infection or diabetes. However, the genetics of type 2 or prediabetes in asymptomatic adults. with the use of certain drugs (e.g., diabetes is poorly understood. In adults (Fig. 2.1) (diabetes.org/socrisktest). For corticosteroids, atypical antipsychotics, without traditional risk factors for additional background regarding risk fac- and sodium–glucose cotransporter 2 in- type 2 diabetes and/or younger age, con- tors and screening for prediabetes, see pp. hibitors) (45,46). Type 2 diabetes fre- sider antibody testing to exclude the S18–S20 (SCREENING AND TESTING FOR PREDIABETES quently goes undiagnosed for many diagnosis of type 1 diabetes (i.e., GAD). AND TYPE 2 DIABETES IN ASYMPTOMATIC ADULTS and years because hyperglycemia develops SCREENING AND TESTING FOR PREDIABETES AND TYPE 2 gradually and, at earlier stages, is often Screening and Testing for DIABETES IN CHILDREN AND ADOLESCENTS). not severe enough for the patient to Prediabetes and Type 2 Diabetes in notice the classic diabetes symptoms. Asymptomatic Adults Type 2 Diabetes Nevertheless, even undiagnosed pa- Screening for prediabetes and type 2 Type 2 diabetes, previously referred to tients are at increased risk of develop- diabetes risk through an informal as- as “noninsulin-dependent diabetes” or ing macrovascular and microvascular sessment of risk factors (Table 2.3)orwith “adult-onset diabetes,” accounts for 90– complications. an assessment tool, such as the ADA risk 95% of all diabetes. This form encom- Whereas patients with type 2 diabetes test (Fig. 2.1) (diabetes.org/socrisktest), passes individuals who have relative may have insulin levels that appear nor- is recommended to guide providers on (rather than absolute) insulin deficiency mal or elevated, the higher blood glu- whether performing a diagnostic test and have peripheral insulin resistance. cose levels in these patients would be (Table 2.2) is appropriate. Prediabetes At least initially, and often throughout expected to result in even higher insulin and type 2 diabetes meet criteria for their lifetime, these individuals may not values had their b-cell function been conditions in which early detection is need insulin treatment to survive. normal. Thus, insulin secretion is defec- appropriate. Both conditions are com- There are various causes of type 2 di- tive in these patients and insufficient mon and impose significant clinical and abetes. Although the specific etiologies to compensate for insulin resistance. public health burdens. There is often a long presymptomatic phase before the diagnosis of type 2 diabetes. Simple tests Table 2.5—Criteria defining prediabetes* FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG) to detect preclinical disease are readily OR available. The duration of glycemic bur- 2-h PG during 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT) den is a strong predictor of adverse out- OR comes. There are effective interventions that prevent progression from prediabe- A1C 5.7–6.4% (39–47 mmol/mol) tes to diabetes (see Section 3 “Prevention *For all three tests, risk is continuous, extending below the lower limit of the range and becoming or Delay of Type 2 Diabetes”) and re- disproportionately greater at the higher end of the range. duce the risk of diabetes complications care.diabetesjournals.org Classification and Diagnosis of Diabetes S19

Figure 2.1—ADA risk test (diabetes.org/socrisktest).

(see Section 10 “Cardiovascular Disease of Asian and Hispanic Americans with effectiveness of such screening have and Risk Management” and Section 11 diabetes are undiagnosed (38,39). Al- not been conducted and are unlikely “Microvascular Complications and Foot though screening of asymptomatic indi- to occur. Care”). viduals to identify those with prediabetes A large European randomized con- Approximately one-quarter of people or diabetes might seem reasonable, trolled trial compared the impact of with diabetes in the U.S. and nearly half rigorous clinical trials to prove the screening for diabetes and intensive S20 Classiﬁcation and Diagnosis of Diabetes Diabetes Care Volume 42, Supplement 1, January 2019

multifactorial intervention with that of (52). The finding that one-third to one- practices had dysglycemia (61). Further screening and routine care (47). General half of diabetes in Asian Americans is research is needed to demonstrate practice patients between the ages of undiagnosed suggests that testing is the feasibility, effectiveness, and cost- 40 and 69 years were screened for di- not occurring at lower BMI thresholds effectiveness of screening in this setting. abetes and randomly assigned by prac- (53,54). tice to intensive treatment of multiple Evidence also suggests that other pop- Screening and Testing for Prediabetes risk factors or routine diabetes care. ulations may benefit from lower BMI cut and Type 2 Diabetes in Children and After 5.3 years of follow-up, CVD risk points. For example, in a large multi- Adolescents factors were modestly but significantly ethnic cohort study, for an equivalent In the last decade, the incidence and improved with intensive treatment com- incidence rate of diabetes, a BMI of prevalence of type 2 diabetes in adoles- pared with routine care, but the inci- 30 kg/m2 in non-Hispanic whites was cents has increased dramatically, es- dence of first CVD events or mortality equivalent to a BMI of 26 kg/m2 in Afri- pecially in racial and ethnic minority was not significantly different between can Americans (55). populations (33). See Table 2.4 for rec- the groups (40). The excellent care pro- ommendations on risk-based screening Medications vided to patients in the routine care for type 2 diabetes or prediabetes in Certain medications, such as glucocorti- group and the lack of an unscreened asymptomatic children and adolescents coids, thiazide diuretics, some HIV med- control arm limited the authors’ ability in a clinical setting (13). See Tables 2.2 ications, and atypical antipsychotics (56), to determine whether screening and and 2.5 for the criteria for the diagno- are known to increase the risk of diabetes early treatment improved outcomes com- sis of diabetes and prediabetes, respec- and should be considered when deciding pared with no screening and later treat- tively, which apply to children, adolescents, whether to screen. ment after clinical diagnoses. Computer and adults. See Section 13 “Children simulation modeling studies suggest that Testing Interval and Adolescents” for additional infor- major benefitsarelikelytoaccruefrom The appropriate interval between screen- mation on type 2 diabetes in children the early diagnosis and treatment of ing tests is not known (57). The rationale and adolescents. hyperglycemia and cardiovascular risk for the 3-year interval is that with this Some studies question the validity of factors in type 2 diabetes (48); more- interval, the number of false-positive A1C in the pediatric population, espe- over, screening, beginning at age 30 tests that require confirmatory testing cially among certain ethnicities, and sug- or 45 years and independent of risk will be reduced and individuals with gest OGTT or FPG as more suitable factors, may be cost-effective (,$11,000 false-negative tests will be retested diagnostic tests (62). However, many per quality-adjusted life-year gained) (49). before substantial time elapses and of these studies do not recognize that Additional considerations regarding complications develop (57). diabetes diagnostic criteria are based on testing for type 2 diabetes and predia- long-term health outcomes, and valida- Community Screening betes in asymptomatic patients include tions are not currently available in the Ideally, testing should be carried out the following. pediatric population (63). The ADA ac- within a health care setting because of knowledges the limited data supporting the need for follow-up and treatment. Age A1C for diagnosing type 2 diabetes in Community screening outside a health Age is a major risk factor for diabetes. children and adolescents. Although A1C care setting is generally not recom- Testing should begin at no later than age is not recommended for diagnosis of di- mended because people with positive 45 years for all patients. Screening should abetes in children with cystic fibrosis or tests may not seek, or have access to, be considered in overweight or obese symptoms suggestive of acute onset of appropriate follow-up testing and care. adults of any age with one or more risk type 1 diabetes and only A1C assays with- However, in specific situations where factors for diabetes. out interference are appropriate for chil- an adequate referral system is estab- dren with hemoglobinopathies, the ADA BMI and Ethnicity lished beforehand for positive tests, In general, BMI $25 kg/m2 is a risk factor continues to recommend A1C for diagnosis community screening may be consid- for diabetes. However, data suggest that of type 2 diabetes in this cohort (64,65). ered. Community testing may also be the BMI cut point should be lower for poorly targeted; i.e., it may fail to reach the Asian American population (50,51). the groups most at risk and inappro- GESTATIONAL DIABETES The BMI cut points fall consistently be- priately test those at very low risk or MELLITUS tween 23 and 24 kg/m2 (sensitivity of 80%) even those who have already been Recommendations for nearly all Asian American subgroups diagnosed (58). 2.14 Test for undiagnosed diabetes at (with levels slightly lower for Japanese the first prenatal visit in those Americans). This makes a rounded cut Screening in Dental Practices with risk factors using standard point of 23 kg/m2 practical. An argument Because periodontal disease is associ- diagnostic criteria. B can be made to push the BMI cut point ated with diabetes, the utility of screen- 2.15 Test for gestational diabetes mel- to lower than 23 kg/m2 in favor of increased ing in a dental setting and referral to litus at 24–28 weeks of gestation sensitivity; however, this would lead to primary care as a means to improve the in pregnant women not previ- an unacceptably low specificity (13.1%). diagnosis of prediabetes and diabetes ously known to have diabetes. A Data from the WHO also suggest that a hasbeenexplored(59–61), with one 2.16 Test women with gestational di- BMI of $23 kg/m2 should be used to study estimating that 30% of patients abetes mellitus for prediabetes define increased risk in Asian Americans $30 years of age seen in general dental care.diabetesjournals.org Classification and Diagnosis of Diabetes S21

(Table 2.3) at their initial prenatal Diagnosis or diabetes at 4–12 weeks post- visit, using standard diagnostic criteria GDM carries risks for the mother, fetus, partum, using the 75-g oral glu- (Table 2.2). Women diagnosed with di- and neonate. Not all adverse outcomes are cose tolerance test and clinically abetes by standard diagnostic criteria of equal clinical importance. The Hyper- appropriate nonpregnancy diag- in the first trimester should be classified glycemia and Adverse Pregnancy Out- nostic criteria. B as having preexisting pregestational di- come (HAPO) study (74), a large-scale 2.17 Women with a history of gesta- abetes (type 2 diabetes or, very rarely, multinational cohort study completed tional diabetes mellitus should type 1 diabetes or monogenic diabe- by more than 23,000 pregnant women, have lifelong screening for the tes). Women found to have prediabetes demonstrated that risk of adverse ma- development of diabetes or pre- in the first trimester may be encour- ternal, fetal, and neonatal outcomes diabetes at least every 3 years. B aged to make lifestyle changes to reduce continuously increased as a function of 2.18 Women with a history of gesta- their risk of developing type 2 diabetes, maternal glycemia at 24–28 weeks of ges- tional diabetes mellitus found to and perhaps GDM, though more study tation, even within ranges previously con- have prediabetes should receive is needed (68). GDM is diabetes that is sidered normal for pregnancy. For most intensive lifestyle interventions or first diagnosed in the second or third complications, there was no threshold for metformin to prevent diabetes. A trimester of pregnancy that is not clearly risk. These results have led to careful re- either preexisting type 1 or type 2 di- consideration of the diagnostic criteria for Definition abetes (see Section 14 “Management GDM. GDM diagnosis (Table 2.6)canbe For many years, GDM was defined as any of Diabetes in Pregnancy”). The Inter- accomplished with either of two strategies: degree of glucose intolerance that was national Association of the Diabetes first recognized during pregnancy (40), and Pregnancy Study Groups (IADPSG) 1. “One-step” 75-g OGTT or regardless of whether the condition GDM diagnostic criteria for the 75-g 2. “Two-step” approach with a 50-g may have predated the pregnancy or OGTT as well as the GDM screening (nonfasting) screen followed by a persisted after the pregnancy. This def- and diagnostic criteria used in the two- 100-g OGTT for those who screen inition facilitated a uniform strategy for step approach were not derived from positive detection and classification of GDM, but data in the first half of pregnancy, so the it was limited by imprecision. diagnosis of GDM in early pregnancy by Different diagnostic criteria will identify The ongoing epidemic of obesity and either FPG or OGTT values is not evidence different degrees of maternal hypergly- diabetes has led to more type 2 diabetes based (69). cemia and maternal/fetal risk, leading in women of childbearing age, with an Because GDM confers increased risk some experts to debate, and disagree on, increase in the number of pregnant for the development of type 2 diabetes optimal strategies for the diagnosis of women with undiagnosed type 2 dia- after delivery (70,71) and because effec- GDM. betes (66). Because of the number of tive prevention interventions are avail- One-Step Strategy pregnant women with undiagnosed type able (72,73), women diagnosed with The IADPSG defined diagnostic cut points 2 diabetes, it is reasonable to test women GDM should receive lifelong screening for GDM as the average fasting, 1-h, and with risk factors for type 2 diabetes (67) for prediabetes and type 2 diabetes. 2-h PG values during a 75-g OGTT in

Table 2.6—Screening for and diagnosis of GDM One-step strategy Perform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 and 2 h, at 24–28 weeks of gestation in women not previously diagnosed with diabetes. The OGTT should be performed in the morning after an overnight fast of at least 8 h. The diagnosis of GDM is made when any of the following plasma glucose values are met or exceeded: c Fasting: 92 mg/dL (5.1 mmol/L) c 1 h: 180 mg/dL (10.0 mmol/L) c 2 h: 153 mg/dL (8.5 mmol/L) Two-step strategy Step 1: Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h, at 24–28 weeks of gestation in women not previously diagnosed with diabetes. If the plasma glucoselevel measured1 hafter the load is $130 mg/dL,135mg/dL, or 140mg/dL (7.2mmol/L,7.5 mmol/L,or 7.8 mmol/L,respectively), proceed to a 100-g OGTT. Step 2: The 100-g OGTT should be performed when the patient is fasting. The diagnosis of GDM is made if at least two* of the following four plasma glucose levels (measured fasting and 1 h, 2 h, 3 h during OGTT) are met or exceeded: Carpenter-Coustan (86) or NDDG (87)

c Fasting 95 mg/dL (5.3 mmol/L) 105 mg/dL (5.8 mmol/L) c 1 h 180 mg/dL (10.0 mmol/L) 190 mg/dL (10.6 mmol/L) c 2 h 155 mg/dL (8.6 mmol/L) 165 mg/dL (9.2 mmol/L) c 3 h 140 mg/dL (7.8 mmol/L) 145 mg/dL (8.0 mmol/L) NDDG, National Diabetes Data Group. *ACOG notes that one elevated value can be used for diagnosis (82). S22 Classiﬁcation and Diagnosis of Diabetes Diabetes Care Volume 42, Supplement 1, January 2019

women at 24–28 weeks of gestation criteria versus older criteria have been identified by the two-step approach, who participated in the HAPO study at published to date. Data are also lacking reduces rates of neonatal macrosomia, which odds for adverse outcomes reached on how the treatment of lower levels large-for-gestational-age births (85), and 1.75 times the estimated odds of these of hyperglycemia affects a mother’s fu- shoulder dystocia, without increasing outcomes at the mean fasting, 1-h, and ture risk for the development of type 2 small-for-gestational-age births. ACOG 2-h PG levels of the study population. diabetes and her offspring’sriskfor currently supports the two-step ap- This one-step strategy was anticipated obesity, diabetes, and other meta- proach but notes that one elevated to significantly increase the incidence of bolic disorders. Additional well-designed value, as opposed to two, may be GDM (from 5–6% to 15–20%), primarily clinical studies are needed to deter- used for the diagnosis of GDM (82). If because only one abnormal value, not mine the optimal intensity of monitor- this approach is implemented, the in- two, became sufficient to make the di- ing and treatment of women with GDM cidence of GDM by the two-step strat- agnosis (75). The anticipated increase in diagnosed by the one-step strategy egy will likely increase markedly. the incidence of GDM could have a sub- (79,80). ACOG recommends either of two sets of stantial impact on costs and medical diagnostic thresholds for the 3-h 100-g infrastructure needs and has the poten- Two-Step Strategy OGTT (86,87). Each is based on different tial to “medicalize” pregnancies previ- In 2013, the National Institutes of Health mathematical conversions of the original ously categorized as normal. A recent (NIH) convened a consensus develop- recommended thresholds, which used follow-up study of women participating ment conference to consider diagnostic whole blood and nonenzymatic methods in a blinded study of pregnancy OGTTs criteria for diagnosing GDM (81). The for glucose determination. A secondary found that 11 years after their pregnan- 15-member panel had representatives analysis of data from a randomized clin- cies, women who would have been from obstetrics/gynecology, maternal- ical trial of identification and treatment diagnosed with GDM by the one-step ap- fetal medicine, pediatrics, diabetes re- of mild GDM (88) demonstrated that proach, as compared with those without, search, biostatistics, and other related treatment was similarly beneficial in were at 3.4-fold higher risk of developing fields. The panel recommended a two- patients meeting only the lower thresh- prediabetes and type 2 diabetes and had step approach to screening that used a olds (86) and in those meeting only the children with a higher risk of obesity and 1-h 50-g glucose load test (GLT) followed higher thresholds (87). If the two-step increased body fat, suggesting that the by a 3-h 100-g OGTT for those who approach is used, it would appear advan- larger group of women identified by the screened positive. The American Col- tageous to use the lower diagnostic one-step approach would benefit from lege of Obstetricians and Gynecologists thresholdsasshowninstep2inTable 2.6. increased screening for diabetes and (ACOG) recommends any of the com- prediabetes that would accompany a monly used thresholds of 130, 135, or Future Considerations history of GDM (76). Nevertheless, the 140 mg/dL for the 1-h 50-g GLT (82). A The conflicting recommendations from ADA recommends these diagnostic cri- systematic review for the U.S. Preventive expert groups underscore the fact that teria with the intent of optimizing ges- Services Task Force compared GLT cut- there are data to support each strategy. tational outcomes because these criteria offs of 130 mg/dL (7.2 mmol/L) and A cost-benefit estimation comparing the were the only ones based on pregnancy 140 mg/dL (7.8 mmol/L) (83). The higher two strategies concluded that the one- outcomes rather than end points such cutoff yielded sensitivity of 70–88% and step approach is cost-effective only if as prediction of subsequent maternal specificity of 69–89%, while the lower patients with GDM receive postdelivery diabetes. cutoff was 88–99% sensitive and 66– counseling and care to prevent type 2 The expected benefits to the off- 77% specific. Data regarding a cutoff diabetes (89). The decision of which spring are inferred from intervention of 135 mg/dL are limited. As for other strategy to implement must therefore trials that focused on women with lower screening tests, choice of a cutoff is be made based on the relative values levels of hyperglycemia than identified based upon the trade-off between sen- placed on factors that have yet to be using older GDM diagnostic criteria. sitivity and specificity. The use of A1C at measured (e.g., willingness to change Those trials found modest benefits includ- 24–28 weeks of gestation as a screening practice based on correlation studies ing reduced rates of large-for-gestational- test for GDM does not function as well rather than intervention trial results, age births and preeclampsia (77,78). It as the GLT (84). available infrastructure, and importance is important to note that 80–90% of Key factors cited by the NIH panel in of cost considerations). women being treated for mild GDM in their decision-making process were the As the IADPSG criteria (“one-step these two randomized controlled trials lack of clinical trial data demonstrating strategy”) have been adopted interna- could be managed with lifestyle therapy the benefits of the one-step strategy tionally, further evidence has emerged to alone. The OGTT glucose cutoffs in these and the potential negative consequences support improved pregnancy outcomes two trials overlapped with the thresh- of identifying a large group of women with cost savings (90) and may be the olds recommended by the IADPSG, and with GDM, including medicalization of preferred approach. Data comparing in one trial (78), the 2-h PG threshold pregnancy with increased health care population-wide outcomes with one- (140 mg/dL [7.8 mmol/L]) was lower utilization and costs. Moreover, screening step versus two-step approaches have than the cutoff recommended by the with a 50-g GLT does not require fasting been inconsistent to date (91,92). In IADPSG (153 mg/dL [8.5 mmol/L]). No and is therefore easier to accomplish addition, pregnancies complicated by randomized controlled trials of identify- for many women. Treatment of higher- GDM per the IADPSG criteria, but not ing and treating GDM using the IADPSG threshold maternal hyperglycemia, as recognized as such, have comparable care.diabetesjournals.org Classification and Diagnosis of Diabetes S23

outcomes to pregnancies diagnosed as weight, height, BMI, or lung function. 2.25 Immunosuppressive regimens GDM by the more stringent two-step Continuous glucose monitoring or shown to provide the best out- criteria (93,94). There remains strong HOMA of b-cell function (96) may be comes for patient and graft consensus that establishing a uniform more sensitive than OGTT to detect survival should be used, irre- approach to diagnosing GDM will benefit risk for progression to CFRD; how- spective of posttransplantation patients, caregivers, and policy makers. ever, evidence linking these results diabetes mellitus risk. E Longer-term outcome studies are cur- to long-term outcomes is lacking, and rently underway. these tests are not recommended for screening (97). Several terms are used in the literature CYSTIC FIBROSIS–RELATED CFRD mortality has significantly de- to describe the presence of diabetes DIABETES creased over time, and the gap in mor- following organ transplantation. “New- tality between cystic fibrosis patients onset diabetes after transplantation” Recommendations with and without diabetes has consid- (NODAT) is one such designation that 2.19 Annual screening for cystic erably narrowed (98). There are limited describes individuals who develop new- fibrosis–related diabetes with clinicaltrialdataontherapyforCFRD.The onset diabetes following transplant. an oral glucose tolerance test largest study compared three regimens: NODAT excludes patients with pretrans- should begin by age 10 years premeal insulin aspart, repaglinide, or plant diabetes that was undiagnosed in all patients with cystic fibrosis oral placebo in cystic fibrosis patients as well as posttransplant hyperglycemia not previously diagnosed with with diabetes or abnormal glucose tol- that resolves by the time of discharge cystic fibrosis–related diabe- erance. Participants all had weight loss in (103). Another term, “posttransplan- tes. B the year preceding treatment; however, tation diabetes mellitus” (PTDM) (103, 2.20 A1C is not recommended as a in the insulin-treated group, this pat- 104), describes the presence of diabetes screening test for cystic fibrosis– tern was reversed, and patients gained in the posttransplant setting irrespec- related diabetes. B 0.39 (6 0.21) BMI units (P 5 0.02). The tive of the timing of diabetes onset. 2.21 Patients with cystic fibrosis– repaglinide-treated group had initial Hyperglycemia is very common dur- related diabetes should be weight gain, but this was not sustained ing the early posttransplant period, with treated with insulin to attain in- by 6 months. The placebo group contin- ;90% of kidney allograft recipients ex- dividualized glycemic goals. A ued to lose weight (99). Insulin remains hibiting hyperglycemia in the first few 2.22 Beginning 5 years after the di- the most widely used therapy for CFRD weeks following transplant (103–106). agnosis of cystic fibrosis–related (100). In most cases, such stress- or steroid- diabetes, annual monitoring for Additional resources for the clinical induced hyperglycemia resolves by the complications of diabetes is rec- management of CFRD can be found in time of discharge (106,107). Although ommended. E the position statement “Clinical Care the use of immunosuppressive therapies Guidelines for Cystic Fibrosis2Related is a major contributor to the develop- Cystic fibrosis–related diabetes (CFRD) Diabetes: A Position Statement of the ment of PTDM, the risks of transplant is the most common comorbidity in American Diabetes Association and a Clin- rejection outweigh the risks of PTDM and people with cystic fibrosis, occurring in ical Practice Guideline of the Cystic Fibrosis the role of the diabetes care provider is about 20% of adolescents and 40–50% Foundation, Endorsed by the Pediatric to treat hyperglycemia appropriately re- of adults (95). Diabetes in this popu- Endocrine Society” (101) and in the In- gardless of the type of immunosuppres- lation, compared with individuals with ternational Society for Pediatric and Ad- sion (103). Risk factors for PTDM include type 1 or type 2 diabetes, is associated olescent Diabetes’s 2014 clinical practice both general diabetes risks (such as age, with worse nutritional status, more consensus guidelines (102). family history of diabetes, etc.) as well as severe inflammatory lung disease, transplant-specific factors, such as use and greater mortality. Insulin insuffi- POSTTRANSPLANTATION of immunosuppressant agents (108). ciency is the primary defect in CFRD. DIABETES MELLITUS Whereas posttransplantation hypergly- Genetically determined b-cell func- cemia is an important risk factor for Recommendations tion and insulin resistance associated subsequent PTDM, a formal diagnosis 2.23 Patients should be screened with infection and inflammation may of PTDM is optimally made once the after organ transplantation for also contribute to the development patient is stable on maintenance immu- hyperglycemia, with a formal of CFRD. Milder abnormalities of glu- nosuppression and in the absence of diagnosis of posttransplantation cose tolerance are even more common acute infection (106–108). The OGTT is diabetes mellitus being best and occur at earlier ages than CFRD. considered the gold standard test for made once a patient is stable Whether individuals with IGT should be the diagnosis of PTDM (103,104,109, on an immunosuppressive regi- treatedwithinsulinreplacementhas 110). However, screening patients using men and in the absence of an not currently been determined. Al- fasting glucose and/or A1C can identify acute infection. E though screening for diabetes before high-risk patients requiring further as- 2.24 The oral glucose tolerance test the age of 10 years can identify risk sessment and may reduce the number is the preferred test to make for progression to CFRD in those with of overall OGTTs required. a diagnosis of posttransplanta- abnormal glucose tolerance, no benefit Few randomized controlled studies have tion diabetes mellitus. B hasbeenestablishedwithrespectto reported on the short- and long-term S24 Classification and Diagnosis of Diabetes Diabetes Care Volume 42, Supplement 1, January 2019

use of antihyperglycemic agents in the dose adjustments may be required be- life should have immediate ge- setting of PTDM (108,111,112). Most cause of decreases in the glomerular netic testing for neonatal diabe- studies have reported that transplant filtration rate, a relatively common com- tes. A patients with hyperglycemia and PTDM plication in transplant patients. A small 2.27 Children and adults, diagnosed after transplantation have higher rates short-term pilot study reported that in early adulthood, who have of rejection, infection, and rehospitali- metformin was safe to use in renal trans- diabetes not characteristic of zation (106,108,113). plant recipients (114), but its safety has type 1 or type 2 diabetes that Insulin therapy is the agent of choice not been determined in other types of occurs in successive generations for the management of hyperglycemia organ transplant. Thiazolidinediones have (suggestive of an autosomal and diabetes in the hospital setting. Af- been used successfully in patients with dominant pattern of inheri- ter discharge, patients with preexisting liver and kidney transplants, but side tance) should have genetic test- diabetes could go back on their pre- effects include fluid retention, heart fail- ing for maturity-onset diabetes transplantregimeniftheywereingood ure, and osteopenia (115,116). Dipeptidyl of the young. A control before transplantation. Those peptidase 4 inhibitors do not interact with 2.28 In both instances, consulta- with previously poor control or with per- immunosuppressant drugs and have tion with a center specializing sistent hyperglycemia should continue in- demonstrated safety in small clinical trials in diabetes genetics is recom- sulin with frequent home self-monitoring (117,118). Well-designed intervention mended to understand the sig- of blood glucose to determine when trials examining the efficacy and safety nificance of these mutations and insulin dose reductions may be needed of these and other antihyperglycemic how best to approach further andwhenitmaybeappropriatetoswitch agents in patients with PTDM are needed. evaluation, treatment, and ge- to noninsulin agents. netic counseling. E No studies to date have established which noninsulin agents are safest or MONOGENIC DIABETES most efficacious in PTDM. The choice SYNDROMES Monogenic defects that cause b-cell dys- of agent is usually made based on the function, such as neonatal diabetes and Recommendations side effect profile of the medication and MODY, represent a small fraction of 2.26 All children diagnosed with di- possible interactions with the patient’s patients with diabetes (,5%). Table 2.7 abetes in the first 6 months of immunosuppression regimen (108). Drug describes the most common causes of

Table 2.7—Most common causes of monogenic diabetes (119) Gene Inheritance Clinical features MODY GCK AD GCK-MODY: stable, nonprogressive elevated fasting blood glucose; typically does not require treatment; microvascular complications are rare; small rise in 2-h PG level on OGTT (,54 mg/dL [3 mmol/L]) HNF1A AD HNF1A-MODY: progressive insulin secretory defect with presentation in adolescence or early adulthood; lowered renal threshold for glucosuria; large rise in 2-h PG level on OGTT (.90 mg/dL [5 mmol/L]); sensitive to sulfonylureas HNF4A AD HNF4A-MODY: progressive insulin secretory defect with presentation in adolescence or early adulthood; may have large birth weight and transient neonatal hypoglycemia; sensitive to sulfonylureas HNF1B AD HNF1B-MODY: developmental renal disease (typically cystic); genitourinary abnormalities; atrophy of the pancreas; hyperuricemia; gout Neonatal diabetes KCNJ11 AD Permanent or transient: IUGR; possible developmental delay and seizures; responsive to sulfonylureas INS AD Permanent: IUGR; insulin requiring ABCC8 AD Permanent or transient: IUGR; rarely developmental delay; responsive to sulfonylureas 6q24 AD for paternal Transient: IUGR; macroglossia; umbilical hernia; mechanisms include UPD6, (PLAGL1, HYMA1) duplications paternal duplication or maternal methylation defect; may be treatable with medications other than insulin GATA6 AD Permanent: pancreatic hypoplasia; cardiac malformations; pancreatic exocrine insufficiency; insulin requiring EIF2AK3 AR Permanent: Wolcott-Rallison syndrome: epiphyseal dysplasia; pancreatic exocrine insufficiency; insulin requiring FOXP3 X-linked Permanent: immunodysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome: autoimmune diabetes; autoimmune thyroid disease; exfoliative dermatitis; insulin requiring AD, autosomal dominant; AR, autosomal recessive; IUGR, intrauterine growth restriction. care.diabetesjournals.org Classification and Diagnosis of Diabetes S25

monogenic diabetes. For a comprehen- considered first-line therapy. Mutations the absence of glucose-lowering ther- sive list of causes, see Genetic Diagnosis or deletions in HNF1B are associated apy (125). Genetic counseling is re- of Endocrine Disorders (119). with renal cysts and uterine malforma- commendedtoensurethataffected tions (renal cysts and diabetes [RCAD] individuals understand the patterns of Neonatal Diabetes syndrome). Other extremely rare forms inheritance and the importance of a Diabetes occurring under 6 months of of MODY have been reported to involve correct diagnosis. age is termed “neonatal” or “congenital” other transcription factor genes includ- The diagnosis of monogenic diabetes diabetes, and about 80–85% of cases can ing PDX1 (IPF1) and NEUROD1. should be considered in children and be found to have an underlying mono- adults diagnosed with diabetes in early genic cause (120). Neonatal diabetes Diagnosis of Monogenic Diabetes adulthood with the following findings: occurs much less often after 6 months A diagnosis of one of the three most of age, whereas autoimmune type 1 di- common forms of MODY, including ○ Diabetes diagnosed within the first abetes rarely occurs before 6 months GCK-MODY, HNF1A-MODY, and HNF4A- 6 months of life (with occasional cases of age. Neonatal diabetes can either be MODY, allows for more cost-effective presenting later, mostly INS and transient or permanent. Transient dia- therapy (no therapy for GCK-MODY; ABCC8 mutations) (120,126) betes is most often due to overexpres- sulfonylureas as first-line therapy for ○ Diabetes without typical features of sion of genes on chromosome 6q24, is HNF1A-MODY and HNF4A-MODY). Ad- type 1 or type 2 diabetes (negative recurrent in about half of cases, and may ditionally, diagnosis can lead to iden- diabetes-associated autoantibodies, be treatable with medications other than tification of other affected family nonobese, lacking other metabolic insulin. Permanent neonatal diabetes is members. features especially with strong family most commonly due to autosomal dom- A diagnosis of MODY should be con- history of diabetes) inant mutations in the genes encoding the sidered in individuals who have atypical ○ Stable, mild fasting hyperglycemia Kir6.2 subunit (KCNJ11) and SUR1 subunit diabetes and multiple family members (100–150 mg/dL [5.5–8.5 mmol/L]), (ABCC8)oftheb-cell KATP channel. Correct with diabetes not characteristic of type 1 stable A1C between 5.6 and 7.6% diagnosis has critical implications because or type 2 diabetes, although admittedly (between 38 and 60 mmol/mol), es- “ ” most patients with KATP-related neonatal atypical diabetes is becoming increas- pecially if nonobese diabetes will exhibit improved glycemic ingly difficult to precisely define in the absence of a definitive set of tests for control when treated with high-dose oral References either type of diabetes. In most cases, the sulfonylureas instead of insulin. Insulin 1. American Diabetes Association. Diagnosis gene (INS) mutations are the second most presence of autoantibodies for type 1 and classification of diabetes mellitus. Diabetes common cause of permanent neonatal diabetes precludes further testing for Care 2014;37(Suppl. 1):S81–S90 diabetes, and, while intensive insulin monogenic diabetes, but the presence of 2. Dabelea D, Rewers A, Stafford JM, et al.; management is currently the preferred autoantibodies in patients with mono- SEARCH for Diabetes in Youth Study Group. genic diabetes has been reported (121). Trends in the prevalence of ketoacidosis at di- treatment strategy, there are impor- abetes diagnosis: the SEARCH for Diabetes in tant genetic considerations, as most of Individuals in whom monogenic diabetes Youth Study. Pediatrics 2014;133:e938–e945 the mutations that cause diabetes are is suspected should be referred to a 3. Newton CA, Raskin P. Diabetic ketoacidosis in dominantly inherited. specialist for further evaluation if avail- type 1 and type 2 diabetes mellitus: clinical and able, and consultation is available from biochemical differences. Arch Intern Med 2004; 164:1925–1931 Maturity-Onset Diabetes of the Young several centers. Readily available com- 4. Skyler JS, Bakris GL, Bonifacio E, et al. Differ- MODY is frequently characterized by mercial genetic testing following the entiationof diabetes bypathophysiology,natural onset of hyperglycemia at an early age criteria listed below now enables a history, and prognosis. Diabetes 2017;66:241– (classically before age 25 years, although cost-effective (122), often cost-saving, 255 diagnosis may occur at older ages). genetic diagnosis that is increasingly 5. Insel RA, Dunne JL, Atkinson MA, et al. Staging presymptomatic type 1 diabetes: a scientific MODY is characterized by impaired in- supported by health insurance. A bio- statement of JDRF, the Endocrine Society, and sulin secretion with minimal or no de- marker screening pathway such as the the American Diabetes Association. Diabetes fects in insulin action (in the absence of combination of urinary C-peptide/ Care 2015;38:1964–1974 coexistent obesity). It is inherited in an creatinine ratio and antibody screening 6. International Expert Committee. Interna- autosomal dominant pattern with ab- may aid in determining who should get tional Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. normalities in at least 13 genes on dif- genetic testing for MODY (123). It is Diabetes Care 2009;32:1327–1334 ferent chromosomes identified to date. critical to correctly diagnose one of 7. Knowler WC, Barrett-Connor E, Fowler SE, The most commonly reported forms the monogenic forms of diabetes be- et al.; Diabetes Prevention Program Research are GCK-MODY (MODY2), HNF1A-MODY cause these patients may be incorrectly Group. Reduction in the incidence of type 2 (MODY3), and HNF4A-MODY (MODY1). diagnosed with type 1 or type 2 diabetes, diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403 Clinically, patients with GCK-MODY leading to suboptimal, even potentially 8. Tuomilehto J, Lindstrom¨ J, Eriksson JG, et al.; exhibit mild, stable, fasting hyperglyce- harmful, treatment regimens and delays Finnish Diabetes Prevention Study Group. Pre- mia and do not require antihyperglyce- in diagnosing other family members vention of type 2 diabetes mellitus by changes mic therapy except sometimes during (124). The correct diagnosis is especially in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344: pregnancy. Patients with HNF1A- or critical for those with GCK-MODY mu- 1343–1350 HNF4A-MODY usually respond well to tations where multiple studies have 9. Meijnikman AS, De Block CEM, Dirinck E, et al. low doses of sulfonylureas, which are shown that no complications ensue in Not performing an OGTT results in significant S26 Classification and Diagnosis of Diabetes Diabetes Care Volume 42, Supplement 1, January 2019

underdiagnosis of (pre)diabetes in a high risk difference, must make a difference. Diabetes 40. Expert Committee on the Diagnosis and adult Caucasian population. Int J Obes 2017;41: Care 2016;39:1462–1467 Classification of Diabetes Mellitus. Report of 1615–1620 25. Paterson AD. HbA1c for type 2 diabetes the Expert Committee on the Diagnosis and 10. Cowie CC, Rust KF, Byrd-Holt DD, et al. diagnosis in Africans and African Americans: Classification of Diabetes Mellitus. Diabetes Prevalence of diabetes and high risk for diabetes personalized medicine NOW! PLoS Med 2017; Care 1997;20:1183–1197 using A1C criteria in the U.S. population in 1988– 14:e1002384 41. Zhang X, Gregg EW, Williamson DF, et al. A1C 2006. Diabetes Care 2010;33:562–568 26. Cappellini MD, Fiorelli G. Glucose-6- level and future risk of diabetes: a systematic 11. Eckhardt BJ, Holzman RS, Kwan CK, Baghdadi phosphate dehydrogenase deficiency. Lancet review. Diabetes Care 2010;33:1665–1673 J, Aberg JA. Glycated hemoglobin A1c as screen- 2008;371:64–74 42. Selvin E, Steffes MW, Zhu H, et al. Glycated ing for diabetes mellitus in HIV-infected individ- 27. Picon´ MJ, Murri M, Munoz~ A, Fernandez-´ hemoglobin, diabetes, and cardiovascular risk uals. AIDS Patient Care STDS 2012;26:197–201 Garc´ıa JC, Gomez-Huelgas R, Tinahones FJ. He- in nondiabetic adults. N Engl J Med 2010;362: 12. Kim PS, Woods C, Georgoff P, et al. A1C moglobin A1c versus oral glucose tolerance test in 800–811 underestimates glycemia in HIV infection. Di- postpartum diabetes screening. Diabetes Care 43. Ackermann RT, Cheng YJ, Williamson DF, abetes Care 2009;32:1591–1593 2012;35:1648–1653 Gregg EW. Identifying adults at high risk for 13. Arslanian S, Bacha F, Grey M, Marcus MD, 28. Gobl¨ CS, Bozkurt L, Yarragudi R, Tura A, diabetes and cardiovascular disease using he- White NH, Zeitler P. Evaluation and management Pacini G, Kautzky-Willer A. Is early postpartum moglobin A1c National Health and Nutrition of youth-onset type 2 diabetes: a position state- HbA1c an appropriate risk predictor after preg- Examination Survey 2005-2006. Am J Prev ment by the American Diabetes Association. nancy with gestational diabetes mellitus? Acta Med 2011;40:11–17 Diabetes Care 2018;41:2648–2668 Diabetol 2014;51:715–722 44. Diabetes Prevention Program Research 14. LacyME,WelleniusGA,SumnerAE,CorreaA, 29. Megia A, Naf¨ S, Herranz L, et al. The use- Group. HbA1c as a predictor of diabetes and Carnethon MR, Liem RI,et al. Association of sickle fulness of HbA1c in postpartum reclassification as an outcome in the Diabetes Prevention Pro- cell trait with hemoglobin A1c in African Amer- of gestational diabetes. BJOG 2012;119:891–894 gram: a randomized clinical trial. Diabetes Care icans. JAMA 2017;317:507–515 30. Welsh KJ, Kirkman MS, Sacks DB. Role of 2015;38:51–58 15. Wheeler E, Leong A, Liu C-T, et al.; EPIC-CVD glycated proteins in the diagnosis and manage- 45. Umpierrez G, Korytkowski M. Diabetic Consortium; EPIC-InterAct Consortium; Lifelines ment of diabetes: research gaps and future emergencies - ketoacidosis, hyperglycaemic hy- Cohort Study. Impact of common genetic deter- directions. Diabetes Care 2016;39:1299–1306 perosmolar state and hypoglycaemia. Nat Rev minants of hemoglobin A1c on type 2 diabe- 31. Kim C, Bullard KM, Herman WH, Beckles GL. Endocrinol 2016;12:222–232 tes risk and diagnosis in ancestrally diverse Association between iron deficiency and A1C 46. Fadini GP, Bonora BM, Avogaro A. SGLT2 populations: a transethnic genome-wide meta- levels among adults without diabetes in the inhibitors and diabetic ketoacidosis: data from analysis. PLoS Med 2017;14:e1002383 National Health and Nutrition Examination Sur- the FDA Adverse Event Reporting System. Dia- 16. Ziemer DC, Kolm P, Weintraub WS, et al. vey, 1999-2006. Diabetes Care 2010;33:780–785 betologia 2017;60:1385–1389 Glucose-independent, black-white differences in 32. Selvin E, Wang D, Matsushita K, Grams ME, 47. Griffin SJ, Borch-Johnsen K, Davies MJ, et al. hemoglobin A1c levels: a cross-sectional analysis Coresh J. Prognostic implications of single- Effect of early intensive multifactorial therapy of 2 studies. Ann Intern Med 2010;152:770–777 sample confirmatory testing for undiagnosed on 5-year cardiovascular outcomes in individuals 17. Kumar PR, Bhansali A, Ravikiran M, et al. diabetes: a prospective cohort study. Ann Intern with type 2 diabetes detected by screening Utility of glycated hemoglobin in diagnosing Med 2018;169:156–164 (ADDITION-Europe): a cluster-randomised trial. type 2 diabetes mellitus: a community-based 33. Dabelea D, Mayer-Davis EJ, Saydah S, et al.; Lancet 2011;378:156–167 study. J Clin Endocrinol Metab 2010;95:2832– SEARCH for Diabetes in Youth Study. Prevalence 48. Herman WH, Ye W, Griffin SJ, et al. Early 2835 of type 1 and type 2 diabetes among children and detection and treatment of type 2 diabetes 18. Herman WH. Are there clinical implications adolescents from 2001 to 2009. JAMA 2014;311: reduce cardiovascular morbidity and mortality: of racial differences in HbA1c? Yes, to not con- 1778–1786 a simulation of the results of the Anglo-Danish- sider can do great harm! Diabetes Care 2016;39: 34. Ziegler AG, Rewers M, Simell O, et al. Se- Dutch Study of Intensive Treatment in People 1458–1461 roconversion to multiple islet autoantibodies with Screen-Detected Diabetes in Primary Care 19. Herman WH, Ma Y, Uwaifo G, et al.; Diabetes and risk of progression to diabetes in children. (ADDITION-Europe). Diabetes Care 2015;38: Prevention Program Research Group. Differen- JAMA 2013;309:2473–2479 1449–1455 ces in A1C by race and ethnicity among patients 35. Sosenko JM, Skyler JS, Palmer JP, et al.; Type 49. Kahn R, Alperin P, Eddy D, et al. Age at with impaired glucose tolerance in the Diabetes 1 Diabetes TrialNet Study Group; Diabetes Pre- initiation and frequency of screening to detect Prevention Program. Diabetes Care 2007;30: vention Trial-Type 1 Study Group. The prediction type 2 diabetes: a cost-effectiveness analysis. 2453–2457 of type 1 diabetes by multiple autoantibody Lancet 2010;375:1365–1374 20. Bergenstal RM, Gal RL, Connor CG, et al.; T1D levels and their incorporation into an autoanti- 50. Araneta MRG, Kanaya A, Fujimoto W, et al. Exchange Racial Differences Study Group. Racial body risk score in relatives of type 1 diabetic Optimum BMI cut-points to screen Asian Amer- differences in the relationship of glucose con- patients. Diabetes Care 2013;36:2615–2620 icans for type 2 diabetes: The UCSD Filipino centrations and hemoglobin A1c levels. Ann 36. Steck AK, Vehik K, Bonifacio E, et al.; TEDDY Health Study and the North Kohala Study [Ab- Intern Med 2017;167:95–102 Study Group. Predictors of progression from the stract]. Diabetes 2014;63(Suppl. 1):A20 21. Selvin E, Steffes MW, Ballantyne CM, appearance of islet autoantibodies to early child- 51. Hsu WC, Araneta MRG, Kanaya AM, Chiang Hoogeveen RC, Coresh J, Brancati FL. Racial hood diabetes: The Environmental Determinants JL, Fujimoto W. BMI cut points to identify at-risk differencesinglycemicmarkers:across-sectional of Diabetes in the Young (TEDDY). Diabetes Care Asian Americans for type 2 diabetes screening. analysis of community-based data. Ann Intern 2015;38:808–813 Diabetes Care 2015;38:150–158 Med 2011;154:303–309 37. Orban T, Sosenko JM, Cuthbertson D, et al.; 52. WHO Expert Consultation. Appropriate 22. Herman WH, Dungan KM, Wolffenbuttel Diabetes Prevention Trial-Type 1 Study Group. body-mass index for Asian populations and its BHR, et al. Racial and ethnic differences in Pancreatic islet autoantibodies as predictors implications for policy and intervention strate- mean plasma glucose, hemoglobin A1c, and of type 1 diabetes in the Diabetes Prevention gies. Lancet 2004;363:157–163 1,5-anhydroglucitol in over 2000 patients with Trial–Type 1. Diabetes Care 2009;32:2269– 53. Menke A, Casagrande S, Geiss L, Cowie CC. type 2 diabetes. J Clin Endocrinol Metab 2009; 2274 Prevalence of and trends in diabetes among 94:1689–1694 38. Genuth S, Alberti KG, Bennett P, et al.; Expert adults in the United States, 1988-2012. JAMA 23. Selvin E, Rawlings AM, Bergenstal RM, Committee on the Diagnosis and Classification of 2015;314:1021–1029 Coresh J, Brancati FL. No racial differences in Diabetes Mellitus. Follow-up report on the di- 54. Centers for Disease Control and Prevention. the association of glycated hemoglobin with agnosis of diabetes mellitus. Diabetes Care 2003; National diabetes statistics report: estimates of kidney disease and cardiovascular outcomes. 26:3160–3167 diabetes and its burden in the United States, Diabetes Care 2013;36:2995–3001 39. American Diabetes Association. Diagnosis 2017 [Internet]. Available from https://www.cdc 24. Selvin E. Are there clinical implications of and classification of diabetes mellitus. Diabetes .gov/diabetes/data/statistics/statistics-report. racial differences in HbA1c? A difference, to be a Care 2011;34(Suppl. 1):S62–S69 html. Accessed 20 September 2018 care.diabetesjournals.org Classification and Diagnosis of Diabetes S27

55. Chiu M, Austin PC, Manuel DG, Shah BR, Tu Diabetes and Pregnancy Study Groups criteria. U.S. Preventive Services Task Force. Ann Intern JV. Deriving ethnic-specific BMI cutoff points for Eur J Endocrinol 2016;175:287–297 Med 2013;159:115–122 assessing diabetes risk. Diabetes Care 2011;34: 71. Kim C, Newton KM, Knopp RH. Gestational 84. Khalafallah A, Phuah E, Al-Barazan AM, et al. 1741–1748 diabetes and the incidence of type 2 diabetes: Glycosylated haemoglobin for screening and 56. Erickson SC, Le L, Zakharyan A, et al. New- a systematic review. Diabetes Care 2002;25: diagnosis of gestational diabetes mellitus. BMJ onset treatment-dependent diabetes mellitus 1862–1868 Open 2016;6:e011059 and hyperlipidemia associated with atypical an- 72. Ratner RE, Christophi CA, Metzger BE, et al.; 85. Horvath K, Koch K, Jeitler K, et al. Effects of tipsychotic use in older adults without schizo- Diabetes Prevention Program Research Group. treatment in women with gestational diabetes phrenia or bipolar disorder. J Am Geriatr Soc Preventionofdiabetesinwomenwithahistoryof mellitus: systematic review and meta-analysis. 2012;60:474–479 gestational diabetes: effects of metformin and BMJ 2010;340:c1395 57. Johnson SL, Tabaei BP, Herman WH. The lifestyle interventions. J Clin Endocrinol Metab 86. Carpenter MW, Coustan DR. Criteria for efficacy and cost of alternative strategies for 2008;93:4774–4779 screening tests for gestational diabetes. Am J systematic screening for type 2 diabetes in the 73. Aroda VR, Christophi CA, Edelstein SL, et al.; Obstet Gynecol 1982;144:768–773 U.S. population 45–74 years of age. Diabetes Diabetes Prevention Program Research Group. 87. National Diabetes Data Group. Classification Care 2005;28:307–311 The effect of lifestyle intervention and metfor- and diagnosis of diabetes mellitus and other 58. Tabaei BP, Burke R, Constance A, et al. min on preventing or delaying diabetes among categories of glucose intolerance. Diabetes 1979; Community-based screening for diabetes in women with and without gestational diabetes: 28:1039–1057 Michigan. Diabetes Care 2003;26:668–670 the Diabetes Prevention Program Outcomes 88. Harper LM, Mele L, Landon MB, et al.; Eunice 59. Lalla E, Kunzel C, Burkett S, Cheng B, Lamster Study 10-year follow-up. J Clin Endocrinol Metab KennedyShriver NationalInstituteof Child Health IB. Identification of unrecognized diabetes and 2015;100:1646–1653 and Human Development (NICHD) Maternal- pre-diabetes in a dental setting. J Dent Res 2011; 74. Metzger BE, Lowe LP, Dyer AR, et al.; HAPO Fetal Medicine Units (MFMU) Network. Carpenter- 90:855–860 Study Cooperative Research Group. Hyperglyce- Coustan compared with National Diabetes Data 60. Lalla E, Cheng B, Kunzel C, Burkett S, Lamster mia and adverse pregnancy outcomes. N Engl J Group criteria for diagnosing gestational diabe- IB. Dental findings and identification of undiag- Med 2008;358:1991–2002 tes. Obstet Gynecol 2016;127:893–898 nosed hyperglycemia. J Dent Res 2013;92:888– 75. Sacks DA, Hadden DR, Maresh M, et al.; 89. Werner EF, Pettker CM, Zuckerwise L, et al. 892 HAPO Study Cooperative Research Group. Fre- Screening for gestational diabetes mellitus: are 61. Herman WH, Taylor GW, Jacobson JJ, Burke quency of gestational diabetes mellitus at col- the criteria proposed by the International Asso- R, Brown MB. Screening for prediabetes and laborating centers based on IADPSG consensus ciation of the Diabetes and Pregnancy Study type 2 diabetes in dental offices. J Public Health panel-recommended criteria: the Hyperglyce- Groups cost-effective? Diabetes Care 2012;35: Dent 2015;75:175–182 mia and Adverse Pregnancy Outcome (HAPO) 529–535 62. Buse JB, Kaufman FR, Linder B, Hirst K, El Study. Diabetes Care 2012;35:526–528 90. Duran A, Saenz´ S, Torrejon´ MJ, et al. In- Ghormli L, Willi S; HEALTHY Study Group. Di- 76. Lowe WL Jr, Scholtens DM, Lowe LP, et al.; troduction of IADPSG criteria for the screening abetes screening with hemoglobin A1c versus HAPO Follow-up Study Cooperative Research and diagnosis of gestational diabetes mellitus fasting plasma glucose in a multiethnic middle- Group. Association of gestational diabetes with results in improved pregnancy outcomes at a school cohort. Diabetes Care 2013;36:429–435 maternal disorders of glucose metabolism and lower cost in a large cohort of pregnant women: 63. Kapadia C, Zeitler P; Drugs and Therapeutics childhood adiposity. JAMA 2018;320:1005– the St. Carlos Gestational Diabetes Study. Di- Committee of the Pediatric Endocrine Society. 1016 abetes Care 2014;37:2442–2450 Hemoglobin A1c measurement for the diagnosis 77. Landon MB, Spong CY, Thom E, et al.; Eunice 91. Wei Y, Yang H, Zhu W, et al. International of type 2 diabetes in children. Int J Pediatr KennedyShriver NationalInstituteof Child Health Association of Diabetes and Pregnancy Study Endocrinol 2012;2012:31 and Human Development Maternal-Fetal Med- Group criteria is suitable for gestational diabetes 64. Kester LM, Hey H, Hannon TS. Using hemo- icine Units Network. A multicenter, randomized mellitus diagnosis: further evidence from China. globin A1c for prediabetes and diabetes diagno- trial of treatment for mild gestational diabetes. Chin Med J (Engl) 2014;127:3553–3556 sis in adolescents: can adult recommendations N Engl J Med 2009;361:1339–1348 92. Feldman RK, Tieu RS, Yasumura L. Gesta- be upheld for pediatric use? J Adolesc Health 78. Crowther CA, Hiller JE, Moss JR, McPhee tional diabetes screening: the International As- 2012;50:321–323 AJ, Jeffries WS, Robinson JS; Australian Car- sociation of the Diabetes and Pregnancy Study 65. Wu E-L, Kazzi NG, Lee JM. Cost-effectiveness bohydrate Intolerance Study in Pregnant Groups compared with Carpenter-Coustan of screening strategies for identifying pediatric Women (ACHOIS) Trial Group. Effect of treat- screening. Obstet Gynecol 2016;127:10–17 diabetes mellitus and dysglycemia. JAMA Pediatr ment of gestational diabetes mellitus on 93. Ethridge JK Jr, Catalano PM, Waters TP. 2013;167:32–39 pregnancy outcomes. N Engl J Med 2005; Perinatal outcomes associated with the diagno- 66. Lawrence JM, Contreras R, Chen W, Sacks 352:2477–2486 sis of gestational diabetes made by the Interna- DA. Trends in the prevalence of preexisting 79. Tam WH, Ma RCW, Ozaki R, et al. In utero tional Association of the Diabetes and Pregnancy diabetes and gestational diabetes mellitus exposure to maternal hyperglycemia increases Study Groups criteria. Obstet Gynecol 2014;124: among a racially/ethnically diverse population childhood cardiometabolic risk in offspring. Di- 571–578 of pregnant women, 1999–2005. Diabetes Care abetes Care 2017;40:679–686 94. Mayo K, Melamed N, Vandenberghe H, 2008;31:899–904 80. Landon MB, Rice MM, Varner MW, et al.; Berger H. The impact of adoption of the 67. Poltavskiy E, Kim DJ, Bang H. Comparison of Eunice Kennedy Shriver National Institute of Child international association of diabetes in preg- screening scores for diabetes and prediabetes. Health and Human Development Maternal-Fetal nancy study group criteria for the screening and Diabetes Res Clin Pract 2016;118:146–153 Medicine Units (MFMU) Network. Mild gesta- diagnosis of gestational diabetes. Am J Obstet 68. Hughes RCE, Rowan J, Williman J. Predia- tional diabetes mellitus and long-term child Gynecol 2015;212:224.e1–224.e9 betes in pregnancy, can early intervention im- health. Diabetes Care 2015;38:445–452 95. Moran A, Pillay K, Becker D, Granados A, prove outcomes? A feasibility study for a parallel 81. Vandorsten JP, Dodson WC, Espeland MA, Hameed S, Acerini CL. ISPAD Clinical Practice randomised clinical trial. BMJ Open 2018;8: et al. NIH consensus development conference: Consensus Guidelines 2018: management of e018493 diagnosing gestational diabetes mellitus. NIH cystic fibrosis-related diabetes in children and 69. McIntyre HD, Sacks DA, Barbour LA, et al. Consens State Sci Statements 2013;29:1–31 adolescents. Pediatr Diabetes 2018;19(Suppl. Issues with the diagnosis and classification of 82. Committee on Practice BulletinsdObstetrics. 27):64–74 hyperglycemia in early pregnancy. Diabetes Care Practice Bulletin No. 190: gestational diabe- 96. Mainguy C, Bellon G, Delaup V, et al. 2016;39:53–54 tes mellitus. Obstet Gynecol 2018;131:e49– Sensitivity and specificity of different methods 70. Noctor E, Crowe C, Carmody LA, et al.; e64 for cystic fibrosis-related diabetes screening: ATLANTIC-DIP investigators. Abnormal glucose 83. Donovan L, Hartling L, Muise M, Guthrie A, is the oral glucose tolerance test still the tolerance post-gestational diabetes mellitus as Vandermeer B, Dryden DM. Screening tests for standard? J Pediatr Endocrinol Metab 2017; defined by the International Association of gestational diabetes: a systematic review for the 30:27–35 S28 Classification and Diagnosis of Diabetes Diabetes Care Volume 42, Supplement 1, January 2019

97. Ode KL, Moran A. New insights into cystic 107. Chakkera HA, Weil EJ, Castro J, et al. Hy- 118. Lane JT, Odegaard DE, Haire CE, Collier DS, fibrosis-related diabetes in children. Lancet Di- perglycemia during the immediate period after Wrenshall LE, Stevens RB. Sitagliptin therapy in abetes Endocrinol 2013;1:52–58 kidney transplantation. Clin J Am Soc Nephrol kidney transplant recipients with new-onset di- 98. Moran A, Dunitz J, Nathan B, Saeed A, Holme 2009;4:853–859 abetes after transplantation. Transplanta- B, Thomas W. Cystic fibrosis–related diabetes: 108. Wallia A, Illuri V, Molitch ME. Diabetes care tion 2011;92:e56–e57 current trends in prevalence, incidence, and after transplant: definitions, risk factors, and clin- 119. Carmody D, Støy J, Greeley SA, Bell GI, mortality. Diabetes Care 2009;32:1626–1631 ical management. Med Clin North Am 2016;100: Philipson LH. A clinical guide to monogenic di- 99. Moran A, Pekow P, Grover P, et al.; Cystic 535–550 abetes. In Genetic Diagnosis of Endocrine Dis- Fibrosis Related Diabetes Therapy Study Group. 109. Sharif A, Moore RH, Baboolal K. The use of orders. 2nd ed. Weiss RE, Refetoff S, Eds. Insulin therapy to improve BMI in cystic fibrosis– oral glucose tolerance tests to risk stratify for Philadelphia, PA, Elsevier, 2016 related diabetes without fasting hyperglyce- new-onset diabetes after transplantation: an 120. De Franco E, Flanagan SE, Houghton JAL, mia: results of the Cystic Fibrosis Related Di- underdiagnosed phenomenon. Transplantation et al. The effect of early, comprehensive genomic abetes Therapy Trial. Diabetes Care 2009;32: 2006;82:1667–1672 testing on clinical care in neonatal diabetes: an 1783–1788 110. Hecking M, Kainz A, Werzowa J, et al. international cohort study. Lancet 2015;386: 100. Onady GM, Stolfi A. Insulin and oral agents Glucose metabolism after renal transplantation. 957–963 for managing cystic fibrosis–related diabetes. Diabetes Care 2013;36:2763–2771 121. Urbanova´ J, Rypaćkovˇ a´ B, Prochazkov´ aZ,´ Cochrane Database Syst Rev 2016;4:CD004730 111. Galindo RJ, Fried M, Breen T, Tamler R. et al. Positivity for islet cell autoantibodies in 101. Moran A, Brunzell C, Cohen RC, et al.; CFRD Hyperglycemia management in patients with patients with monogenic diabetes is associ- Guidelines Committee. Clinical care guidelines posttransplantation diabetes. Endocr Pract ated with later diabetes onset and higher for cystic fibrosis–related diabetes: a position 2016;22:454–465 HbA1c level. Diabet Med 2014;31:466–471 statement of the American Diabetes Association 112. Jenssen T, Hartmann A. Emerging treat- 122. Naylor RN, John PM, Winn AN, et al. and a clinical practice guideline of the Cystic Fi- ments for post-transplantation diabetes melli- Cost-effectiveness of MODY genetic testing: brosis Foundation, endorsed by the Pediatric En- tus. Nat Rev Nephrol 2015;11:465–477 translating genomic advances into practical docrine Society. Diabetes Care 2010;33:2697–2708 113. Thomas MC, Mathew TH, Russ GR, Rao health applications. Diabetes Care 2014;37: 102. Moran A, Pillay K, Becker DJ, Acerini CL; MM, Moran J. Early peri-operative glycaemic 202–209 International Society for Pediatric and Adoles- control and allograft rejection in patients with 123. Shields BM, Shepherd M, Hudson M, et al.; cent Diabetes. ISPAD Clinical Practice Consensus diabetes mellitus: a pilot study. Transplantation UNITED study team. Population-based assess- Guidelines 2014. Management of cystic fibrosis- 2001;72:1321–1324 ment of a biomarker-based screening pathway to related diabetes in children and adolescents. 114. Kurian B, Joshi R, Helmuth A. Effectiveness aid diagnosis of monogenic diabetes in young- Pediatr Diabetes 2014;15(Suppl. 20):65–76 and long-term safety of thiazolidinediones and onset patients. Diabetes Care 2017;40:1017– 103. Sharif A, Hecking M, de Vries APJ, et al. metformin in renal transplant recipients. Endocr 1025 Proceedings from an international consensus Pract 2008;14:979–984 124. Hattersley A, Bruining J, Shield J, Njolstad P, meeting on posttransplantation diabetes melli- 115. Budde K, Neumayer H-H, Fritsche L, Donaghue KC. The diagnosis and management tus: recommendations and future directions. Am Sulowicz W, Stomporˆ T, Eckland D. The pharma- of monogenic diabetes in children and adoles- J Transplant 2014;14:1992–2000 cokinetics of pioglitazone in patients with im- cents. Pediatr Diabetes 2009;10(Suppl. 12):33– 104. Hecking M, Werzowa J, Haidinger M, et al. paired renal function. Br J Clin Pharmacol 2003; 42 Novel views on new-onset diabetes after trans- 55:368–374 125. Rubio-Cabezas O, Hattersley AT, Njølstad plantation: development, prevention and treat- 116. Luther P, Baldwin D Jr. Pioglitazone in PR, et al.; International Society for Pediatric and ment. Nephrol Dial Transplant 2013;28:550–566 the management of diabetes mellitus after Adolescent Diabetes. ISPAD Clinical Practice 105. Ramirez SC, Maaske J, Kim Y, et al. The transplantation. Am J Transplant 2004;4:2135– Consensus Guidelines 2014. The diagnosis and association between glycemic control and clin- 2138 management of monogenic diabetes in children ical outcomes after kidney transplantation. En- 117. Strøm Halden TA, Asberg˚ A, Vik K, and adolescents. Pediatr Diabetes 2014;15 docr Pract 2014;20:894–900 Hartmann A, Jenssen T. Short-term efficacy (Suppl. 20):47–64 106. Thomas MC, Moran J, Mathew TH, Russ GR, and safety of sitagliptin treatment in long- 126. Greeley SAW, Naylor RN, Philipson LH, Bell Rao MM. Early peri-operative hyperglycaemia term stable renal recipients with new-onset GI. Neonatal diabetes: an expanding list of genes and renal allograft rejection in patients without diabetes after transplantation. Nephrol Dial allows for improved diagnosis and treatment. diabetes. BMC Nephrol 2000;1:1 Transplant 2014;29:926–933 Curr Diab Rep 2011;11:519–532 Diabetes Care Volume 42, Supplement 1, January 2019 S29

3. Prevention or Delay of Type 2 American Diabetes Association Diabetes: Standards of Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S29–S33 | https://doi.org/10.2337/dc19-S003 .PEETO RDLYO YE2DIABETES 2 TYPE OF DELAY OR PREVENTION 3.

For guidelines related to screening for increased risk for type 2 diabetes (prediabetes), please refer to Section 2 “Classiﬁcation and Diagnosis of Diabetes.”

Recommendation 3.1 At least annual monitoring for the development of type 2 diabetes in those with prediabetes is suggested. E

Screeningforprediabetesandtype2diabetesriskthroughaninformalassessment of risk factors (Table 2.3) or with an assessment tool, such as the American Diabetes Association risk test (Fig. 2.1), is recommended to guide providers on whether performing a diagnostic test for prediabetes (Table 2.5)andprevi- ously undiagnosed type 2 diabetes (Table 2.2) is appropriate (see Section 2 “Classification and Diagnosis of Diabetes”). Those determined to be at high risk for type 2 diabetes, including people with A1C 5.726.4% (39247 mmol/mol), impaired glucose tolerance, or impaired fasting glucose, are ideal candidates for diabetes prevention efforts. Using A1C to screen for prediabetes may be problematic in the presence of certain hemoglobinopathies or conditions that affect red blood cell turnover. See Section 2 “Classification and Diagnosis of Diabetes” and Section 6 “Glycemic Targets” for additional details on the appropriate use of the A1C test. At least annual monitoring for the development of diabetes in those with Suggested citation: American Diabetes Associa- prediabetes is suggested. tion. 3. Prevention or delay of type 2 diabetes: Standards of Medical Care in Diabetesd2019. Diabetes Care 2019;42(Suppl. 1):S29–S33 LIFESTYLE INTERVENTIONS © 2018 by the American Diabetes Association. Readers may use this article as long as the work Recommendations is properly cited, the use is educational and not 3.2 Refer patients with prediabetes to an intensive behavioral lifestyle interven- for profit, and the work is not altered. More infor- tion program modeled on the Diabetes Prevention Program (DPP) to achieve mation is available at http://www.diabetesjournals .org/content/license. S30 Prevention or Delay of Type 2 Diabetes Diabetes Care Volume 42, Supplement 1, January 2019

and maintain 7% loss of ini- specific methods used to achieve the Nutrition tial body weight and increase goals (6). Structured behavioral weight loss ther- moderate-intensity physical ac- The 7% weight loss goal was selected apy, including a reduced calorie meal tivity (such as brisk walking) to because it was feasible to achieve and plan and physical activity, is of para- at least 150 min/week. A maintain and likely to lessen the risk of mount importance for those at high 3.3 Based on patient preference, developing diabetes. Participants were risk for developing type 2 diabetes who technology-assisted diabetes encouraged to achieve the 7% weight have overweight or obesity (1,7). Be- prevention interventions may loss during the first 6 months of the cause weight loss through lifestyle be effective in preventing type intervention. However, longer-term changes alone can be difficult to maintain 2 diabetes and should be con- (4-year) data reveal maximal prevention long term (4), people being treated with sidered. B of diabetes observed at about 7–10% weight loss therapy should have access 3.4 Given the cost-effectiveness of weight loss (7). The recommended pace to ongoing support and additional thera- diabetes prevention, such inter- of weight loss was 122 lb/week. Calorie peutic options (such as pharmacother- vention programs should be cov- goals were calculated by estimating the apy) if needed. Based on intervention ered by third-party payers. B daily calories needed to maintain the trials, the eating patterns that may be participant’s initial weight and subtract- helpful for those with prediabetes The Diabetes Prevention Program ing 50021,000 calories/day (depending include a Mediterranean eating plan Several major randomized controlled tri- on initial body weight). The initial focus (8–11) and a low-calorie, low-fat eating als, including the Diabetes Prevention was on reducing total dietary fat. After plan (5). Additional research is needed Program (DPP) (1), the Finnish Diabetes several weeks, the concept of calorie regarding whether a low-carbohydrate Prevention Study (DPS) (2), and the Da balance and the need to restrict calories eating plan is beneficial for persons with Qing Diabetes Prevention Study (Da Qing as well as fat was introduced (6). prediabetes (12). In addition, evidence study) (3), demonstrate that lifestyle/ The goal for physical activity was se- suggests that the overall quality of food behavioral therapy featuring an indi- lected to approximate at least 700 kcal/ consumed (as measured by the Alterna- vidualized reduced calorie meal plan is week expenditure from physical activity. tive Healthy Eating Index), with an em- highly effective in preventing type 2 For ease of translation, this goal was phasis on whole grains, legumes, nuts, diabetes and improving other cardiome- described as at least 150 min of moderate- fruits and vegetables, and minimal re- tabolic markers (such as blood pressure, intensity physical activity per week fined and processed foods, is also im- lipids, and inflammation). The strongest similar in intensity to brisk walking. Par- portant (13–15). evidence for diabetes prevention comes ticipants were encouraged to distribute Whereas overall healthy low-calorie from the DPP trial (1). The DPP demon- their activity throughout the week with eating patterns should be encouraged, strated that an intensive lifestyle inter- a minimum frequency of three times per there is also some evidence that partic- vention could reduce the incidence of week with at least 10 min per session. A ular dietary components impact diabetes type 2 diabetes by 58% over 3 years. maximum of 75 min of strength training risk in observational studies. Higher in- Follow-up of three large studies of life- could be applied toward the total takes of nuts (16), berries (17), yogurt style intervention for diabetes preven- 150 min/week physical activity goal (6). (18,19), coffee, and tea (20) are associ- tion has shown sustained reduction in To implement the weight loss and ated with reduced diabetes risk. Con- the rate of conversion to type 2 diabetes: physical activity goals, the DPP used an in- versely, red meats and sugar-sweetened 45% reduction at 23 years in the Da Qing dividual model of treatment rather than beverages are associated with an in- study (3), 43% reduction at 7 years in the a group-based approach. This choice was creased risk of type 2 diabetes (13). DPS (2), and 34% reduction at 10 years (4) based on a desire to intervene before As is the case for those with diabetes, and 27% reduction at 15 years (5) in the participants had the possibility of devel- individualized medical nutrition therapy U.S. Diabetes Prevention Program Out- oping diabetes or losing interest in the (see Section 5 “Lifestyle Management” comes Study (DPPOS). Notably, in the program. The individual approach also for more detailed information) is effec- 23-year follow-up for the Da Qing study, allowed for tailoring of interventions to tive in lowering A1C in individuals di- reductions in all-cause mortality and reflect the diversity of the population (6). agnosed with prediabetes (21). cardiovascular disease–related mor- The DPP intervention was adminis- tality were observed for the lifestyle tered as a structured core curriculum Physical Activity intervention groups compared with the followed by a more flexible maintenance Just as 150 min/week of moderate- control group (3). program of individual sessions, group intensity physical activity, such as brisk The two major goals of the DPP in- classes, motivational campaigns, and re- walking, showed beneficial effects in tensive, behavioral, lifestyle intervention start opportunities. The 16-session core those with prediabetes (1), moderate- were to achieve and maintain a minimum curriculum was completed within the intensity physical activity has been of 7% weight loss and 150 min of physical first 24 weeks of the program and in- shown to improve insulin sensitivity activity similar in intensity to brisk walk- cluded sections on lowering calories, in- and reduce abdominal fat in children ing per week. The DPP lifestyle interven- creasing physical activity, self-monitoring, and young adults (22,23). On the basis tion was a goal-based intervention: all maintaining healthy lifestyle behaviors, of these findings, providers are encour- participants were given the same weight and psychological, social, and motivational aged to promote a DPP-style program, loss and physical activity goals, but in- challenges. For further details on the core including its focus on physical activity, to dividualization was permitted in the curriculum sessions, refer to ref. 6. all individuals who have been identified care.diabetesjournals.org Prevention or Delay of Type 2 Diabetes S31

to be at an increased risk of type 2 are promising (39). In an effort to expand Administration specifically for diabetes diabetes. In addition to aerobic activity, preventive services using a cost-effective prevention. One has to balance the risk/ an exercise regimen designed to prevent model that began in April 2018, the Centers benefit of each medication. Metformin diabetes may include resistance training for Medicare & Medicaid Services has has the strongest evidence base (50) and (6,24). Breaking up prolonged sedentary expanded Medicare reimbursement cov- demonstrated long-term safety as phar- time may also be encouraged, as it is erage for the National DPP lifestyle inter- macologic therapy for diabetes preven- associated with moderately lower post- vention to organizations recognized by the tion (48). For other drugs, cost, side prandial glucose levels (25,26). The pre- CDC that become Medicare suppliers for effects, and durable efficacy require ventive effects of exercise appear to this service (https://innovation.cms.gov/ consideration. extend to the prevention of gestational initiatives/medicare-diabetes-prevention- Metformin was overall less effective diabetes mellitus (GDM) (27). program/). than lifestyle modification in the DPP and DPPOS, though group differences Technology-Assisted Interventions to Tobacco Use declined over time (5) and metformin Deliver Lifestyle Interventions Smoking may increase the risk of type 2 may be cost-saving over a 10-year period Technology-assisted interventions may diabetes (40); therefore, evaluation for (34). It was as effective as lifestyle mod- effectively deliver the DPP lifestyle tobacco use and referral for tobacco ification in participants with BMI $35 2 intervention, reducing weight and, cessation, if indicated, should be part kg/m but not significantly better than therefore, diabetes risk (28–31). Such of routine care for those at risk for di- placebo in those over 60 years of age (1). technology-assisted interventions may abetes. Of note, the years immediately In the DPP, for women with history of deliver content through smartphone following smoking cessation may rep- GDM, metformin and intensive lifestyle and web-based applications and tele- resent a time of increased risk for di- modification led to an equivalent 50% health (28). The Centers for Disease abetes (40–42) and patients should be reduction in diabetes risk (51), and both Control and Prevention (CDC) Diabetes monitored for diabetes development interventions remained highly effective Prevention Recognition Program (DPRP) and receive evidence-based interven- during a 10-year follow-up period (52). (www.cdc.gov/diabetes/prevention/ tions for diabetes prevention as de- In the Indian Diabetes Prevention Pro- lifestyle-program) does certify technology- scribed in this section. See Section gramme (IDPP-1), metformin and the assisted modalities as effective vehicles 5 “Lifestyle Management” for more de- lifestyle intervention reduced diabetes for DPP-based interventions; such pro- tailed information. risk similarly at 30 months; of note, the grams must use an approved curricu- lifestyle intervention in IDPP-1 was lum, include interaction with a coach less intensive than that in the DPP (53). (which may be virtual), and attain the PHARMACOLOGIC Based on findings from the DPP, met- DPRP outcomes of participation, phys- INTERVENTIONS formin should be recommended as an ical activity reporting, and weight loss. option for high-risk individuals (e.g., Recommendations The selection of an in-person or virtual 3.5 Metformin therapy for preven- those with a history of GDM or those $ 2 program should be based on patient tion of type 2 diabetes should be with BMI 35 kg/m ). Consider monitor- preference. considered in those with predia- ing vitamin B12 levels in those taking betes, especially for those with metformin chronically to check for fi Cost-effectiveness BMI $35 kg/m2, those aged possible de ciency (54) (see Section 9 “ A cost-effectiveness model suggested that ,60 years, and women with Pharmacologic Approaches to Glycemic ” the lifestyle intervention used in the DPP prior gestational diabetes melli- Treatment for more details). was cost-effective (32,33). Actual cost data tus. A fi from the DPP and DPPOS con rmed this 3.6 Long-term use of metformin may (34). Group delivery of DPP content in PREVENTION OF be associated with biochemical CARDIOVASCULAR DISEASE community or primary care settings has vitamin B12 deficiency, and pe- the potential to reduce overall program riodic measurement of vitamin Recommendation 3.7 costs while still producing weight loss and B12 levels should be considered Prediabetesisassociatedwith – ; diabetesriskreduction(35 37).Theuseof in metformin-treated patients, heightened cardiovascular risk community health workers to support DPP especially in those with anemia therefore, screening for and treat- fi efforts has been shown to be effective with or peripheral neuropathy. B ment of modi able risk factors cost savings (38) (see Section 1 “Improving for cardiovascular disease is sug- Care and Promoting Health in Populations” gested. B for more information). The CDC coordi- Pharmacologic agents including metfor- nates the National Diabetes Prevention min, a-glucosidase inhibitors, glucagon- Peoplewithprediabetes oftenhaveother Program (National DPP), a resource de- like peptide 1 receptor agonists, cardiovascular risk factors, including hy- signed to bring evidence-based lifestyle thiazolidinediones, and several agents ap- pertensionand dyslipidemia (55),and are change programs for preventing type 2 proved for weight loss have been shown in at increased risk for cardiovascular dis- diabetes to communities (www.cdc.gov/ research studies to decrease the incidence ease (56). Although treatment goals for diabetes/prevention/index.htm). Early of diabetes to various degrees in those with people with prediabetes are the same as results from the CDC’sNationalDPP prediabetes (1,43–49), though none are for the general population (57), in- during the first 4 years of implementation approved by the U.S. Food and Drug creased vigilance is warranted to identify S32 Prevention or Delay of Type 2 Diabetes Diabetes Care Volume 42, Supplement 1, January 2019

and treat these and other cardiovascular and microvascular complications over 15-year 20. Mozaffarian D. Dietary and policy priorities risk factors (e.g., smoking). follow-up: the Diabetes Prevention Program for cardiovascular disease, diabetes, and obesity: Outcomes Study. Lancet Diabetes Endocrinol a comprehensive review. Circulation 2016;133: 2015;3:866–875 187–225 DIABETES SELF-MANAGEMENT 6. Diabetes Prevention Program (DPP) Research 21. Parker AR, Byham-Gray L, Denmark R, Group. The Diabetes Prevention Program (DPP): Winkle PJ. The effect of medical nutrition therapy EDUCATION AND SUPPORT description of lifestyle intervention. Diabetes by a registered dietitian nutritionist in patients – Recommendation Care 2002;25:2165 2171 with prediabetes participating in a randomized 3.8 Diabetes self-management edu- 7. Hamman RF, Wing RR, Edelstein SL, et al. controlled clinical research trial. J Acad Nutr Diet Effect of weight loss with lifestyle intervention 2014;114:1739–1748 cation and support programs may on risk of diabetes. Diabetes Care 2006;29:2102– 22. Fedewa MV, Gist NH, Evans EM, DishmanRK. be appropriate venues for people 2107 Exercise and insulin resistance in youth: a meta- with prediabetes to receive edu- 8. Salas-Salvado´ J, Bullo´ M, Babio N, et al.; analysis. Pediatrics 2014;133:e163–e174 cation and support to develop PREDIMED Study Investigators. Reduction in 23. Davis CL, Pollock NK, Waller JL, et al. Exercise and maintain behaviors that the incidence of type 2 diabetes with the Med- dose and diabetes risk in overweight and obese iterranean diet: results of the PREDIMED-Reus children: a randomized controlled trial. JAMA can prevent or delay the devel- nutrition intervention randomized trial. Dia- 2012;308:1103–1112 opment of type 2 diabetes. B betes Care 2011;34:14–19 24. Sigal RJ, Alberga AS, Goldfield GS, et al. 9. Salas-Salvado´ J, Guasch-Ferre´ M, Lee C-H, Effects of aerobic training, resistance training, As for those with established diabetes, Estruch R, Clish CB, Ros E. Protective effects or both on percentage body fat and cardiome- the standards for diabetes self-management of the Mediterranean diet on type 2 diabetes tabolic risk markers in obese adolescents: the and metabolic syndrome. J Nutr 2016;146:920S– healthy eating aerobic and resistance training in education and support (see Section 5 927S youth randomized clinical trial. JAMA Pediatr “Lifestyle Management”) can also apply 10. Bloomfield HE, Koeller E, Greer N, 2014;168:1006–1014 to people with prediabetes. Currently, MacDonald R, Kane R, Wilt TJ. Effects on health 25. Thorp AA, Kingwell BA, Sethi P, Hammond L, there are significant barriers to the pro- outcomes of a Mediterranean diet with no re- Owen N, Dunstan DW. Alternating bouts of vision of education and support to those striction on fat intake: a systematic review and sitting and standing attenuate postprandial glu- meta-analysis. Ann Intern Med 2016;165:491– cose responses. Med Sci Sports Exerc 2014;46: with prediabetes. However, the strate- 500 2053–2061 gies for supporting successful behavior 11. Estruch R, Ros E, Salas-Salvado´ J, et al.; 26. Healy GN, Dunstan DW, Salmon J, et al. change and the healthy behaviors rec- PREDIMED Study Investigators. Primary preven- Breaks in sedentary time: beneficial associations ommended for people with prediabetes tion of cardiovascular disease with a Mediter- with metabolic risk. Diabetes Care 2008;31:661– are comparable to those for diabetes. ranean diet supplemented with extra-virgin olive 666 oil or nuts. N Engl J Med 2018;378:e34 27. Russo LM, Nobles C, Ertel KA, Chasan-Taber Although reimbursement remains a bar- 12. Noto H, Goto A, Tsujimoto T, Noda M. Long- L, Whitcomb BW. Physical activity interventions rier, studies show that providers of di- term low-carbohydrate diets and type 2 diabe- in pregnancy and risk of gestational diabetes abetes self-management education and tes risk: a systematic review and meta-analysis mellitus: a systematic review and meta-analysis. support are particularly well equipped to of observational studies. J Gen Fam Med 2016; Obstet Gynecol 2015;125:576–582 – assist people with prediabetes in devel- 17:60 70 28. Grock S, Ku J-H, Kim J, Moin T. A review of 13. Ley SH, Hamdy O, Mohan V, Hu FB. Pre- technology-assisted interventions for diabetes oping and maintaining behaviors that vention and management of type 2 diabetes: prevention. Curr Diab Rep 2017;17:107 can prevent or delay the development dietary components and nutritional strategies. 29. Sepah SC, Jiang L, Peters AL. Translating the of diabetes (21,58). Lancet 2014;383:1999–2007 Diabetes Prevention Program into an online 14. Jacobs S, Harmon BE, Boushey CJ, et al. A social network: validation against CDC stan- priori-defined diet quality indexes and risk of dards. Diabetes Educ 2014;40:435–443 References type 2 diabetes: the Multiethnic Cohort. Diabe- 30. Bian RR, Piatt GA, Sen A, et al. The effect of 1. Knowler WC, Barrett-Connor E, Fowler SE, tologia 2015;58:98–112 technology-mediated diabetes prevention in- et al.; Diabetes Prevention Program Research 15. Chiuve SE, Fung TT, Rimm EB, et al. Alter- terventions on weight: a meta-analysis. J Med Group. Reduction in the incidence of type 2 native dietary indices both strongly predict risk Internet Res 2017;19:e76 diabetes with lifestyle intervention or metfor- of chronic disease. J Nutr 2012;142:1009–1018 31. Sepah SC, Jiang L, Peters AL. Long-term min. N Engl J Med 2002;346:393–403 16. Afshin A, Micha R, Khatibzadeh S, Mozaffarian outcomes of a Web-based diabetes prevention 2. Lindstrom¨ J, Ilanne-Parikka P, Peltonen M, D. Consumption of nuts and legumes and risk of program: 2-year results of a single-arm longitu- et al.; Finnish Diabetes Prevention Study Group. incident ischemic heart disease, stroke, and di- dinal study. J Med Internet Res 2015;17:e92 Sustained reduction in the incidence of type 2 abetes: a systematic review and meta-analysis. 32. Herman WH, Hoerger TJ, Brandle M, et al.; diabetes by lifestyle intervention: follow-up of Am J Clin Nutr 2014;100:278–288 Diabetes Prevention Program Research Group. the Finnish Diabetes Prevention Study. Lancet 17. Mursu J, Virtanen JK, Tuomainen T-P, Nurmi The cost-effectiveness of lifestyle modification 2006;368:1673–1679 T, Voutilainen S. Intake of fruit, berries, and or metformin in preventing type 2 diabetes in 3. Li G, Zhang P, Wang J, et al. Cardiovascular vegetables and risk of type 2 diabetes in Finnish adults with impaired glucose tolerance. Ann mortality, all-cause mortality, and diabetes in- men: the Kuopio Ischaemic Heart Disease Risk Intern Med 2005;142:323–332 cidence after lifestyle intervention for people Factor Study. Am J Clin Nutr 2014;99:328–333 33. Chen F, Su W, Becker SH, et al. Clinical and with impaired glucose tolerance in the Da Qing 18. Chen M, Sun Q, Giovannucci E, et al. Dairy economic impact of a digital, remotely-delivered Diabetes Prevention Study: a 23-year follow-up consumption and risk of type 2 diabetes: 3 co- intensive behavioral counseling program on study. Lancet Diabetes Endocrinol 2014;2:474– horts of US adults and an updated meta-analysis. Medicare beneficiaries at risk for diabetes and 480 BMC Med 2014;12:215 cardiovascular disease. PLoS One 2016;11: 4. Knowler WC, Fowler SE, Hamman RF, et al.; 19. Dehghan M, Mente A, Rangarajan S, et al.; e0163627 Diabetes Prevention Program Research Group. Prospective Urban Rural Epidemiology (PURE) 34. Diabetes Prevention Program Research 10-year follow-up of diabetes incidence and study investigators. Association of dairy intake Group. The 10-year cost-effectiveness of lifestyle weight loss in the Diabetes Prevention Program with cardiovascular disease and mortality in intervention or metformin for diabetes preven- Outcomes Study. Lancet 2009;374:1677–1686 21 countries from five continents (PURE): a pro- tion: an intent-to-treat analysis of the DPP/ 5. Nathan DM, Barrett-Connor E, Crandall JP, spective cohort study. Lancet. 11 September DPPOS. Diabetes Care 2012;35:723–730 et al. Long-term effects of lifestyle interven- 2018 [Epub ahead of print]. DOI: 10.1016/ 35. Ackermann RT, Finch EA, Brizendine E, Zhou tion or metformin on diabetes development S0140-6736(18)31812-9 H, Marrero DG. Translating the Diabetes care.diabetesjournals.org Prevention or Delay of Type 2 Diabetes S33

Prevention Program into the community. The diabetes mellitus: the STOP-NIDDM randomised 52. Aroda VR, Christophi CA, Edelstein SL, et al.; DEPLOYPilot Study.Am J Prev Med2008;35:357– trial. Lancet 2002;359:2072–2077 Diabetes Prevention Program Research Group. 363 44. Torgerson JS, Hauptman J, Boldrin MN, The effect of lifestyle intervention and metformin 36. Balk EM, Earley A, Raman G, Avendano EA, Sjostr¨ om¨ L. XENical in the prevention of Diabetes on preventing or delaying diabetes among Pittas AG, Remington PL. Combined diet and in Obese Subjects (XENDOS) study: a randomized women with and without gestational diabetes: physical activity promotion programs to prevent study of orlistat as an adjunct to lifestyle changes the Diabetes Prevention Program Outcomes type 2 diabetes among persons at increased risk: for the prevention of type 2 diabetes in obese Study 10-year follow-up. J Clin Endocrinol Metab a systematic review for the Community Preven- patients. Diabetes Care 2004;27:155–161 2015;100:1646–1653 tive Services Task Force. Ann Intern Med 2015; 45. le Roux CW, Astrup A, Fujioka K, et al.; SCALE 53. Ramachandran A, Snehalatha C, Mary S, 163:437–451 Obesity Prediabetes NN8022-1839 Study Group. Mukesh B, Bhaskar AD, Vijay V; Indian Diabetes 37. Li R,QuS,ZhangP,et al.Economic evaluation 3 years of liraglutide versus placebo for type 2 Prevention Programme (IDPP). The Indian Di- of combined diet and physical activity promo- diabetes risk reduction and weight management abetes Prevention Programme shows that life- tion programs to prevent type 2 diabetes among in individuals with prediabetes: a randomised, style modification and metformin prevent type 2 persons at increased risk: a systematic review for double-blind trial. Lancet 2017;389:1399–1409 diabetes in Asian Indian subjects with impaired the Community Preventive Services Task Force. 46. Gerstein HC, Yusuf S, Bosch J, et al.; DREAM glucose tolerance (IDPP-1). Diabetologia 2006; Ann Intern Med 2015;163:452–460 (Diabetes REduction Assessment with ramipril 49:289–297 38. The Community Guide. Diabetes preven- and rosiglitazone Medication) Trial Investigators. 54. Aroda VR, Edelstein SL, Goldberg RB, et al.; tion: interventions engaging community health Effect of rosiglitazone on the frequency of di- Diabetes Prevention Program Research Group. workers [Internet], 2016. Available from https:// abetes in patients with impaired glucose toler- Long-term metformin use and vitamin B12 de- www.thecommunityguide.org/findings/diabetes- ance or impaired fasting glucose: a randomised ficiency in the Diabetes Prevention Program prevention-interventions-engaging-community- controlled trial. Lancet 2006;368:1096–1105 Outcomes Study. J Clin Endocrinol Metab health-workers. Accessed 25 September 2018 47. DeFronzo RA, Tripathy D, Schwenke DC, 2016;101:1754–1761 39. Ely EK, Gruss SM, Luman ET, et al. A national et al.; ACT NOW Study. Pioglitazone for diabetes 55. Ali MK, Bullard KM, Saydah S, Imperatore G, effort to prevent type 2 diabetes: participant- prevention in impaired glucose tolerance. N Engl Gregg EW. Cardiovascular and renal burdens of level evaluation of CDC’s National Diabetes Pre- J Med 2011;364:1104–1115 prediabetes in the USA: analysis of data from vention Program. Diabetes Care 2017;40:1331– 48. Diabetes Prevention Program Research serial cross-sectional surveys, 1988–2014. Lancet 1341 Group. Long-term safety, tolerability, and weight Diabetes Endocrinol 2018;6:392–403 40. Yeh H-C, Duncan BB, Schmidt MI, Wang N-Y, loss associated with metformin in the Diabetes 56.HuangY,CaiX,MaiW,LiM,HuY.Asso- Brancati FL. Smoking, smoking cessation, and risk Prevention Program Outcomes Study. Diabetes ciation between prediabetes and risk of car- for type 2 diabetes mellitus: a cohort study. Ann Care 2012;35:731–737 diovascular disease and all cause mortality: Intern Med 2010;152:10–17 49. Garvey WT, Ryan DH, Henry R, et al. Pre- systematic review and meta-analysis. BMJ 41. Oba S, Noda M, Waki K, et al. Smoking vention of type 2 diabetes in subjects with 2016;355:i5953 cessation increases short-term risk of type 2 prediabetes and metabolic syndrome treated 57. Bress AP, King JB, Kreider KE, et al.; SPRINT diabetes irrespective of weight gain: the Japan with phentermine and topiramate extended re- Research Group. Effect of intensive versus Public Health Center-Based Prospective Study lease. Diabetes Care 2014;37:912–921 standard blood pressure treatment according to [published correction appears in PLoS One 2013; 50. Moin T, Schmittdiel JA, Flory JH, et al. Review baseline prediabetes status: a post hoc analysis 8:10.1371/annotation/23aa7c42-9a4d-42a7- of metformin use for type 2 diabetes prevention. of a randomized trial. Diabetes Care 2017;40: 8f50-9d0ac4b85396]. PLoS One 2012;7:e17061 Am J Prev Med 2018;55:565–574 1401–1408 42. Hu Y, Zong G, Liu G, et al. Smoking cessation, 51. Ratner RE, Christophi CA, Metzger BE, et al.; 58. Butcher MK, Vanderwood KK, Hall TO, weight change, type 2 diabetes, and mortality. Diabetes Prevention Program Research Group. Gohdes D, Helgerson SD, Harwell TS. Capacity N Engl J Med 2018;379:623–632 Prevention of diabetes in women with a history of diabetes education programs to provide both 43. Chiasson J-L, Josse RG, Gomis R, Hanefeld M, of gestational diabetes: effects of metformin diabetes self-management education and to Karasik A, Laakso M; STOP-NIDDM Trail Research and lifestyle interventions. J Clin Endocrinol implement diabetes prevention services. J Public Group. Acarbose for prevention of type 2 Metab 2008;93:4774–4779 Health Manag Pract 2011;17:242–247 S34 Diabetes Care Volume 42, Supplement 1, January 2019

4. Comprehensive Medical American Diabetes Association Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S34–S45 | https://doi.org/10.2337/dc19-S004

PATIENT-CENTERED COLLABORATIVE CARE

Recommendations 4.1 A patient-centered communication style that uses person-centered and strength-based language and active listening, elicits patient preferences and beliefs, and assesses literacy, numeracy, and potential barriers to care should be used to optimize patient health outcomes and health-related quality of life. B 4.2 Diabetes care should be managed by a multidisciplinary team that may draw from primary care physicians, subspecialty physicians, nurse practitioners, physician assistants, nurses, dietitians, exercise specialists, pharmacists, dentists, podiatrists, and mental health professionals. E

A successful medical evaluation depends on beneﬁcial interactions between the patient and the care team. The Chronic Care Model (1–3) (see Section 1 “Improving Care and Promoting Health in Populations”) is a patient-centered approach to care that requires a close working relationship between the patient and clinicians Suggested citation: American Diabetes Associa- involved in treatment planning. People with diabetes should receive health care tion. 4. Comprehensive medical evaluation and from an interdisciplinary team that may include physicians, nurse practitioners, assessment of comorbidities: Standards of physician assistants, nurses, dietitians, exercise specialists, pharmacists, dentists, Medical Care in Diabetesd2019. Diabetes Care podiatrists, and mental health professionals. Individuals with diabetes must assume 2019;42(Suppl. 1):S34–S45 an active role in their care. The patient, family or support people, physicians, and © 2018 by the American Diabetes Association. health care team should together formulate the management plan, which includes Readers may use this article as long as the work “ ” is properly cited, the use is educational and not lifestyle management (see Section 5 Lifestyle Management ). for proﬁt, and the work is not altered. More infor- The goals of treatment for diabetes are to prevent or delay complications mation is available at http://www.diabetesjournals and maintain quality of life (Fig. 4.1). Treatment goals and plans should be created .org/content/license. care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S35

Figure 4.1—Decision cycle for patient-centered glycemic management in type 2 diabetes. Adapted from Davies et al. (119).

with the patients based on their individ- assess and address self-management assessment, patient education, and ual preferences, values, and goals. The barriers without blaming patients for treatment planning. management plan should take into “noncompliance” or “nonadherence” Language has a strong impact on per- account the patient’s age, cognitive abil- when the outcomes of self-management ceptions and behavior. The use of em- ities, school/work schedule and condi- are not optimal (8). The familiar terms powering language in diabetes care and tions, health beliefs, support systems, “noncompliance” and “nonadherence” education can help to inform and motivate eating patterns, physical activity, social denote a passive, obedient role for a people, yet language that shames and situation, financial concerns, cultural fac- person with diabetes in “following doc- judges may undermine this effort. The tors, literacy and numeracy (mathemat- tor’s orders” that is at odds with the American Diabetes Association (ADA) and ical literacy), diabetes complications active role people with diabetes take in American Association of Diabetes Educa- and duration of disease, comorbidities, directing the day-to-day decision mak- tors consensus report, “The Use of Lan- health priorities, other medical condi- ing, planning, monitoring, evaluation, guage in Diabetes Care and Education,” tions, preferences for care, and life and problem-solving involved in diabetes provides the authors’ expert opinion re- expectancy. Various strategies and tech- self-management. Using a nonjudg- garding the use of language by health care niques should be used to support mental approach that normalizes peri- professionals when speaking or writing patients’ self-management efforts, in- odic lapses in self-management may help aboutdiabetesforpeoplewithdiabetesor cluding providing education on problem- minimize patients’ resistance to report- for professional audiences (14). Although solving skills for all aspects of diabetes ing problems with self-management. further research is needed to address the management. Empathizing and using active listening impact of language on diabetes outcomes, Provider communications withpatients techniques, such as open-ended ques- the report includes five key consensus and families should acknowledge that tions, reflective statements, and summa- recommendations for language use: multiple factors impact glycemic manage- rizing what the patient said, can help ment but also emphasize that collab- facilitate communication. Patients’ per- ○ Use language that is neutral, nonjudg- oratively developed treatment plans ceptions about their own ability, or self- mental, and based on facts, actions, or and a healthy lifestyle can significantly efficacy, to self-manage diabetes are one physiology/biology. improve disease outcomes and well- important psychosocial factor related to ○ Use language that is free from stigma. being (4–7). Thus, the goal of provider- improved diabetes self-management ○ Use language that is strength based, patient communication is to establish and treatment outcomes in diabetes (9– respectful, and inclusive and that im- a collaborative relationship and to 13) and should be a target of ongoing parts hope. S36 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 42, Supplement 1, January 2019

○ Use language that fosters collabora- of the patient throughout the process. for complications and comorbidities. Dis- tion between patients and providers. While a comprehensive list is provided cussing and implementing an approach ○ Use language that is person centered in Table 4.1, in clinical practice, the to glycemic control with the patient is a (e.g., “person with diabetes” is pre- provider may need to prioritize the com- part, not the sole goal, of the patient ferred over “diabetic”). ponents of the medical evaluation given encounter. the available resources and time. The goal is to provide the health care team COMPREHENSIVE MEDICAL information to optimally support a pa- Immunizations EVALUATION tient. In addition to the medical history, Recommendations Recommendations physical examination, and laboratory 4.7 Provide routinely recommended 4.3 A complete medical evaluation tests, providers should assess diabetes vaccinations for children and should be performed at the ini- self-management behaviors, nutrition, adults with diabetes by age. C tial visit to: and psychosocial health (see Section 5 4.8 Annual vaccination against in- ○ Confirm the diagnosis and classify “Lifestyle Management”) and give guid- fluenza is recommended for all diabetes. B ance on routine immunizations. The people $6 months of age, es- ○ Evaluate for diabetes complica- assessment of sleep pattern and dura- pecially those with diabetes. C tions and potential comorbid tion should be considered; a recent meta- 4.9 Vaccination against pneumo- conditions. B analysis found that poor sleep quality, coccal disease, including pneu- ○ Review previous treatment and short sleep, and long sleep were associ- mococcal pneumonia, with risk factor control in patients ated with higher A1C in people with 13-valent pneumococcal conju- with established diabetes. B type 2 diabetes (15). Interval follow-up gate vaccine (PCV13) is recom- ○ Begin patient engagement in the visits should occur at least every 3–6 mended for children before age formulation of a care manage- months, individualized to the patient, 2 years. People with diabetes ment plan. B and then annually. ages 2 through 64 years should ○ Develop a plan for continuing Lifestyle management and psychoso- also receive 23-valent pneu- care. B cial care are the cornerstones of diabe- mococcal polysaccharide vaccine 4.4 A follow-up visit should include tes management. Patients should be (PPSV23). At age $65 years, most components of the initial referred for diabetes self-management regardless of vaccination his- comprehensive medical evalua- education and support, medical nutri- tory, additional PPSV23 vacci- tion including: interval medical tion therapy, and assessment of psy- nation is necessary. C history, assessment of medication- chosocial/emotional health concerns if 4.10 Administer a 2- or 3-dose series taking behavior and intolerance/ indicated. Patients should receive rec- of hepatitis B vaccine, depend- side effects, physical examina- ommended preventive care services ing on the vaccine, to unvacci- tion, laboratory evaluation as ap- (e.g., immunizations, cancer screening, nated adults with diabetes ages propriate to assess attainment etc.), smoking cessation counseling, and 18 through 59 years. C of A1C and metabolic targets, ophthalmological, dental, and podiatric 4.11 Consider administering 3-dose and assessment of risk for compli- referrals. series of hepatitis B vaccine to cations, diabetes self-management The assessment of risk of acute and unvaccinated adults with dia- behaviors, nutrition, psychosocial chronic diabetes complications and treat- betes ages $60 years. C health, and the need for referrals, ment planning are key components of immunizations, or other routine initial and follow-up visits (Table 4.2). Children and adults with diabetes health maintenance screening. B The risk of atherosclerotic cardiovascu- should receive vaccinations according 4.5 Ongoing management should be lar disease and heart failure (Section to age-appropriate recommendations guided by the assessment of di- 10 “Cardiovascular Disease and Risk (16,17). The child and adolescent (#18 abetes complications and shared Management”), chronic kidney disease years of age) vaccination schedule is decision making to set therapeu- staging (Section 11 “Microvascular available at www.cdc.gov/vaccines/ tic goals. B Complications and Foot Care”), and schedules/hcp/imz/child-adolescent.html, 4.6 The 10-year risk of a first athero- risk of treatment-associated hypogly- and the adult ($19 years of age) vacci- sclerotic cardiovascular disease cemia (Table 4.3) should be used to nation schedule is available at www.cdc event should be assessed using individualize targets for glycemia (Sec- .gov/vaccines/schedules/hcp/imz/adult the race- and sex-specific Pooled tion 6 “Glycemic Targets”), blood pres- .html. These immunization schedules in- Cohort Equations to better strat- sure, and lipids and to select specific clude vaccination schedules specifically ify atherosclerotic cardiovascular glucose-lowering medication (Section 9 for children, adolescents, and adults with disease risk. B “Pharmacologic Approaches to Glycemic diabetes. Treatment”), antihypertension medica- People with diabetes are at higher The comprehensive medical evaluation tion, or statin treatment intensity. risk for hepatitis B infection and are includes the initial and follow-up evalua- Additional referrals should be ar- more likely to develop complications tions, assessment of complications, psy- ranged as necessary (Table 4.4). Clini- from influenza and pneumococcal dis- chosocial assessment, management of cians should ensure that individuals ease. The Centers for Disease Control and comorbid conditions, and engagement with diabetes are appropriately screened Prevention (CDC) Advisory Committee care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S37

Continued on p. S38 S38 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 42, Supplement 1, January 2019

on Immunization Practices (ACIP) recom- the elderly and people with chronic dis- recommendations from the CDC ACIP mends influenza, pneumococcal, and eases. Influenza vaccination in people that adults age $65 years, who are at hepatitis B vaccinations specifically for with diabetes has been found to signif- higher risk for pneumococcal disease, people with diabetes. Vaccinations icantly reduce influenza and diabetes- receive an additional 23-valent pneumo- against tetanus-diphtheria-pertussis, related hospital admissions (18). coccal polysaccharide vaccine (PPSV23), measles-mumps-rubella, human papillo- regardless of prior pneumococcal vacci- mavirus, and shingles are also important Pneumococcal Pneumonia nation history. See detailed recommen- for adults with diabetes, as they are for Like influenza, pneumococcal pneumo- dations at www.cdc.gov/vaccines/hcp/ the general population. nia is a common, preventable disease. acip-recs/vacc-specific/pneumo.html. People with diabetes are at increased Influenza risk for the bacteremic form of pneu- Hepatitis B Influenza is a common, preventable in- mococcal infection and have been re- Compared with the general population, fectious disease associated with high ported to have a high risk of nosocomial people with type 1 or type 2 diabetes mortality and morbidity in vulnerable bacteremia, with a mortality rate as have higher rates of hepatitis B. This may populations including the young and high as 50% (19). The ADA endorses be due to contact with infected blood care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S39

“ Table 4.2—Assessment and treatment plan* disease) (see Section 13 Children and Assess risk of diabetes complications Adolescents”). c ASCVD and heart failure history c ASCVDrisk factors (see Table 10.2) and 10-year ASCVD risk assessment Cancer c Staging of chronic kidney disease (see Table 11.1) Diabetes is associated with increased c Hypoglycemia risk (Table 4.3) risk of cancers of the liver, pancreas, Goal setting endometrium, colon/rectum, breast, c Set A1C/blood glucose target c If hypertension present, establish blood pressure target and bladder (29). The association may c Diabetes self-management goals (e.g., monitoring frequency) result from shared risk factors between Therapeutic treatment plan type 2 diabetes and cancer (older age, c Lifestyle management obesity, and physical inactivity) but may c Pharmacologic therapy (glucose lowering) also be due to diabetes-related factors c Pharmacologic therapy (cardiovascular disease risk factors and renal) (30), such as underlying disease physiol- c Use of glucose monitoring and insulin delivery devices ogy or diabetes treatments, although c Referral to diabetes education and medical specialists (as needed) evidencefortheselinks isscarce.Patients ASCVD, atherosclerotic cardiovascular disease. *Assessment and treatment planning is an with diabetes should be encouraged to essential component of initial and all follow-up visits. undergo recommended age- and sex- appropriate cancer screenings and to reduce their modifiable cancer risk fac- or through improper equipment use Autoimmune Diseases tors (obesity, physical inactivity, and (glucose monitoring devices or infected Recommendation smoking). New onset of atypical diabetes needles). Because of the higher likeli- 4.12 Consider screening patients (lean body habitus, negative family his- hood of transmission, hepatitis B vac- with type 1 diabetes for auto- tory) in a middle-aged or older patient cine is recommended for adults with immune thyroid disease and may precede the diagnosis of pancre- diabetes age ,60 years. For adults age celiac disease soon after diag- atic adenocarcinoma (31). However, in $60 years, hepatitis B vaccine may be nosis. B the absence of other symptoms (e.g., administered at the discretion of the weight loss, abdominal pain), routine treating clinician based on the patient’s People with type 1 diabetes are at in- screening of all such patients is not likelihood of acquiring hepatitis B creased risk for other autoimmune currently recommended. infection. diseases including thyroid disease, primary adrenal insufficiency, celiac disease, Cognitive Impairment/Dementia ASSESSMENT OF COMORBIDITIES autoimmune gastritis, autoimmune hep- Besides assessing diabetes-related com- atitis, dermatomyositis, and myasthenia Recommendation 4.13 In people with a history of cog- plications, clinicians and their patients gravis (25–27). Type 1 diabetes may also nitive impairment/dementia, in- need to be aware of common comorbid- occur with other autoimmune diseases tensive glucose control cannot ities that affect people with diabetes in the context of specificgeneticdis- be expected to remediate def- and may complicate management orders or polyglandular autoimmune syn- icits. Treatment should be (20–24). Diabetes comorbidities are con- dromes (28). In autoimmune diseases, tailored to avoid significant ditions that affect people with diabetes the immune system fails to maintain hypoglycemia. B more often than age-matched people self-tolerance to specific peptides within without diabetes. This section includes target organs. It is likely that many factors Diabetes is associated with a significantly many of the common comorbidities ob- trigger autoimmune disease; however, increased risk and rate of cognitive de- served in patients with diabetes but is not common triggering factors are known cline and an increased risk of demen- necessarily inclusive of all the conditions for only some autoimmune condi- tia (32,33). A recent meta-analysis of that have been reported. tions (i.e., gliadin peptides in celiac prospective observational studies in people with diabetes showed 73% in- Table 4.3—Assessment of hypoglycemia risk creased risk of all types of dementia, Factors that increase risk of treatment-associated hypoglycemia 56% increased risk of Alzheimer de- c Use of insulin or insulin secretagogues (i.e., sulfonylureas, meglitinides) mentia, and 127% increased risk of c Impaired kidney or hepatic function vascular dementia compared with in- c Longer duration of diabetes dividuals without diabetes (34). The c Frailty and older age reverse is also true: people with Alz- c Cognitive impairment heimer dementia are more likely to c Impaired counterregulatory response, hypoglycemia unawareness develop diabetes than people without c Physical or intellectual disability that may impair behavioral response to hypoglycemia Alzheimer dementia. In a 15-year pro- c Alcohol use c Polypharmacy (especially ACE inhibitors, angiotensin receptor blockers, nonselective spective study of community-dwelling b-blockers) people .60 years of age, the presence of diabetes at baseline significantly See references 114–118. increasedtheage-andsex-adjusted S40 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 42, Supplement 1, January 2019

Table 4.4—Referrals for initial care evidence to recommend any dietary has also shown some promise in pre- management change for the prevention or treatment liminary studies, although benefits may c Eye care professional for annual dilated of cognitive dysfunction (41). be mediated, at least in part, by weight eye exam loss (48–50). Statins c Family planning for women of reproductive age A systematic review has reported that Pancreatitis c Registered dietitian for medical nutrition data do not support an adverse effect therapy of statins on cognition (42). The U.S. Food Recommendation c Diabetes self-management education and Drug Administration postmarket- 4.15 Islet autotransplantation should and support ing surveillance databases have also be considered for patients re- c Dentist for comprehensive dental and revealed a low reporting rate for cog- quiring total pancreatectomy periodontal examination nitive-related adverse events, including for medically refractory chronic c Mental health professional, if indicated cognitive dysfunction or dementia, with pancreatitis to prevent postsur- statin therapy, similar to rates seen with gical diabetes. C other commonly prescribed cardiovas- incidence of all-cause dementia, Alz- cular medications (42). Therefore, fear Diabetes is linked to diseases of the heimer dementia, and vascular demen- of cognitive decline should not be a bar- exocrine pancreas such as pancreatitis, tia compared with rates in those with rier to statin use in individuals with di- which may disrupt the global architecture normal glucose tolerance (35). abetes and a high risk for cardiovascular or physiology of the pancreas, often re- disease. sulting in both exocrine and endocrine Hyperglycemia dysfunction. Up to half of patients with In those with type 2 diabetes, the degree Nonalcoholic Fatty Liver Disease diabetes may have impaired exocrine pan- and duration of hyperglycemia are related creas function (51). People with diabetes Recommendation todementia.Morerapidcognitivedeclineis are at an approximately twofold higher risk 4.14 Patients with type 2 diabetes or associated with both increased A1C and of developing acute pancreatitis (52). prediabetes and elevated liver longerdurationofdiabetes(34).TheAction Conversely, prediabetes and/or dia- enzymes (alanine aminotrans- to Control Cardiovascular Risk in Diabetes betes has been found to develop in ap- ferase) or fatty liver on ultra- (ACCORD) study found that each 1% higher proximately one-third of patients after sound should be evaluated for A1C level was associated with lower cog- an episode of acute pancreatitis (53), presence of nonalcoholic steato- nitive function in individuals with type 2 thus the relationship is likely bidirec- hepatitis and liver fibrosis. C diabetes (36). However, the ACCORD tional. Postpancreatitis diabetes may study found no difference in cognitive include either new-onset disease or previ- Diabetes is associated with the develop- outcomes in participants randomly ously unrecognized diabetes (54). Studies ment of nonalcoholic fatty liver disease, assigned to intensive and standard of patients treated with incretin-based including its more severe manifesta- glycemic control, supporting the recom- therapies for diabetes have also reported tions of nonalcoholic steatohepatitis, mendation that intensive glucose con- that pancreatitis may occur more fre- liver fibrosis, cirrhosis, and hepatocel- trol should not be advised for the quently with these medications, but re- lular carcinoma (43). Elevations of he- improvement of cognitive function in sults have been mixed (55,56). patic transaminase concentrations are individuals with type 2 diabetes (37). Islet autotransplantation should be associated with higher BMI, waist cir- Hypoglycemia considered for patients requiring total cumference, and triglyceride levels and In type 2 diabetes, severe hypoglycemia pancreatectomy for medically refractory lower HDL cholesterol levels. Noninva- is associated with reduced cognitive chronic pancreatitis to prevent postsur- sive tests, such as elastography or fi- function, and those with poor cognitive gical diabetes. Approximately one-third brosis biomarkers, may be used to function have more severe hypoglyce- of patients undergoing total pancreatec- assess risk of fibrosis, but referral to mia. In a long-term study of older pa- tomy with islet autotransplantation are a liver specialist and liver biopsy may tients with type 2 diabetes, individuals insulin free 1 year postoperatively, and be required for definitive diagnosis with one or more recorded episode of observational studies from different (43a). Interventions that improve met- severe hypoglycemia had a stepwise in- centers have demonstrated islet graft abolic abnormalities in patients with crease in risk of dementia (38). Likewise, function up to a decade after the surgery diabetes (weight loss, glycemic control, the ACCORD trial found that as cog- in some patients (57–61). Both patient and treatment with specificdrugsfor nitive function decreased, the risk of and disease factors should be carefully hyperglycemia or dyslipidemia) are also severe hypoglycemia increased (39). considered when deciding the indica- beneficial for fatty liver disease (44,45). Tailoring glycemic therapy may help to tions and timing of this surgery. Surger- Pioglitazone and vitamin E treatment of prevent hypoglycemia in individuals with ies should be performed in skilled biopsy-proven nonalcoholic steatohe- cognitive dysfunction. facilities that have demonstrated exper- patitishavebeenshowntoimprove tise in islet autotransplantation. Nutrition liver histology, but effects on longer- In one study, adherence to the Mediter- term clinical outcomes are not known ranean diet correlated with improved (46,47). Treatment with liraglutide and Fractures cognitive function (40). However, a re- with sodium–glucose cotransporter 2 in- Age-specific hip fracture risk is signifi- cent Cochrane review found insufficient hibitors (dapagliflozin and empagliflozin) cantly increased in people with both care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S41

type 1 (relative risk 6.3) and type 2 reverse transcriptase inhibitors (NRTIs). men with diabetes who have symptoms (relative risk 1.7) diabetes in both sexes New-onset diabetes is estimated to oc- or signs of low testosterone (hypogonad- (62). Type 1 diabetes is associated with cur in more than 5% of patients infected ism), a morning total testosterone should osteoporosis, but in type 2 diabetes, an with HIV on PIs, whereas more than 15% be measured using an accurate and reli- increased risk of hip fracture is seen may have prediabetes (68). PIs are asso- able assay. Free or bioavailable testos- despite higher bone mineral density ciated with insulin resistance and may also terone levels should also be measured in (BMD) (63). In three large observational lead to apoptosis of pancreatic b-cells. men with diabetes who have total tes- studies of older adults, femoral neck NRTIs also affect fat distribution (both tosterone levels close to the lower limit, BMD T score and the World Health lipohypertrophy and lipoatrophy), which given expected decreases in sex hormone– Organization Fracture Risk Assessment is associated with insulin resistance. binding globulin with diabetes. Further Tool (FRAX) score were associated with Individuals with HIV are at higher risk testing (such as luteinizing hormone and hip and nonspine fractures. Fracture for developing prediabetes and diabe- follicle-stimulating hormone levels) may be risk was higher in participants with di- tes on antiretroviral (ARV) therapies, so needed to distinguish between primary abetes compared with those without a screening protocol is recommended and secondary hypogonadism. diabetes for a given T score and age (69). The A1C test may underestimate or for a given FRAX score (64). Providers glycemia in people with HIV and is not should assess fracture history and risk recommended for diagnosis and may Obstructive Sleep Apnea factors in older patients with diabetes present challenges for monitoring (70). Age-adjusted rates of obstructive sleep and recommend measurement of BMD if In those with prediabetes, weight loss apnea, a risk factor for cardiovascular appropriate for the patient’s age and sex. through healthy nutrition and physical disease, are significantly higher (4- to Fracture prevention strategies for people activity may reduce the progression 10-fold) with obesity, especially with with diabetes are the same as for the toward diabetes. Among patients with central obesity (75). The prevalence of general population and include vitamin HIV and diabetes, preventive health care obstructive sleep apnea in the popula- D supplementation. For patients with using an approach similar to that used in tion with type 2 diabetes may be as high type 2 diabetes with fracture risk fac- patients without HIV is critical to reduce as 23%, and the prevalence of any sleep- tors, thiazolidinediones (65) and sodium– the risks of microvascular and macro- disordered breathing may be as high as glucose cotransporter 2 inhibitors (66) vascular complications. 58% (76,77). In obese participants en- should be used with caution. For patients with HIV and ARV- rolled in the Action for Health in Diabetes associated hyperglycemia, it may be ap- (Look AHEAD) trial, it exceeded 80% (78). Hearing Impairment propriate to consider discontinuing the Patients with symptoms suggestive of Hearing impairment, both in high fre- problematic ARV agents if safe and ef- obstructive sleep apnea (e.g., excessive quency and low/midfrequency ranges, is fective alternatives are available (71). daytime sleepiness, snoring, witnessed more common in people with diabetes Before making ARV substitutions, care- apnea) should be considered for screen- than in those without, perhaps due to fully consider the possible effect on HIV ing (79). Sleep apnea treatment (lifestyle neuropathy and/or vascular disease. In a virological control and the potential ad- modification, continuous positive airway National Health and Nutrition Examina- verse effects of new ARV agents. In some pressure, oral appliances, and surgery) tion Survey (NHANES) analysis, hearing cases, antihyperglycemia agents may significantly improves quality of life and impairment was about twice as prevalent still be necessary. blood pressure control. The evidence in people with diabetes compared with for a treatment effect on glycemic con- those without, after adjusting for age trol is mixed (80). Low Testosterone in Men and other risk factors for hearing impairment (67). Recommendation Periodontal Disease 4.17 In men with diabetes who have Periodontal disease is more severe, and symptoms or signs of hypogo- may be more prevalent, in patients with HIV nadism, such as decreased sex- diabetes than in those without (81,82). Recommendation ual desire (libido) or activity, or Current evidence suggests that perio- 4.16 Patients with HIV should be erectile dysfunction, consider dontal disease adversely affects diabetes screened for diabetes and pre- screening with a morning serum outcomes, although evidence for treat- diabetes with a fasting glucose testosterone level. B ment benefits remains controversial (24). test before starting antiretroviral therapy, atthetime ofswitch- Mean levels of testosterone are lower in Psychosocial/Emotional Disorders ing antiretroviral therapy, and menwithdiabetescomparedwithage- Prevalence of clinically significant psy- 3–6 months after starting or matched men without diabetes, but chopathology diagnoses are considerably switching antiretroviral therapy. obesity is a major confounder (72,73). more common in people with diabetes If initial screening results are Treatment in asymptomatic men is con- than in those without the disease (83). normal, checking fasting glucose troversial. Testosterone replacement in Symptoms, both clinical and subclinical, every year is advised. E men with symptomatic hypogonadism that interfere with the person’s ability to may have benefits including improved carry out daily diabetes self-management Diabetes risk is increased with certain sexual function, well-being, muscle mass tasks must be addressed. Providers should protease inhibitors (PIs) and nucleoside and strength, and bone density (74). In consider an assessment of symptoms of S42 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 42, Supplement 1, January 2019

depression, anxiety, and disordered eat- occur (90). People with diabetes who ex- and family history of type 2 diabetes ing and of cognitive capacities using hibit excessive diabetes self-management (96–98). Elevated depressive symptoms patient-appropriate standardized/validated behaviors well beyond what is prescribed and depressive disorders affect one in tools at the initial visit, at periodic in- orneededtoachieveglycemictargetsmay four patients with type 1 or type 2 di- tervals, and when there is a change in be experiencing symptoms of obsessive- abetes (99). Thus, routine screening for disease, treatment, or life circumstance. compulsive disorder (91). depressive symptoms is indicated in this Including caregivers and family members General anxiety is a predictor of high-risk population including people in this assessment is recommended. injection-related anxiety and associated with type 1 or type 2 diabetes, gesta- Diabetes distress is addressed in Section with fear of hypoglycemia (88,92). Fear tional diabetes mellitus, and postpartum 5 “Lifestyle Management,” as this state is of hypoglycemia and hypoglycemia un- diabetes. Regardless of diabetes type, very common and distinct from the psy- awareness often co-occur, and interven- women have significantly higher rates chological disorders discussed below tions aimed at treating one often benefit of depression than men (100). (84). both (93). Fear of hypoglycemia may Routine monitoring with patient- explain avoidance of behaviors associ- appropriate validated measures can help ated with lowering glucose such as in- to identify if referral is warranted. Adult Anxiety Disorders creasing insulin doses or frequency of patients with a history of depressive Recommendations monitoring. If fear of hypoglycemia is symptoms or disorder need ongoing 4.18 Consider screening for anxiety identified and a person does not have monitoring of depression recurrence in people exhibiting anxiety symptoms of hypoglycemia, a structured within the context of routine care (96). or worries regarding diabetes program of blood glucose awareness Integrating mental and physical health complications, insulin injections training delivered in routine clinical care can improve outcomes. When a or infusion, taking medications, practice can improve A1C, reduce the patient is in psychological therapy (talk and/or hypoglycemia that in- rate of severe hypoglycemia, and restore therapy), the mental health provider terfere with self-management hypoglycemia awareness (94,95). should be incorporated into the diabe- behaviors and those who ex- tes treatment team (101). press fear, dread, or irrational Depression thoughts and/or show anxiety Disordered Eating Behavior symptoms such as avoidance Recommendations behaviors, excessive repetitive 4.20 Providers should consider an- Recommendations behaviors, or social withdrawal. nual screening of all patients 4.23 Providers should consider Refer for treatment if anxiety with diabetes, especially those reevaluating the treatment reg- is present. B with a self-reported history of imen of people with diabetes 4.19 People with hypoglycemia un- depression, fordepressivesymp- who present with symptoms of awareness, which can co-occur toms with age-appropriate de- disordered eating behavior, an with fear of hypoglycemia, should pression screening measures, eating disorder, or disrupted be treated using blood glucose recognizing that further evalu- patterns of eating. B awareness training (or other ation will be necessary for in- 4.24 Consider screening for disor- evidence-based intervention) dividuals who have a positive dered or disrupted eating using to help reestablish awareness screen. B validated screening measures of hypoglycemia and reduce 4.21 Beginning at diagnosis of com- when hyperglycemia and weight fear of hypoglycemia. A plications or when there are loss are unexplained based on significant changes in medical self-reported behaviors related Anxiety symptoms and diagnosable status, consider assessment for to medication dosing, meal disorders (e.g., generalized anxiety depression. B plan, and physical activity. In disorder, body dysmorphic disorder, 4.22 Referrals for treatment of de- addition, a review of the med- obsessive-compulsive disorder, spe- pression should be made to ical regimen is recommended cific phobias, and posttraumatic stress mental health providers with to identify potential treatment- disorder) are common in people with experience using cognitive be- related effects on hunger/ diabetes (85). havioral therapy, interpersonal caloric intake. B The Behavioral Risk Factor Surveil- therapy, or other evidence- lance System (BRFSS) estimated the life- based treatment approaches Estimated prevalence of disordered eat- time prevalence of generalized anxiety in conjunction with collaborative ing behaviors and diagnosable eating disorder to be 19.5% in people with care with the patient’sdiabetes disorders in people with diabetes varies either type 1 or type 2 diabetes (86). treatment team. A (102–104). For people with type 1 di- Common diabetes-specific concerns in- abetes, insulin omission causing glycos- clude fears related to hypoglycemia (87, History of depression, current depres- uria in order to lose weight is the most 88), not meeting blood glucose targets sion, and antidepressant medication use commonly reported disordered eating (85), and insulin injections or infusion are risk factors for the development of behavior (105,106); in people with (89). Onset of complications presents type 2 diabetes, especially if the individ- type 2 diabetes, bingeing (excessive food another critical point when anxiety can ual has other risk factors such as obesity intake with an accompanying sense of care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S43

loss of control) is most commonly re- olanzapine, require greater monitoring 14. Dickinson JK, Guzman SJ, MaryniukMD, et al. ported. For people with type 2 diabe- because of an increase in risk of type 2 The use of language in diabetes care and – tes treated with insulin, intentional diabetes associated with this medica- education. Diabetes Care 2017;40:1790 1799 15. Lee SWH, Ng KY, Chin WK. The impact of omission is also frequently reported tion (113). sleep amount and sleep quality on glycemic (107). People with diabetes and diagnos- control in type 2 diabetes: a systematic review – able eating disorders have high rates of References and meta-analysis. Sleep Med Rev 2017:31:91 101 comorbid psychiatric disorders (108). 1. Stellefson M, Dipnarine K, Stopka C. The 16. Robinson CL, Romero JR, Kempe A, Pellegrini Chronic Care Model and diabetes management People with type 1 diabetes and eating C; Advisory Committee on Immunization Prac- in US primary care settings: a systematic review. disorders have high rates of diabetes tices (ACIP) Child/Adolescent Immunization Prev Chronic Dis 2013;10:E26 distress and fear of hypoglycemia (109). Work Group. Advisory Committee on Immuni- 2. Coleman K, Austin BT, Brach C, Wagner zation Practices recommended immuniza- When evaluating symptoms of disor- EH. Evidence on the Chronic Care Model in tion schedule for children and adolescents dered or disrupted eating in people the new millennium. Health Aff (Millwood) aged 18 years or youngerdUnited States, 2009;28:75–85 with diabetes, etiology and motivation 2017. MMWR Morb Mortal Wkly Rep 2017; 3. Gabbay RA, Bailit MH, Mauger DT, Wagner EH, for the behavior should be considered 66:134–135 Siminerio L. Multipayer patient-centered med- (104,110). Adjunctive medication such as 17. Kim DK, Riley LE, Harriman KH, Hunter P, ical home implementation guided by the chronic Bridges CB. Advisory Committee on Immuniza- glucagon-like peptide 1 receptor agonists care model. Jt Comm J Qual Patient Saf 2011;37: tion Practices recommended immunization (111) may help individuals not only to 265–273 schedule for adults aged 19 years or olderd 4. UK Prospective Diabetes Study (UKPDS) meet glycemic targets but also to regu- United States, 2017. MMWR Morb Mortal Wkly Group. Intensive blood-glucose control with late hunger and food intake, thus having Rep 2017;66:136–138 sulphonylureas or insulin compared with con- the potential to reduce uncontrollable ventional treatment and risk of complications in 18. Goeijenbier M, van Sloten TT, Slobbe L, et al. fi fl hunger and bulimic symptoms. patients with type 2 diabetes (UKPDS 33). Lancet Bene ts of u vaccination for persons with dia- – 1998;352:837–853 betes mellitus: a review. Vaccine 2017;35:5095 5. Nathan DM, Genuth S, Lachin J, et al.; Diabetes 5101 fl Serious Mental Illness Control and Complications Trial Research Group. 19. Smith SA, Poland GA. Use of in uenza and The effect of intensive treatment of diabetes pneumococcal vaccines in people with diabetes. – Recommendations on the development and progression of long- Diabetes Care 2000;23:95 108 4.25 Annually screen people who term complications in insulin-dependent diabe- 20. Selvin E, Coresh J, Brancati FL. The burden tes mellitus. N Engl J Med 1993;329:977–986 and treatment of diabetes in elderly individ- are prescribed atypical antipsy- – 6. Lachin JM, Genuth S, Nathan DM, Zinman B, uals in the U.S. Diabetes Care 2006;29:2415 chotic medications for predia- 2419 betes or diabetes. B Rutledge BN; DCCT/EDIC Research Group. Effect of glycemic exposure on the risk of microvascu- 21. Grant RW, Ashburner JM, Hong CS, Chang Y, 4.26 If a second-generation antipsy- lar complications in the Diabetes Control and Barry MJ, Atlas SJ. Defining patient complexity chotic medication is prescribed Complications Trialdrevisited. Diabetes 2008; from the primary care physician’s perspective: for adolescents or adults with 57:995–1001 a cohort study [published correction appears in Ann Intern Med 2012;157:152]. Ann Intern diabetes, changes in weight, 7. White NH, Cleary PA, Dahms W, Goldstein D, Malone J, Tamborlane WV; Diabetes Control Med 2011;155:797–804 glycemic control, and choles- and Complications Trial (DCCT)/Epidemiology 22. Tinetti ME, Fried TR, Boyd CM. Design- terol levels should be carefully of Diabetes Interventions and Complications ing health care for the most common chronic monitored and the treatment (EDIC) Research Group. Beneficial effects of in- conditiondmultimorbidity. JAMA 2012;307:2493– regimen should be reassessed. C tensive therapy of diabetes during adolescence: 2494 23. Sudore RL, Karter AJ, Huang ES, et al. Symp- 4.27 Incorporate monitoring of dia- outcomes after the conclusion of the Diabetes Control and Complications Trial (DCCT). J Pediatr tom burden of adults with type 2 diabetes across betes self-care activities into 2001;139:804–812 the disease course: Diabetes & Aging Study. J treatment goals in people with 8. Anderson RM, Funnell MM. Compliance Gen Intern Med 2012;27:1674–1681 diabetes and serious mental and adherence are dysfunctional concepts in 24. Borgnakke WS, Ylostalo¨ PV, Taylor GW, illness. B diabetes care. Diabetes Educ 2000;26:597–604 Genco RJ. Effect of periodontal disease on di- 9. Sarkar U, Fisher L, Schillinger D. Is self-efficacy abetes: systematic review of epidemiologic ob- associated with diabetes self-management ac- servational evidence. J Periodontol 2013;84 Studies of individuals withserious mental ross race/ethnicity and health literacy? Diabetes (Suppl.):S135–S152 illness, particularly schizophrenia and Care 2006;29:823–829 25. Triolo TM, Armstrong TK, McFann K, et al. other thought disorders, show signifi- 10. King DK, Glasgow RE, Toobert DJ, et al. Self- Additional autoimmune disease found in 33% cantly increased rates of type 2 diabetes efficacy, problem solving, and social-environmental of patients at type 1 diabetes onset. Diabetes – (112). People with schizophrenia should support are associated with diabetes self- Care 2011;34:1211 1213 management behaviors. Diabetes Care 2010; 26. HughesJW,RiddlesworthTD, DiMeglioLA, bemonitoredfortype2diabetes because 33:751–753 Miller KM, Rickels MR, McGill JB. Autoimmune of the known comorbidity. Disordered 11. Nouwen A, Urquhart Law G, Hussain S, diseases in children and adults with type 1 thinking and judgment can be expected McGovern S, Napier H. Comparison of the diabetes from the T1D Exchange Clinic Reg- to make it difficult to engage in behaviors role of self-efficacy and illness representations istry. J Clin Endocrinol Metab 2016;101:4931– that reduce risk factors for type 2 di- in relation to dietary self-care and diabetes 4937 distress in adolescents with type 1 diabetes. 27. Kahaly GJ, Hansen MP. Type 1 diabetes abetes, such as restrained eating for Psychol Health 2009;24:1071–1084 associated autoimmunity. Autoimmun Rev weight management. Coordinated man- 12. Beckerle CM, Lavin MA. Association of 2016;15:644–648 agement of diabetes or prediabetes and self-efficacy and self-care with glycemic control 28. Eisenbarth GS, Gottlieb PA. Autoimmune serious mental illness is recommended to in diabetes. Diabetes Spectr 2013;26:172–178 polyendocrine syndromes. N Engl J Med 2004; 13. Iannotti RJ, Schneider S, Nansel TR, et al. 350:2068–2079 achieve diabetes treatment targets. In Self-efficacy, outcome expectations, and diabetes 29. Suh S, Kim K-W. Diabetes and cancer: is addition, those taking second-genera- self-management in adolescents with type 1 di- diabetes causally related to cancer? Diabetes tion (atypical) antipsychotics, such as abetes. J Dev Behav Pediatr 2006;27:98–105 Metab J 2011;35:193–198 S44 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 42, Supplement 1, January 2019

30. Giovannucci E, Harlan DM, Archer MC, et al. medical position statement: nonalcoholic fatty 59. Quartuccio M, Hall E, Singh V, et al. Glycemic Diabetes and cancer: a consensus report. CA liver disease. Gastroenterology 2002;123:1702– predictors of insulin independence after to- Cancer J Clin 2010;60:207–221 1704 tal pancreatectomy with islet autotransplanta- 31. Aggarwal G, Kamada P, Chari ST. Prevalence 45. Cusi K, Orsak B, Bril F, et al. Long-term tion. J Clin Endocrinol Metab 2017;102:801–809 of diabetes mellitus in pancreatic cancer com- pioglitazone treatment for patients with non- 60. Webb MA, Illouz SC, Pollard CA, et al. Islet pared to common cancers. Pancreas 2013;42: alcoholic steatohepatitis and prediabetes or auto transplantation following total pancreatec- 198–201 type 2 diabetes mellitus: a randomized trial. tomy: a long-term assessment of graft func- 32. Cukierman T, Gerstein HC, Williamson JD. Ann Intern Med 2016;165:305–315 tion. Pancreas 2008;37:282–287 Cognitive decline and dementia in diabetesd 46. Belfort R, Harrison SA, Brown K, et al. A 61. Wu Q, Zhang M, Qin Y, et al. Systematic systematic overview of prospective observational placebo-controlled trial of pioglitazone in sub- review and meta-analysis of islet autotransplan- studies. Diabetologia 2005;48:2460–2469 jects with nonalcoholic steatohepatitis. N Engl J tation after total pancreatectomy in chronic 33. Biessels GJ, Staekenborg S, Brunner E, Med 2006;355:2297–2307 pancreatitis patients. Endocr J 2015;62:227–234 Brayne C, Scheltens P. Risk of dementia in di- 47. Sanyal AJ, Chalasani N, Kowdley KV, et al.; 62. Janghorbani M, Van Dam RM, Willett WC, abetes mellitus: a systematic review. Lancet NASH CRN. Pioglitazone, vitamin E, or placebo Hu FB. Systematic review of type 1 and type 2 Neurol 2006;5:64–74 for nonalcoholic steatohepatitis. N Engl J Med diabetes mellitus and risk of fracture. Am J 34. Gudala K, Bansal D, Schifano F, Bhansali A. 2010;362:1675–1685 Epidemiol 2007;166:495–505 Diabetes mellitus and risk of dementia: a meta- 48. Armstrong MJ, Gaunt P, Aithal GP, et al.; 63. Vestergaard P. Discrepancies in bone min- analysis of prospective observational studies. LEAN Trial Team. Liraglutide safety and efficacy eral density and fracture risk in patients with J Diabetes Investig 2013;4:640–650 in patients with non-alcoholic steatohepatitis type 1 and type 2 diabetesda meta-analysis. 35. Ohara T, Doi Y, Ninomiya T, et al. Glucose (LEAN):amulticentre,double-blind, randomised, Osteoporos Int 2007;18:427–444 tolerance status and risk of dementia in the placebo-controlled phase 2 study. Lancet 2016; 64. Schwartz AV, Vittinghoff E, Bauer DC, et al.; community: the Hisayama study. Neurology 387:679–690 Study of Osteoporotic Fractures (SOF) Research 2011;77:1126–1134 49. Shimizu M, Suzuki K, Kato K, et al. Evaluation Group; Osteoporotic Fractures in Men (MrOS) 36. Cukierman-Yaffe T, Gerstein HC, Williamson of the effects of dapagliflozin, a sodium-glucose Research Group; Health, Aging, and Body Com- JD, et al.; Action to Control Cardiovascular Risk in co-transporter-2 inhibitor, on hepatic steatosis position (Health ABC) Research Group. Asso- Diabetes-Memory in Diabetes (ACCORD-MIND) and fibrosis using transient elastography in pa- ciation of BMD and FRAX score with risk of Investigators. Relationship between baseline tients with type 2 diabetes and non-alcoholic fracture in older adults with type 2 diabetes. glycemic control and cognitive function in fatty liver disease. Diabetes Obes Metab. 3 Sep- JAMA 2011;305:2184–2192 individuals with type 2 diabetes and other car- tember 2018 [Epub ahead of print]. DOI: 10.1111/ 65. Kahn SE, Zinman B, Lachin JM, et al.; A diovascular risk factors: the Action to Control dom.13520 Diabetes Outcome Progression Trial (ADOPT) Cardiovascular Risk in Diabetes-Memory in Di- 50. Sattar N, Fitchett D, Hantel S, George JT, Study Group. Rosiglitazone-associated fractures abetes (ACCORD-MIND) trial. Diabetes Care Zinman B. Empagliflozin is associated with im- in type 2 diabetes: an analysis from A Diabetes 2009;32:221–226 provements in liver enzymes potentially consis- Outcome Progression Trial (ADOPT). Diabetes 37. Launer LJ, Miller ME, Williamson JD, et al.; tent with reductions in liver fat: results from Care 2008;31:845–851 ACCORD MIND Investigators. Effects of inten- randomised trials including the EMPA-REG 66. Taylor SI, Blau JE, Rother KI. Possible adverse sive glucose lowering on brain structure and OUTCOME trial. Diabetologia 2018;61:2155–2163 effects of SGLT2 inhibitors on bone. Lancet Di- function in people with type 2 diabetes (ACCORD 51. Hardt PD, Brendel MD, Kloer HU, Bretzel RG. abetes Endocrinol 2015;3:8–10 MIND): a randomised open-label substudy. Lan- Is pancreatic diabetes (type 3c diabetes) under- 67. Bainbridge KE, Hoffman HJ, Cowie CC. Di- cet Neurol 2011;10:969–977 diagnosed and misdiagnosed? Diabetes Care abetes and hearing impairment in the United 38. Whitmer RA, Karter AJ, Yaffe K, Quesenberry 2008;31(Suppl. 2):S165–S169 States: audiometric evidence from the National CP Jr, Selby JV. Hypoglycemic episodes and risk 52. Lee Y-K, Huang M-Y, Hsu C-Y, Su Y-C. Bi- Health and Nutrition Examination Survey, 1999 of dementia in older patients with type 2 di- directional relationship between diabetes and to 2004. Ann Intern Med 2008;149:1–10 abetes mellitus. JAMA 2009;301:1565–1572 acute pancreatitis: a population-based cohort 68. Monroe AK, Glesby MJ, Brown TT. Diagnos- 39. Punthakee Z, Miller ME, Launer LJ, et al.; study in Taiwan. Medicine (Baltimore) 2016;95: ing and managing diabetes in HIV-infected pa- ACCORD Group of Investigators; ACCORD-MIND e2448 tients: current concepts. Clin Infect Dis 2015; Investigators. Poor cognitive function and risk 53. Das SLM, Singh PP, Phillips ARJ, Murphy R, 60:453–462 of severe hypoglycemia in type 2 diabetes: post Windsor JA, Petrov MS. Newly diagnosed di- 69. Schambelan M, Benson CA, Carr A, et al.; hoc epidemiologic analysis of the ACCORD trial. abetes mellitus after acute pancreatitis: a sys- International AIDS Society-USA. Management Diabetes Care 2012;35:787–793 tematic review and meta-analysis. Gut 2014;63: of metabolic complications associated with anti- 40. Scarmeas N, Stern Y, Mayeux R, Manly JJ, 818–831 retroviral therapy for HIV-1 infection: recom- Schupf N, Luchsinger JA. Mediterranean diet 54. Petrov MS. Diabetes of the exocrine pan- mendations of an International AIDS Society- and mild cognitive impairment. Arch Neurol creas: American Diabetes Association-compliant USA panel. J Acquir Immune Defic Syndr 2002; 2009;66:216–225 lexicon. Pancreatology 2017;17:523–526 31:257–275 41. Ooi CP, Loke SC, Yassin Z, Hamid T-A. Car- 55. Thomsen RW, Pedersen L, Møller N, Kahlert 70. Kim PS, Woods C, Georgoff P, et al. A1C bohydrates for improving the cognitive perfor- J, Beck-Nielsen H, Sørensen HT. Incretin-based underestimates glycemia in HIV infection. Di- mance of independent-living older adults with therapy and risk of acute pancreatitis: a nation- abetes Care 2009;32:1591–1593 normal cognition or mild cognitive impairment. wide population-based case-control study. Di- 71. Wohl DA, McComsey G, Tebas P, et al. Cochrane Database Syst Rev 2011;4:CD007220 abetes Care 2015;38:1089–1098 Current concepts in the diagnosis and manage- 42. Richardson K, Schoen M, French B, et al. 56. Tkaćˇ I, Raz I. Combined analysis of three ment of metabolic complications of HIV infection Statins and cognitive function: a systematic re- large interventional trials with gliptins indicates and its therapy. Clin Infect Dis 2006;43:645–653 view. Ann Intern Med 2013;159:688–697 increased incidence of acute pancreatitis in 72. Dhindsa S, Miller MG, McWhirter CL, et al. 43. El-Serag HB, Tran T, Everhart JE. Diabetes patients with type 2 diabetes. Diabetes Care Testosterone concentrations in diabetic and increases the risk of chronic liver disease and 2017;40:284–286 nondiabetic obese men. Diabetes Care 2010; hepatocellular carcinoma. Gastroenterology 57. Bellin MD, Gelrud A, Arreaza-Rubin G, et al. 33:1186–1192 2004;126:460–468 Total pancreatectomy with islet autotransplan- 73. Grossmann M. Low testosterone in men 43a. Chalasani N, Younossi Z, Lavine JE, et al. tation: summary of an NIDDK workshop. Ann with type 2 diabetes: significance and treatment. The diagnosis and management of nonalcoholic Surg 2015;261:21–29 J Clin Endocrinol Metab 2011;96:2341–2353 fatty liver disease: practice guidance from the 58. Sutherland DER, Radosevich DM, Bellin 74. Bhasin S, Cunningham GR, Hayes FJ, et al.; American Association for the Study of Liver MD, et al. Total pancreatectomy and islet Endocrine Society Task Force. Testosterone ther- Diseases. Hepatology 2018;67:328–357 autotransplantation for chronic pancreatitis. J apy in men with androgen deficiency syndromes: 44. American Gastroenterological Association. Am Coll Surg 2012;214:409–424; discussion an Endocrine Society clinical practice guideline. J American Gastroenterological Association 424–426 Clin Endocrinol Metab 2010;95:2536–2559 care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S45

75. Li C, Ford ES, Zhao G, Croft JB, Balluz LS, 90. Young-Hyman D, Peyrot M. Psychoso- 105. Pinhas-Hamiel O, Hamiel U, Greenfield Y, Mokdad AH. Prevalence of self-reported clini- cial Care for People with Diabetes. Alexandria, et al. Detecting intentional insulin omission for cally diagnosed sleep apnea according to obesity VA, American Diabetes Association, 2012 weight loss in girls with type 1 diabetes mellitus. status in men and women: National Health and 91. American Psychiatric Association. Diagnos- Int J Eat Disord 2013;46:819–825 Nutrition Examination Survey, 2005–2006. Prev tic and Statistical Manual of Mental Disorders, 106. Goebel-Fabbri AE, Fikkan J, Franko DL, Med 2010;51:18–23 Fifth Edition [Internet], 2013. Available from Pearson K, Anderson BJ, Weinger K. Insulin re- 76. West SD, Nicoll DJ, Stradling JR. Prevalence http://psychiatryonline.org/doi/book/10.1176/ striction and associated morbidity and mortality of obstructive sleep apnoea in men with type 2 appi.books.9780890425596. Accessed 9 Novem- in women with type 1 diabetes. Diabetes Care diabetes. Thorax 2006;61:945–950 ber 2018 2008;31:415–419 77. Resnick HE, Redline S, Shahar E, et al.; Sleep 92. Mitsonis C, Dimopoulos N, Psarra V. P01-138 107. Weinger K, Beverly EA. Barriers to achiev- Heart Health Study. Diabetes and sleep distur- Clinical implications of anxiety in diabetes: a crit- ing glycemic targets: who omits insulin and why? bances: findings from the Sleep Heart Health ical review of the evidence base (abstract). Eur Diabetes Care 2010;33:450–452 Study. Diabetes Care 2003;26:702–709 Psychiatry 2009;24(Suppl. 1):S526 108. Hudson JI, Hiripi E, Pope HG Jr, Kessler RC. 78. Foster GD, Sanders MH, Millman R, et al.; 93. Yeoh E, Choudhary P, Nwokolo M, Ayis S, The prevalence and correlates of eating dis- Sleep AHEAD Research Group. Obstructive sleep Amiel SA. Interventions that restore awareness orders in the National Comorbidity Survey Rep- apnea among obese patients with type 2 di- of hypoglycemia in adults with type 1 diabetes: lication. Biol Psychiatry 2007;61:348–358 abetes. Diabetes Care 2009;32:1017–1019 a systematic review and meta-analysis. Diabetes 109. Martyn-Nemeth P, Quinn L, Hacker E, Park 79. Bibbins-Domingo K, Grossman DC, Curry SJ, Care 2015;38:1592–1609 H, Kujath AS. Diabetes distress may adversely et al.; US Preventive Services Task Force. Screen- 94. Cox DJ, Gonder-Frederick L, Polonsky W, affect the eating styles of women with type 1 ing for obstructive sleep apnea in adults: US Schlundt D, Kovatchev B, Clarke W. Blood glucose diabetes. Acta Diabetol 2014;51:683–686 Preventive Services Task Force recommendation awarenesstraining(BGAT-2):long-term benefits. 110. Peterson CM, Fischer S, Young-Hyman D. statement. JAMA 2017;317:407–414 Diabetes Care 2001;24:637–642 Topical review: a comprehensive risk model 80. Shaw JE, Punjabi NM, Wilding JP, Alberti 95. Gonder-Frederick LA, Schmidt KM, Vajda KA, for disordered eating in youth with type 1 di- KGMM, Zimmet PZ; International Diabetes Fed- et al. Psychometric properties of the hypogly- abetes. J Pediatr Psychol 2015;40:385–390 eration Taskforce on Epidemiology and Preven- cemia fear survey-II for adults with type 1 di- 111. Garber AJ. Novel GLP-1 receptor agonists tion. Sleep-disordered breathing and type 2 abetes. Diabetes Care 2011;34:801–806 for diabetes. Expert Opin Investig Drugs 2012; diabetes: a report from the International Diabetes 96. Lustman PJ, Griffith LS, Clouse RE. Depres- 21:45–57 Federation Taskforce on Epidemiology and Pre- sion in adults with diabetes. Results of 5-yr 112. Suvisaari J, Peral¨ a¨ J, Saarni SI, et al. Type vention. Diabetes Res Clin Pract 2008;81:2–12 follow-up study. Diabetes Care 1988;11:605– 2 diabetes among persons with schizophrenia 81. Khader YS, Dauod AS, El-Qaderi SS, Alkafajei 612 and other psychotic disorders in a general pop- A, Batayha WQ. Periodontal status of diabetics 97. de Groot M, Crick KA, Long M, Saha C, ulation survey. Eur Arch Psychiatry Clin Neurosci compared with nondiabetics: a meta-analysis. Shubrook JH. Lifetime duration of depressive 2008;258:129–136 J Diabetes Complications 2006;20:59–68 disorders in patients with type 2 diabetes. Di- 113. Koro CE, Fedder DO, L’Italien GJ, et al. 82. Casanova L, Hughes FJ, Preshaw PM. Di- abetes Care 2016;39:2174–2181 Assessment of independent effect of olanzapine abetes and periodontal disease: a two-way re- 98. Rubin RR, Ma Y, Marrero DG, et al.; Diabetes and risperidone on risk of diabetes among lationship. Br Dent J 2014;217:433–437 Prevention Program Research Group. Elevated patients with schizophrenia: population based 83. de Groot M, Golden SH, Wagner J. Psycho- depression symptoms, antidepressant medicine nested case-control study. BMJ 2002;325:243 logical conditions in adults with diabetes. Am use, and risk of developing diabetes during the 114. Lipska KJ, Ross JS, Wang Y, et al. National Psychol 2016;71:552–562 Diabetes Prevention Program. Diabetes Care trends in US hospital admissions for hypergly- 84. Young-Hyman D, de Groot M, Hill-Briggs F, 2008;31:420–426 cemia and hypoglycemia among Medicare ben- Gonzalez JS, Hood K, Peyrot M. Psychosocial 99. Anderson RJ, Freedland KE, Clouse RE, eficiaries, 1999 to 2011. JAMA Intern Med 2014; care for people with diabetes: a position state- Lustman PJ. The prevalence of comorbid de- 174:1116–1124 ment of the American Diabetes Association. pression in adults with diabetes: a meta-analysis. 115. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Diabetes Care 2016;39:2126–2140 Diabetes Care 2001;24:1069–1078 Incidence and risk factors for serious hypogly- 85. Smith KJ, Beland´ M, Clyde M, et al. Associ- 100. Clouse RE, Lustman PJ, Freedland KE, cemia in older persons using insulin or sulfonyl- ation of diabetes with anxiety: a systematic re- Griffith LS, McGill JB, Carney RM. Depression ureas. Arch Intern Med 1997;157:1681–1686 view and meta-analysis. J Psychosom Res 2013; and coronary heart disease in women with di- 116. Abdelhafiz AH, Rodr´ıguez-Manas~ L, Morley 74:89–99 abetes. Psychosom Med 2003;65:376–383 JE, Sinclair AJ. Hypoglycemia in older people - a 86. Li C, Barker L, Ford ES, Zhang X, Strine TW, 101. Katon WJ, Lin EHB, Von Korff M, et al. less well recognized risk factor for frailty. Aging Mokdad AH. Diabetes and anxiety in US adults: Collaborative care for patients with depression Dis 2015;6:156–167 findings from the 2006 Behavioral Risk Factor and chronic illnesses. N Engl J Med 2010;363: 117. Yun J-S, Ko S-H, Ko S-H, et al. Presence of Surveillance System. Diabet Med 2008;25:878–881 2611–2620 macroalbuminuria predicts severe hypoglyce- 87. Cox DJ, Irvine A, Gonder-Frederick L, 102. Pinhas-Hamiel O, Hamiel U, Levy-Shraga Y. mia in patients with type 2 diabetes: a 10-year Nowacek G, Butterfield J. Fear of hypoglycemia: Eating disorders in adolescents with type 1 di- follow-up study. Diabetes Care 2013;36:1283– quantification, validation, and utilization. Diabe- abetes: challenges in diagnosis and treatment. 1289 tes Care 1987;10:617–621 World J Diabetes 2015;6:517–526 118. Chelliah A, Burge MR. Hypoglycaemia in 88. Wild D, von Maltzahn R, Brohan E, 103. PapelbaumM,Appolinario´ JC, Moreira RdeO, elderly patients with diabetes mellitus: causes Christensen T, Clauson P, Gonder-Frederick L. Ellinger VCM, Kupfer R, Coutinho WF. Prevalence and strategies for prevention. Drugs Aging 2004; A critical review of the literature on fear of of eating disorders and psychiatric comorbidity 21:511–530 hypoglycemia in diabetes: implications for in a clinical sample of type 2 diabetes mellitus 119. Davies MJ, D’Alessio DA, Fradkin J, et al. diabetes management and patient education. patients. Rev Bras Psiquiatr 2005;27:135–138 Management of hyperglycemia in type 2 diabe- Patient Educ Couns 2007;68:10–15 104. Young-Hyman DL, Davis CL. Disordered tes, 2018. A consensus report by the American 89. Zambanini A, Newson RB, Maisey M, Feher eating behavior in individuals with diabetes: Diabetes Association (ADA) and the European MD. Injection related anxiety in insulin-treated importance of context, evaluation, and classifi- Association for the Study of Diabetes (EASD). diabetes. Diabetes Res Clin Pract 1999;46:239–246 cation. Diabetes Care 2010;33:683–689 Diabetes Care 2018;41:2669–2701 S46 Diabetes Care Volume 42, Supplement 1, January 2019

5. Lifestyle Management: American Diabetes Association Standards of Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S46–S60 | https://doi.org/10.2337/dc19-S005

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence- grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. 5. LIFESTYLE MANAGEMENT Lifestyle management is a fundamental aspect of diabetes care and includes diabetes self-management education and support (DSMES), medical nutrition therapy (MNT), physical activity, smoking cessation counseling, and psychosocial care. Patients and care providers should focus together on how to optimize lifestyle from the time of the initial comprehensive medical evaluation, throughout all subsequent evaluations and follow-up, and during the assessment of complications and management of comorbid conditions in order to enhance diabetes care.

DIABETES SELF-MANAGEMENT EDUCATION AND SUPPORT

Recommendations 5.1 In accordance with the national standards for diabetes self-management education and support, all people with diabetes should participate in diabetes self-management education to facilitate the knowledge, skills, and ability necessary for diabetes self-care. Diabetes self-management support is additionally recommended to assist with implementing and sustaining skills and behaviors needed for ongoing self-management. B 5.2 There are four critical times to evaluate the need for diabetes self- management education and support: at diagnosis, annually, when complicating factors arise, and when transitions in care occur. E 5.3 Clinical outcomes, health status, and quality of life are key goals of diabetes self-management education and support that should be measured as part of Suggested citation: American Diabetes Associa- C tion. 5. Lifestyle management: Standards of routine care. d 5.4 Medical Care in Diabetes 2019. Diabetes Care Diabetes self-management education and support should be patient cen- 2019;42(Suppl. 1):S46–S60 tered, may be given in group or individual settings or using technology, and © 2018 by the American Diabetes Association. should be communicated with the entire diabetes care team. A Readers may use this article as long as the work is 5.5 Because diabetes self-management education and support can improve properly cited, the use is educational and not outcomes and reduce costs B, adequate reimbursement by third-party payers for proﬁt, and the work is not altered. More infor- is recommended. E mation is available at http://www.diabetesjournals .org/content/license. care.diabetesjournals.org Lifestyle Management S47

DSMES services facilitate the knowledge, 3. When new complicating factors diabetes management (BC-ADM) certifi- skills, and abilities necessary for optimal (health conditions, physical limita- cation demonstrates specialized training diabetes self-care and incorporate the tions, emotional factors, or basic and mastery of a specificbodyofknowl- needs, goals, and life experiences of the living needs) arise that influence edge (4). Additionally, there is growing person with diabetes. The overall objec- self-management evidence for the role of community tives of DSMES are to support informed 4. When transitions in care occur health workers (36,37), as well as peer decision making, self-care behaviors, (36–40) and lay leaders (41), in providing problem-solving, and active collabora- DSMES focuses on supporting patient ongoing support. tion with the health care team to improve empowerment by providing people with DSMES is associated with an increased clinical outcomes, health status, and diabetes the tools to make informed self- use of primary care and preventive ser- quality of life in a cost-effective manner management decisions (6). Diabetes care vices (18,42,43) and less frequent use of (1). Providers are encouraged to consider has shifted to an approach that places acute care and inpatient hospital services the burden of treatment and the pa- thepersonwithdiabetesandhisorher (12). Patients who participate in DSMES tient’s level of confidence/self-efficacy family at the center of the care model, are more likely to follow best practice for management behaviors as well as the working in collaboration with health care treatment recommendations, particu- level of social and family support when professionals. Patient-centered care is re- larly among the Medicare population, providing DSMES. Patient performance spectful of and responsive to individual and have lower Medicare and insurance of self-management behaviors, including patient preferences, needs, and values. claim costs (19,42). Despite these bene- its effect on clinical outcomes, health It ensures that patient values guide all fits, reports indicate that only 5–7% of status, and quality of life, as well as the decision making (7). individuals eligible for DSMES through psychosocial factors impacting the per- Medicare or a private insurance plan son’s self-management should be mon- Evidence for the Benefits actually receive it (44,45). This low par- itored as part of routine clinical care. Studies have found that DSMES is asso- ticipation may be due to lack of referral or In addition, in response to the growing ciated with improved diabetes knowl- other identified barriers such as logistical literature that associates potentially judg- edge and self-care behaviors (8), lower issues (timing, costs) and the lack of a mental words with increased feelings of A1C (7,9–11), lower self-reported weight perceived benefit (46). Thus, in addition shame and guilt, providers are encouraged (12,13), improved quality of life (10,14), to educating referring providers about to consider the impact that language has reduced all-cause mortality risk (15), the benefits of DSMES and the critical on building therapeutic relationships and healthy coping (16,17), and reduced times to refer (1), alternative and in- to choose positive, strength-based words health care costs (18–20). Better out- novative models of DSMES delivery and phrases that put people first (2,3). Pa- comes were reported for DSMES inter- need to be explored and evaluated. tient performance of self-management ventions that were over 10 h in total behaviors as well as psychosocial factors duration (11), included ongoing support Reimbursement impacting the person’s self-management (5,21), were culturally (22,23) and age Medicare reimburses DSMES when that should be monitored. Please see Section appropriate (24,25), were tailored to service meets the national standards 4, “Comprehensive Medical Evaluation individual needs and preferences, and ad- (1,4) and is recognized by the American and Assessment of Comorbidities,” for dressed psychosocial issues and incorpo- Diabetes Association (ADA) or other ap- more on use of language. rated behavioral strategies (6,16,26,27). proval bodies. DSMES is also covered by DSMES and the current national stan- Individual and group approaches are most health insurance plans. Ongoing dards guiding it (1,4) are based on evi- effective (13,28,29), with a slight benefit support has been shown to be instru- dence of benefit. Specifically, DSMES realized by those who engage in both mental for improving outcomes when it helps people with diabetes to identify (11). Emerging evidence demonstrates is implemented after the completion of and implement effective self-manage- the benefit of Internet-based DSMES education services. DSMES is frequently ment strategies and cope with diabetes services for diabetes prevention and reimbursed when performed in person. at the four critical time points (described the management of type 2 diabetes However, although DSMES can also be below) (1). Ongoing DSMES helps people (30–32). Technology-enabled diabe- provided via phone calls and telehealth, with diabetes to maintain effective self- tes self-management solutions improve these remote versions may not always management throughout a lifetime of A1C most effectively when there is be reimbursed. Changes in reimburse- diabetes as they face new challenges two-way communication between the ment policies that increase DSMES ac- and as advances in treatment become patient and the health care team, individ- cess and utilization will result in a positive available (5). ualized feedback, use of patient-generated impact to beneficiaries’ clinical outcomes, Four critical time points have been health data, and education (32). Current quality of life, health care utilization, and defined when the need for DSMES is to research supports nurses, dietitians, and costs (47). be evaluated by the medical care pro- pharmacists as providers of DSMES who vider and/or multidisciplinary team, with may also develop curriculum (33–35). NUTRITION THERAPY referrals made as needed (1): Members of the DSMES team should For many individuals with diabetes, the have specialized clinical knowledge in most challenging part of the treat- 1. At diagnosis diabetes and behavior change principles. ment plan is determining what to eat and 2. Annually for assessment of education, Certification as a certified diabetes ed- following a meal plan. There is not a one- nutrition, and emotional needs ucator (CDE) or board certified-advanced size-fits-all eating pattern for individuals S48 Lifestyle Management Diabetes Care Volume 42, Supplement 1, January 2019

with diabetes, and meal planning should carbohydrate, protein, and fat for all peo- support one eating plan over another be individualized. Nutrition therapy has ple with diabetes. Therefore, macronu- at this time. an integral role in overall diabetes man- trient distribution should be based on A simple and effective approach to agement, and each person with diabetes an individualized assessment of current glycemia and weight management em- should be actively engaged in education, eating patterns, preferences, and meta- phasizing portion control and healthy self-management, and treatment plan- bolic goals. Consider personal preferen- food choices should be considered for ning with his or her health care team, ces (e.g., tradition, culture, religion, those with type 2 diabetes who are not including the collaborative development health beliefs and goals, economics) as taking insulin, who have limited health of an individualized eating plan (35,48). well as metabolic goals when working literacy or numeracy, or who are older All individuals with diabetes should be with individuals to determine the best and prone to hypoglycemia (50). The offered a referral for individualized MNT eating pattern for them (35,51,52). It is diabetes plate method is commonly provided by a registered dietitian (RD) important that each member of the used for providing basic meal planning who is knowledgeable and skilled in health care team be knowledgeable guidance (67) as it provides a visual guide providing diabetes-specific MNT (49). about nutrition therapy principles for showing how to control calories (by MNT delivered by an RD is associated people with all types of diabetes and featuring a smaller plate) and carbohy- with A1C decreases of 1.0–1.9% for peo- be supportive of their implementation. drates (by limiting them to what fits in ple with type 1 diabetes (50) and 0.3–2% Emphasis should be on healthful eat- one-quarter of the plate) and puts an for people with type 2 diabetes (50). See ing patterns containing nutrient-dense emphasis on low-carbohydrate (or non- Table 5.1 for specific nutrition recom- foods, with less focus on specific nu- starchy) vegetables. mendations. Because of the progres- trients (53). A variety of eating patterns sive nature of type 2 diabetes, lifestyle are acceptable for the management of Weight Management changes alone may not be adequate to diabetes (51,54), and a referral to an RD Management and reduction of weight is maintain euglycemia over time. How- or registered dietitian nutritionist (RDN) important for people with type 1 dia- ever, after medication is initiated, nutri- is essential to assess the overall nutrition betes, type 2 diabetes, or prediabetes tion therapy continues to be an important status of, and to work collaboratively who have overweight or obesity. Life- component and should be integrated with, the patient to create a personalized style intervention programs should be with the overall treatment plan (48). meal plan that considers the individual’s intensive and have frequent follow-up health status, skills, resources, food pref- to achieve significant reductions in ex- Goals of Nutrition Therapy for Adults erences, and health goals to coordinate cess body weight and improve clinical With Diabetes and align with the overall treatment indicators. There is strong and consis- 1. To promote and support healthful plan including physical activity and med- tent evidence that modest persistent eating patterns, emphasizing a variety ication. The Mediterranean (55,56), Di- weight loss can delay the progression of nutrient-dense foods in appropri- etary Approaches to Stop Hypertension from prediabetes to type 2 diabetes ate portion sizes, to improve overall (DASH) (57–59), and plant-based (60,61) (51,68,69) (see Section 3 “Prevention health and: diets are all examples of healthful eat- or Delay of Type 2 Diabetes”)andis ○ Achieve and maintain body weight ing patterns that have shown positive beneficial to the management of type goals results in research, but individualized 2 diabetes (see Section 8 “Obesity ○ Attain individualized glycemic, meal planning should focus on per- Management for the Treatment of blood pressure, and lipid goals sonal preferences, needs, and goals. In Type 2 Diabetes”). ○ Delay or prevent the complica- addition, research indicates that low- Studies of reduced calorie interventions of diabetes carbohydrate eating plans may result in tions show reductions in A1C of 0.3% 2. To address individual nutrition needs improved glycemia and have the poten- to 2.0% in adults with type 2 diabetes, based on personal and cultural pref- tial to reduce antihyperglycemic medi- as well as improvements in medication erences, health literacy and numeracy, cations for individuals with type 2 doses and quality of life (50,51). Sustain- access to healthful foods, willing- diabetes (62–64). As research studies ing weight loss can be challenging (70,71) ness and ability to make behavioral on some low-carbohydrate eating plans but has long-term benefits; maintaining changes, and barriers to change generally indicate challenges with long- weight loss for 5 years is associated with 3. To maintain the pleasure of eating by term sustainability, it is important to sustained improvements in A1C and lipid providing nonjudgmental messages reassess and individualize meal plan levels (72). Weight loss can be attained about food choices guidance regularly for those interested with lifestyle programs that achieve a 4. To provide an individual with diabe- in this approach. This meal plan is not 500–750 kcal/day energy deficit or pro- tes the practical tools for developing recommended at this time for women vide ;1,200–1,500 kcal/day for women healthy eating patterns rather than who are pregnant or lactating, people and 1,500–1,800 kcal/day for men, focusing on individual macronutrients, with or at risk for disordered eating, or adjusted for the individual’s baseline micronutrients, or single foods people who have renal disease, and it body weight. For many obese individ- should be used with caution in patients uals with type 2 diabetes, weight loss Eating Patterns, Macronutrient taking sodium–glucose cotransporter of at least 5% is needed to produce Distribution, and Meal Planning 2 (SGLT2) inhibitors due to the potential beneficial outcomes in glycemic con- Evidence suggests that there is not risk of ketoacidosis (65,66). There is in- trol, lipids, and blood pressure (70). an ideal percentage of calories from adequate research in type 1 diabetes to It should be noted, however, that the care.diabetesjournals.org Lifestyle Management S49

Table 5.1—Medical nutrition therapy recommendations Topic Recommendations Evidence rating Effectiveness of 5.6 An individualized medical nutrition therapy program as needed to achieve treatment goals, A nutrition therapy preferably provided by a registered dietitian, is recommended for all people with type 1 or type 2 diabetes, prediabetes, and gestational diabetes mellitus. 5.7 A simple and effective approach to glycemia and weight management emphasizing portion control B and healthy food choices may be considered for those with type 2 diabetes who are not taking insulin, who have limited health literacy or numeracy, or who are older and prone to hypoglycemia. 5.8 Because diabetes nutrition therapy can result in cost savings B and improved outcomes (e.g., B, A, E A1C reduction) A, medical nutrition therapy should be adequately reimbursed by insurance and other payers. E Energy balance 5.9 Weight loss (.5%) achievable by the combination of reduction of calorie intake and lifestyle A modification benefits overweight or obese adults with type 2 diabetes and also those with prediabetes. Intervention programs to facilitate weight loss are recommended. Eating patterns and 5.10 There is no single ideal dietary distribution of calories among carbohydrates, fats, and proteins for E macronutrient people with diabetes; therefore, meal plans should be individualized while keeping total calorie distribution and metabolic goals in mind. 5.11 A variety of eating patterns areacceptable forthe management of type 2 diabetes and prediabetes. B Carbohydrates 5.12 Carbohydrate intake should emphasize nutrient-dense carbohydrate sources that are high in fiber, B including vegetables, fruits, legumes, whole grains, as well as dairy products. 5.13 For people with type 1 diabetes and those with type 2 diabetes who are prescribed a flexible insulin A, B therapy program, education on how to use carbohydrate counting A and in some cases how to consider fat and protein content B to determine mealtime insulin dosing is recommended to improve glycemic control. 5.14 For individuals whose daily insulin dosing is fixed, a consistent pattern of carbohydrate intake with B respect to time and amount may be recommended to improve glycemic control and reduce the risk of hypoglycemia. 5.15 People with diabetes and those at risk are advised to avoid sugar-sweetened beverages (including B, A fruit juices) in order to control glycemia and weight and reduce their risk for cardiovascular disease and fatty liver B and should minimize the consumption of foods with added sugar that have the capacity to displace healthier, more nutrient-dense food choices. A Protein 5.16 In individuals with type 2 diabetes, ingested protein appears to increase insulin response without B increasing plasma glucose concentrations. Therefore, carbohydrate sources high in protein should be avoided when trying to treat or prevent hypoglycemia. Dietary fat 5.17 Data on the ideal total dietary fat content for people with diabetes are inconclusive, so an eating B plan emphasizing elements of a Mediterranean-style diet rich in monounsaturated and polyunsaturated fats may be considered to improve glucose metabolism and lower cardiovascular disease risk and can be an effective alternative to a diet low in total fat but relatively high in carbohydrates. 5.18 Eating foods rich in long-chain n-3 fatty acids, such as fatty fish (EPA and DHA) and nuts and seeds B, A (ALA), is recommended to prevent or treat cardiovascular disease B; however, evidence does not support a beneficial role for the routine use of n-3 dietary supplements. A Micronutrients and 5.19 There is no clear evidence that dietary supplementation with vitamins, minerals (such as C herbal supplements chromium and vitamin D), herbs, or spices (such as cinnamon or aloe vera) can improve outcomes in people with diabetes who do not have underlying deficiencies and they are not generally recommended for glycemic control. Alcohol 5.20 Adults with diabetes who drink alcohol should do so in moderation (no more than one drink C per day for adult women and no more than two drinks per day for adult men). 5.21 Alcohol consumption may place people with diabetes at increased risk for hypoglycemia, especially B if taking insulin or insulin secretagogues. Education and awareness regarding the recognition and management of delayed hypoglycemia are warranted. Sodium 5.22 As for the general population, people with diabetes should limit sodium consumption B to ,2,300 mg/day. Nonnutritive 5.23 The use of nonnutritive sweeteners may have the potential to reduce overall calorie and B sweeteners carbohydrateintakeif substitutedforcaloric (sugar)sweetenersandwithoutcompensation byintake of additional calories from other food sources. For those who consume sugar-sweetened beverages regularly, a low-calorie or nonnutritive-sweetened beverage may serve as a short-term replacement strategy, but overall, people are encouraged to decrease both sweetened and nonnutritive- sweetened beverages and use other alternatives, with an emphasis on water intake. clinical benefits of weight loss are pro- on need, feasibility, and safety (73). structured weight loss plan, is strongly gressive and more intensive weight MNT guidance from an RD/RDN with recommended. loss goals (i.e., 15%) may be appropri- expertise in diabetes and weight man- Studies have demonstrated that a ate to maximize benefit depending agement, throughout the course of a variety of eating plans, varying in S50 Lifestyle Management Diabetes Care Volume 42, Supplement 1, January 2019

macronutrient composition, can be used low-carbohydrate eating plans generally control (51,82,93–96). Individuals who effectively and safely in the short term indicate challenges with long-term sus- consume meals containing more protein (1–2 years) to achieve weight loss in tainability, it is important to reassess and fat than usual may also need to make people with diabetes. This includes struc- and individualize meal plan guidance mealtime insulin dose adjustments to tured low-calorie meal plans that include regularly for those interested in this compensate for delayed postprandial meal replacements (72–74) and the approach. Providers should maintain glycemic excursions (97–99). For individ- Mediterranean eating pattern (75) as consistent medical oversight and recog- uals on a fixed daily insulin schedule, well as low-carbohydrate meal plans nize that certain groups are not ap- meal planning should emphasize a rela- (62). However, no single approach has propriate for low-carbohydrate eating tively fixed carbohydrate consumption been proven to be consistently superior plans, including women who are preg- pattern with respect to both time and (76,77), and more data are needed to nant or lactating, children, and people amount (35). identify and validate those meal plans who have renal disease or disordered that are optimal with respect to long- eating behavior, and these plans should Protein term outcomes as well as patient ac- be used with caution for those taking There is no evidence that adjusting ceptability. The importance of providing SGLT2 inhibitors due to potential risk the daily level of protein intake (typically guidance on an individualized meal plan of ketoacidosis (65,66). There is inade- 1–1.5 g/kg body weight/day or 15–20% containing nutrient-dense foods, such as quate research about dietary patterns total calories) will improve health in vegetables, fruits, legumes, dairy, lean for type 1 diabetes to support one eating individuals without diabetic kidney dis- sources of protein (including plant-based plan over another at this time. ease, and research is inconclusive resources as well as lean meats, fish, and Most individuals with diabetes report garding the ideal amount of dietary poultry), nuts, seeds, and whole grains, a moderate intake of carbohydrate (44– protein to optimize either glycemic con- cannot be overemphasized (77), as well 46% of total calories) (51). Efforts to trol or cardiovascular disease (CVD) as guidance on achieving the desired en- modify habitual eating patterns are risk (84,100). Therefore, protein intake ergy deficit (78–81). Any approach to often unsuccessful in the long term; goals should be individualized based meal planning should be individualized people generally go back to their usual on current eating patterns. Some reconsidering the health status, personal macronutrient distribution (51). Thus, search has found successful manage- preferences, and ability of the person the recommended approach is to in- ment of type 2 diabetes with meal with diabetes to sustain the recommen- dividualize meal plans to meet caloric plans including slightly higher levels of dations in the plan. goals with a macronutrient distribution protein (20–30%), which may contribute that is more consistent with the individ- to increased satiety (58). Carbohydrates ual’s usual intake to increase the likeli- Those with diabetic kidney disease Studies examining the ideal amount of hood for long-term maintenance. (with albuminuria and/or reduced esti- carbohydrate intake for people with As for all individuals in developed mated glomerular filtration rate) should diabetes are inconclusive, although moni- countries, both children and adults aim to maintain dietary protein at the toring carbohydrate intake and consid- with diabetes are encouraged to mini- recommended daily allowance of 0.8 ering the blood glucose response to mize intake of refined carbohydrates g/kg body weight/day. Reducing the dietary carbohydrate are key for improv- and added sugars and instead focus amount of dietary protein below the ing postprandial glucose control (82,83). on carbohydrates from vegetables, le- recommended daily allowance is not The literature concerning glycemic index gumes, fruits, dairy (milk and yogurt), recommended because it does not alter and glycemic load in individuals with di- and whole grains. The consumption of glycemic measures, cardiovascular risk abetes is complex, often yielding mixed sugar-sweetened beverages (including measures, or the rate at which glomer- results, though in some studies lowering fruit juices) and processed “low-fat” ular filtration rate declines (101,102). the glycemic load of consumed carbohy- or “nonfat” food products with high In individuals with type 2 diabetes, drates has demonstrated A1C reductions amounts of refined grains and added protein intake may enhance or increase of 0.2% to 0.5% (84,85). Studies longer sugars is strongly discouraged (90–92). the insulin response to dietary carbohy- than 12 weeks report no significant in- Individuals with type 1 or type 2 di- drates (103). Therefore, use of carbohy- fluence of glycemic index or glycemic load abetes taking insulin at mealtime should drate sources high in protein (such as independent of weight loss on A1C; how- be offered intensive and ongoing edu- milk and nuts) to treat or prevent hypo- ever, mixed results have been reported cation on the need to couple insulin glycemia should be avoided due to the for fasting glucose levels and endoge- administration with carbohydrate in- potential concurrent rise in endogenous nous insulin levels. take. For people whose meal schedule or insulin. For people with type 2 diabetes or carbohydrate consumption is variable, prediabetes, low-carbohydrate eating regular counseling to help them under- Fats plans show potential to improve glyce- stand the complex relationship between The ideal amount of dietary fat for in- mia and lipid outcomes for up to 1 year carbohydrate intake and insulin needs dividuals with diabetes is controversial. (62–64,86–89). Part of the challenge in is important. In addition, education on The National Academy of Medicine has interpreting low-carbohydrate research using the insulin-to-carbohydrate ratios defined an acceptable macronutrient has been due to the wide range of def- for meal planning can assist them with distribution for total fat for all adults initions for a low-carbohydrate eating effectively modifying insulin dosing from tobe20–35%of totalcalorie intake (104). plan (85,86). As research studies on meal to meal and improving glycemic Thetypeoffatsconsumedismore care.diabetesjournals.org Lifestyle Management S51

important than total amount of fat when or peripheral neuropathy (123). Routine beverage may serve as a short-term re- looking at metabolic goals and CVD risk, supplementation with antioxidants, such placement strategy, but overall, people and it is recommended that the per- as vitamins E and C and carotene, is not are encouraged to decrease both sweet- centage of total calories from saturated advised due to lack of evidence of effi- ened and nonnutritive-sweetened bever- fats should be limited (75,90,105–107). cacy and concern related to long-term ages and use other alternatives, with an Multiple randomized controlled trials safety. In addition, there is insufficient emphasis on water intake (132). including patients with type 2 diabetes evidence to support the routine use of have reported that a Mediterranean- herbals and micronutrients, such as cin- PHYSICAL ACTIVITY style eating pattern (75,108–113), rich namon (124), curcumin, vitamin D (125), Recommendations in polyunsaturated and monounsatu- or chromium, to improve glycemia in 5.24 Children and adolescents with rated fats, can improve both glycemic people with diabetes (35,126). However, type 1 or type 2 diabetes or control and blood lipids. However, sup- for special populations, including preg- prediabetes should engage plements do not seem to have the nant or lactating women, older adults, in 60 min/day or more of mod- same effects as their whole-food coun- vegetarians, and people following very erate- or vigorous-intensity terparts. A systematic review concluded low-calorie or low-carbohydrate diets, a aerobic activity, with vigor- that dietary supplements with n-3 fatty multivitamin may be necessary. ous muscle-strengthening and acids did not improve glycemic con- bone-strengthening activities at trol in individuals with type 2 diabe- Alcohol least 3 days/week. C tes (84). Randomized controlled trials Moderate alcohol intake does not have 5.25 Most adults with type 1 C and also do not support recommending n-3 major detrimental effects on long-term type 2 B diabetes should engage supplements for primary or secondary blood glucose control in people with in 150 min or more of moderate- prevention of CVD (114–118). People diabetes. Risks associated with alcohol to-vigorous intensity aerobic ac- with diabetes should be advised to follow consumption include hypoglycemia (par- tivity per week, spread over at the guidelines for the general population ticularly for those using insulin or insulin least 3 days/week, with no more for the recommended intakes of satu- secretagogue therapies), weight gain, than 2 consecutive days without rated fat, dietary cholesterol, and trans and hyperglycemia (for those consuming activity. Shorter durations (min- fat (90). In general, trans fats should excessive amounts) (35,126). People with imum 75 min/week) of vigorous- be avoided. In addition, as saturated diabetes can follow the same guidelines intensity or interval training may fats are progressively decreased in the as those without diabetes if they choose be sufficient for younger and diet, they should be replaced with un- to drink. For women, no more than one more physically fit individuals. saturated fats and not with refined car- drink per day, and for men, no more than 5.26 Adults with type 1 C and type 2 B bohydrates (112). two drinks per day is recommended (one diabetes should engage in 2–3 drink is equal to a 12-oz beer, a 5-oz glass sessions/week of resistance ex- Sodium of wine, or 1.5 oz of distilled spirits). ercise on nonconsecutive days. As for the general population, people 5.27 All adults, and particularly those with diabetes are advised to limit their Nonnutritive Sweeteners with type 2 diabetes, should sodium consumption to ,2,300 mg/day For some people with diabetes who are decrease the amount of time (35). Restriction below 1,500 mg, even accustomed to sugar-sweetened prod- spent in daily sedentary behav- for those with hypertension, is gener- ucts, nonnutritive sweeteners (con- ior. B Prolonged sitting should ally not recommended (119–121). So- taining few or no calories) may be an be interrupted every 30 min for dium intake recommendations should acceptable substitute for nutritive sweet- blood glucose benefits, partic- take into account palatability, availabil- eners (those containing calories such as ularly in adults with type 2 di- ity, affordability, and the difficulty of sugar, honey, agave syrup) when con- abetes. C achieving low-sodium recommenda- sumed in moderation. While use of 5.28 Flexibility training and balance tions in a nutritionally adequate diet nonnutritive sweeteners does not ap- training are recommended 2–3 (122). pear to have a significant effect on times/week for older adults with glycemic control (127), they can reduce diabetes. Yoga and tai chi may overall calorie and carbohydrate intake Micronutrients and Supplements be included based on individual There continues to be no clear evidence (51). Most systematic reviews and meta- preferences to increase flexibility, of benefit from herbal or nonherbal analyses show benefits for nonnutritive muscular strength, and balance. C (i.e., vitamin or mineral) supplementation sweetener use in weight loss (128,129); for people with diabetes without un- however, some research suggests an derlying deficiencies (35). Metformin is association with weight gain (130). Reg- Physical activity is a general term that associated with vitamin B12 deficiency, ulatory agencies set acceptable daily includes all movement that increases with a recent report from the Diabetes intake levels for each nonnutritive energy use and is an important part of Prevention Program Outcomes Study sweetener, defined as the amount that the diabetes management plan. Exercise (DPPOS) suggesting that periodic test- can be safely consumed over a person’s is a more specific form of physical ac- ing of vitamin B12 levels should be lifetime (35,131). For those who consume tivity that is structured and designed considered in patients taking metfor- sugar-sweetened beverages regularly, to improve physical fitness. Both phys- min, particularly in those with anemia a low-calorie or nonnutritive-sweetened ical activity and exercise are important. S52 Lifestyle Management Diabetes Care Volume 42, Supplement 1, January 2019

Exercise has been shown to improve 1 and type 2 diabetes and offers specific should be encouraged to reduce the blood glucose control, reduce cardiovas- recommendation (142). amount of time spent being sedentary cular risk factors, contribute to weight (e.g., working at a computer, watching loss, and improve well-being (133). Phys- Exercise and Children TV) by breaking up bouts of sedentary ical activity is as important for those with All children, including children with di- activity (.30 min) by briefly standing, type 1 diabetes as it is for the general abetes or prediabetes, should be en- walking, or performing other light phys- population, but its specific role in the couraged to engage in regular physical ical activities (150,151). Avoiding ex- prevention of diabetes complications activity. Children should engage in at tended sedentary periods may help and the management of blood glucose least 60 min of moderate-to-vigorous prevent type 2 diabetes for those at is not as clear as it is for those with type aerobic activity every day with muscle- risk and may also aid in glycemic control 2 diabetes. A recent study suggested and bone-strengthening activities at for those with diabetes. that the percentage of people with di- least 3 days per week (143). In general, A wide range of activities, includ- abetes who achieved the recommended youth with type 1 diabetes benefit from ing yoga, tai chi, and other types, can exercise level per week (150 min) var- being physically active, and an active have significant impacts on A1C, flexi- ied by race. Objective measurement lifestyle should be recommended to all bility, muscle strength, and balance by accelerometer showed that 44.2%, (144). Youth with type 1 diabetes who (133,152,153). Flexibility and balance 42.6%, and 65.1% of whites, African engage in more physical activity may exercises may be particularly important Americans, and Hispanics, respectively, have better health-related quality of in older adults with diabetes to maintain met the threshold (134). It is important life (145). range of motion, strength, and balance for diabetes care management teams (142). to understand the difficulty that many Frequency and Type of Physical patients have reaching recommended Activity Physical Activity and Glycemic Control treatment targets and to identify indi- People with diabetes should perform Clinical trials have provided strong evi- vidualized approaches to improve goal aerobic and resistance exercise regularly dence for the A1C-lowering value of achievement. (142). Aerobic activity bouts should ide- resistance training in older adults with Moderate to high volumes of aerobic ally last at least 10 min, with the goal of type 2 diabetes (154) and for an additive activity are associated with substantially ;30 min/day or more, most days of the benefit of combined aerobic and resis- lower cardiovascular and overall mortal- week for adults with type 2 diabetes. tance exercise in adults with type 2 ity risks in both type 1 and type 2 diabetes Daily exercise, or at least not allowing diabetes (155). If not contraindicated, (135). A recent prospective observa- more than 2 days to elapse between patients with type 2 diabetes should be tionalstudy of adults with type1diabetes exercise sessions, is recommended to encouraged to do at least two weekly suggested that higher amounts of phys- decrease insulin resistance, regardless sessions of resistance exercise (exercise ical activity led to reduced cardiovascular of diabetes type (146,147). Over time, with free weights or weight machines), mortality after a mean follow-up time of activities should progress in intensity, with each session consisting of at least 11.4 years for patients with and without frequency, and/or duration to at least one set (group of consecutive repetitive chronic kidney disease (136). Addition- 150 min/week of moderate-intensity ex- exercise motions) of five or more differ- ally, structured exercise interventions ercise. Adults able to run at 6 miles/h ent resistance exercises involving the of at least 8 weeks’ duration have been (9.7 km/h) for at least 25 min can benefit large muscle groups (154). shown to lower A1C by an average of sufficiently from shorter-intensity activ- For type 1 diabetes, although exercise 0.66%inpeoplewithtype2diabetes,even ity (75 min/week) (142). Many adults, in general is associated with improve- without a significant change in BMI (137). including most with type 2 diabetes, ment in disease status, care needs to There are also considerable data for the would be unable or unwilling to partic- be taken in titrating exercise with respect health benefits (e.g., increased cardiovas- ipate in such intense exercise and should to glycemic management. Each individual cular fitness, greater muscle strength, im- engage in moderate exercise for the with type 1 diabetes has a variable gly- proved insulin sensitivity, etc.) of regular recommended duration. Adults with di- cemic response to exercise. This variabil- exercise for those with type 1 diabetes abetes should engage in 2–3 sessions/ ity should be taken into consideration (138). A recent study suggested that week of resistance exercise on noncon- when recommending the type and dura- exercise training in type 1 diabetes secutive days (148). Although heavier tion of exercise for a given individual may also improve several important resistance training with free weights (138). markers such as triglyceride level, LDL, and weight machines may improve gly- Women with preexisting diabetes, waist circumference, and body mass cemic control and strength (149), re- particularly type 2 diabetes, and those (139). Higher levels of exercise intensity sistance training of any intensity is at risk for or presenting with gestational are associated with greater improve- recommended to improve strength, bal- diabetes mellitus should be advised to ments in A1C and in fitness (140). Other ance, and the ability to engage in activ- engage in regular moderate physical benefitsincludeslowingthedeclinein ities of daily living throughout the life activity prior to and during their preg- mobility among overweight patients span. Providers and staff should help nancies as tolerated (142). with diabetes (141). The ADA position patients set stepwise goals toward meet- statement “Physical Activity/Exercise and ing the recommended exercise targets. Pre-exercise Evaluation Diabetes” reviews the evidence for the Recent evidence supports that all in- As discussed more fully in Section benefits of exercise in people with type dividuals, including those with diabetes, 10 “Cardiovascular Disease and Risk care.diabetesjournals.org Lifestyle Management S53

Management,” the best protocol for Exercise in the Presence of Diabetic Kidney Disease assessing asymptomatic patients with Microvascular Complications Physical activity can acutely increase uri- diabetes for coronary artery disease re- See Section 11 “Microvascular Complica- nary albumin excretion. However, there is mains unclear. The ADA consensus report tions and Foot Care” for more information no evidence that vigorous-intensity exer- “Screening for Coronary Artery Disease on these long-term complications. cise increases the rate of progression of ” in Patients With Diabetes (156) con- Retinopathy diabetic kidney disease, and there appears fi cluded that routine testing is not recom- If proliferative diabetic retinopathy or to be no need for speci cexercisere- mended. However, providers should severe nonproliferative diabetic retinop- strictions for people with diabetic kidney perform a careful history, assess cardio- athy is present, then vigorous-intensity disease in general (158). vascular risk factors, and be aware of aerobic or resistance exercise may be the atypical presentation of coronary contraindicated because of the risk of artery disease in patients with diabetes. SMOKING CESSATION: TOBACCO triggering vitreous hemorrhage or ret- AND E-CIGARETTES Certainly, high-risk patients should be inal detachment (158). Consultation encouraged to start with short periods with an ophthalmologist prior to engag- Recommendations of low-intensity exercise and slowly in- ing in an intense exercise regimen may 5.29 Advise all patients not to use crease the intensity and duration as be appropriate. cigarettes and other tobacco tolerated. Providers should assess pa- products A or e-cigarettes. B tients for conditions that might contra- Peripheral Neuropathy 5.30 Include smoking cessation coun- Decreased pain sensation and a higher indicate certain types of exercise or seling and other forms of treat- pain threshold in the extremities result predispose to injury, such as uncontrolled ment as a routine component in an increased risk of skin breakdown, hypertension, untreated proliferative ret- of diabetes care. A inopathy, autonomic neuropathy, periph- infection, and Charcot joint destruction eral neuropathy, and a history of foot with some forms of exercise. Therefore, a Results from epidemiological, case-control, ulcers or Charcot foot. The patient’sage thorough assessment should be done to and cohort studies provide convincing and previous physical activity level should ensure that neuropathy does not alter evidence to support the causal link be- be considered. The provider should cus- kinesthetic or proprioceptive sensation tween cigarette smoking and health risks tomize the exercise regimen to the indi- during physical activity, particularly in (163). Recent data show tobacco use is vidual’s needs. Those with complications those with more severe neuropathy. Stud- higher among adults with chronic con- may require a more thorough evaluation ies have shown that moderate-intensity ditions (164) as well as in adolescents prior to beginning an exercise program walking may not lead to an increased risk and young adults with diabetes (165). (138). of foot ulcers or reulceration in those with Smokers with diabetes (and people peripheral neuropathy who use proper with diabetes exposed to second-hand footwear (159). In addition, 150 min/week Hypoglycemia smoke) have a heightened risk of CVD, In individuals taking insulin and/or in- of moderate exercise was reported to premature death, microvascular com- sulin secretagogues, physical activity may improve outcomes in patients with plications, and worse glycemic control cause hypoglycemia if the medication prediabetic neuropathy (160). All indi- when compared with nonsmokers dose or carbohydrate consumption is viduals with peripheral neuropathy (166,167). Smoking may have a role in not altered. Individuals on these thera- should wear proper footwear and ex- the development of type 2 diabetes pies may need to ingest some added amine their feet daily to detect lesions (168–171). carbohydrate if pre-exercise glucose lev- early. Anyone with a foot injury or open The routine and thorough assessment – els are ,90 mg/dL (5.0 mmol/L), depend- sore should be restricted to non weight- of tobacco use is essential to prevent ing on whether they are able to lower bearing activities. smoking or encourage cessation. Nu- insulin doses during the workout (such as Autonomic Neuropathy merous large randomized clinical trials with an insulin pump or reduced pre- Autonomic neuropathy can increase the have demonstrated the efficacy and exercise insulin dosage), the time of day risk of exercise-induced injury or adverse cost-effectiveness of brief counseling exercise is done, and the intensity and events through decreased cardiac re- in smoking cessation, including the duration of the activity (138,142). In sponsiveness to exercise, postural hy- use of telephone quit lines, in reducing some patients, hypoglycemia after ex- potension, impaired thermoregulation, tobacco use. Pharmacologic therapy to ercise may occur and last for several impaired night vision due to impaired assist with smoking cessation in people hours due to increased insulin sensitiv- papillary reaction, and greater suscepti- with diabetes has been shown to be ity. Hypoglycemia is less common in bility to hypoglycemia (161). Cardiovas- effective (172), and for the patient mo- patients with diabetes who are not cular autonomic neuropathy is also an tivated to quit, the addition of pharma- treated with insulin or insulin secreta- independent risk factor for cardiovascu- cologic therapy to counseling is more gogues, and no routine preventive mea- lar death and silent myocardial ische- effective than either treatment alone sures for hypoglycemia are usually mia (162). Therefore, individuals with (173). Special considerations should in- advised in these cases. Intense activities diabetic autonomic neuropathy should clude assessment of level of nicotine may actually raise blood glucose levels undergo cardiac investigation before dependence, which is associated with instead of lowering them, especially if beginning physical activity more in- difficulty in quitting and relapse (174). pre-exercise glucose levels are elevated tense than that to which they are Although some patients may gain weight (157). accustomed. in the period shortly after smoking S54 Lifestyle Management Diabetes Care Volume 42, Supplement 1, January 2019

cessation (175), recent research has dem- psychological vulnerability at diagno- disordered eating, and cogni- onstrated that this weight gain does not sis, when their medical status changes tive capacities using patient- diminish the substantial CVD benefitre- (e.g., end of the honeymoon period), appropriate standardized and alized from smoking cessation (176). One when the need for intensified treat- validated tools at the initial study in smokers with newly diagnosed ment is evident, and when complica- visit, at periodic intervals, and type 2 diabetes found that smoking tions are discovered. when there is a change in dis- cessation was associated with amelio- Providers can start with informal ease, treatment, or life circum- ration of metabolic parameters and re- verbal inquires, for example, by asking stance. Including caregivers and duced blood pressure and albuminuria if there have been changes in mood family members in this assess- at 1 year (177). during the past 2 weeks or since the ment is recommended. B In recent years e-cigarettes have patient’s last visit. Providers should con- 5.34 Consider screening older adults gained public awareness and popularity sider asking if there are new or different (aged $65 years) with diabetes because of perceptions that e-cigarette barriers to treatment and self-manage- for cognitive impairment and use is less harmful than regular cigarette ment, such as feeling overwhelmed or depression. B smoking (178,179). Nonsmokers should stressed by diabetes or other life stres- be advised not to use e-cigarettes Please refer to the ADA position state- sors. Standardized and validated tools for (180,181). There are no rigorous studies ment “Psychosocial Care for People With psychosocial monitoring and assessment that have demonstrated that e-cigarettes Diabetes” for a list of assessment tools can also be used by providers (187), with are a healthier alternative to smoking fi and additional details (187). positive ndings leading to referral to a or that e-cigarettes can facilitate smok- Complex environmental, social, be- mental health provider specializing in ing cessation (182). On the contrary, a havioral, and emotional factors, known diabetes for comprehensive evaluation, recently published pragmatic trial found as psychosocial factors, influence living diagnosis, and treatment. that use of e-cigarettes for smoking with diabetes, both type 1 and type 2, cessation was not more effective than and achieving satisfactory medical out- “usual care,” which included access to comes and psychological well-being. Thus, Diabetes Distress educational information on the health individuals with diabetes and their fam- benefits of smoking cessation, strategies Recommendation ilies are challenged with complex, multi- to promote cessation, and access to a 5.35 Routinely monitor people with faceted issues when integrating diabetes free text-messaging service that pro- diabetes for diabetes distress, care into daily life. vided encouragement, advice, and tips particularly when treatment tar- Emotional well-being is an important to facilitate smoking cessation (183). Sev- getsarenotmetand/oratthe part of diabetes care and self-management. eral organizations have called for more onset of diabetes complications. B Psychological and social problems can research on the short- and long-term impair the individual’s (188–190) or fam- safety and health effects of e-cigarettes Diabetes distress (DD) is very common ily’s (191) ability to carry out diabetes care (184–186). and is distinct from other psychological tasks and therefore potentially compro- disorders (193–195). DD refers to signif- mise health status. There are opportu- icant negative psychological reactions nities for the clinician to routinely assess related to emotional burdens and wor- PSYCHOSOCIAL ISSUES fi psychosocial status in a timely and ef - ries specific to an individual’s experience Recommendations cient manner for referral to appropri- in having to manage a severe, compli- 5.31 Psychosocial care should be in- ate services. A systematic review and cated, and demanding chronic disease tegrated with a collaborative, meta-analysis showed that psychosocial such as diabetes (194–196). The constant patient-centered approach and interventions modestly but significantly behavioral demands (medication dos- provided to all people with di- improved A1C (standardized mean dif- ing, frequency, and titration; monitoring – abetes, with the goals of op- ference 0.29%) and mental health blood glucose, food intake, eating pat- timizing health outcomes and outcomes (192). However, there was a terns, and physical activity) of diabetes A limited association between the effects health-related quality of life. self-management and the potential or 5.32 on A1C and mental health, and no in- Psychosocial screening and actuality of disease progression are di- tervention characteristics predicted follow-up may include, but are rectly associated with reports of DD benefit on both outcomes. not limited to, attitudes about (194). The prevalence of DD is reported diabetes, expectations for to be 18–45% with an incidence of medical management and out- 38–48% over 18 months (196). In the comes, affect or mood, general Screening Key opportunities for psychosocial screen- second Diabetes Attitudes, Wishes and and diabetes-related quality of ing occur at diabetes diagnosis, during Needs (DAWN2) study, significant DD life, available resources (finan- regularly scheduled management vis- was reported by 45% of the participants, cial, social, and emotional), and its, during hospitalizations, with new but only 24% reported that their health psychiatric history. E onset of complications, or when prob- care teams asked them how diabetes 5.33 Providers should consider assess- lems with glucose control, quality of affected their lives (193). High levels ment for symptoms of diabe- life, or self-management are identi- of DD significantly impact medication- tes distress, depression, anxiety, fied (1). Patients are likely to exhibit taking behaviors and are linked to higher care.diabetesjournals.org Lifestyle Management S55

Table 5.2—Situations that warrant referral of a person with diabetes to a mental health provider for evaluation and treatment c If self-care remains impaired in a person with diabetes distress after tailored diabetes education c If a person has a positive screen on a validated screening tool for depressive symptoms c In the presence of symptoms or suspicions of disordered eating behavior, an eating disorder, or disrupted patterns of eating c If intentional omission of insulin or oral medication to cause weight loss is identified c If a person has a positive screen for anxiety or fear of hypoglycemia c If a serious mental illness is suspected c In youth and families with behavioral self-care difficulties, repeated hospitalizations for diabetic ketoacidosis, or significant distress c If a person screens positive for cognitive impairment c Declining or impaired ability to perform diabetes self-care behaviors c Before undergoing bariatric or metabolic surgery and after surgery if assessment reveals an ongoing need for adjustment support

A1C, lower self-efficacy, and poorer di- psychological status to occur (26,193). with diabetes: a consensus report. Diabetes etary and exercise behaviors (17,194, Providers should identify behavioral and Care 2013;36:463–470 196). DSMES has been shown to reduce mental health providers, ideally those 7. Norris SL, Lau J, Smith SJ, Schmid CH, Engelgau MM. Self-management education for adults DD (17). It may be helpful to provide who are knowledgeable about diabetes with type 2 diabetes: a meta-analysis of the counseling regarding expected diabetes- treatment and the psychosocial aspects of effect on glycemic control. Diabetes Care 2002; related versus generalized psychological diabetes, to whom they can refer patients. 25:1159–1171 distress at diagnosis and when disease The ADA provides a list of mental health 8. Haas L, Maryniuk M, Beck J, et al.; 2012 state or treatment changes (197). providers who have received additional Standards Revision Task Force. National standards for diabetes self-management education DD should be routinely monitored education in diabetes at the ADA Mental and support. Diabetes Care 2014;37(Suppl. 1): (198) using patient-appropriate vali- Health Provider Directory (professional. S144–S153 dated measures (187). If DD is identified, diabetes.org/ada-mental-health-provider- 9. Frosch DL, Uy V, Ochoa S, Mangione CM. thepersonshouldbereferredforspecific directory). Ideally, psychosocial care Evaluation of a behavior support intervention diabetes education to address areas of providers should be embedded in di- for patients with poorly controlled diabetes. Arch Intern Med 2011;171:2011–2017 diabetes self-care that are most relevant abetes care settings. Although the cli- 10. Cooke D, Bond R, Lawton J, et al.; U.K. NIHR to the patient and impact clinical man- nician may not feel qualified to treat DAFNE Study Group. Structured type 1 diabetes agement. People whose self-care re- psychological problems (200), optimizing education delivered within routine care: im- mains impaired after tailored diabetes the patient-provider relationship as a pact on glycemic control and diabetes-specific education should be referred by their foundation may increase the likelihood quality of life. Diabetes Care 2013;36:270– 272 care team to a behavioral health proof the patient accepting referral for other 11. Chrvala CA, Sherr D, Lipman RD. Diabetes vider for evaluation and treatment. services. Collaborative care interventions self-management education for adults with Other psychosocial issues known to and a team approach have demonstrated type 2 diabetes mellitus: a systematic review affect self-management and health out- efficacy in diabetes self-management, of the effect on glycemic control. Patient Educ comes include attitudes about the illness, outcomes of depression, and psychoso- Couns 2016;99:926–943 expectations for medical management cial functioning (17,201). 12. Steinsbekk A, Rygg LØ, Lisulo M, Rise MB, Fretheim A. Group based diabetes self- and outcomes, available resources (fi- References management education compared to routine nancial, social, and emotional) (199), and 1. Powers MA, Bardsley J, Cypress M, et al. treatment for people with type 2 diabetes mellitus. A systematic review with meta-analysis. psychiatric history. For additional infor- Diabetes self-management education and sup- BMC Health Serv Res 2012;12:213 mation on psychiatric comorbidities port in type 2 diabetes: a joint position statement 13. Deakin T, McShane CE, Cade JE, Williams RD. (depression, anxiety, disordered eat- of the American Diabetes Association, the Amer- Group based training for self-management ican Association of Diabetes Educators, and the ing, and serious mental illness), please strategies in people with type 2 diabetes mel- Academy of Nutrition and Dietetics. Diabetes refer to Section 4 “Comprehensive litus. Cochrane Database Syst Rev 2005;2: – Medical Evaluation and Assessment of Care 2015;38:1372 1382 CD003417 2. Dickinson JK, Guzman SJ, Maryniuk MD, et al. Comorbidities.” 14. Cochran J, Conn VS. Meta-analysis of qual- The use of language in diabetes care and edu- ity of life outcomes following diabetes self- – cation. Diabetes Care 2017;40:1790 1799 management training. Diabetes Educ 2008;34: Referral to a Mental Health Specialist 3. Dickinson JK, Maryniuk MD. Building thera- 815–823 Indications for referral to a mental health peutic relationships: choosing words that put 15. He X, Li J, Wang B, et al. Diabetes self- fi – specialist familiar with diabetes man- people rst. Clin Diabetes 2017;35:51 54 management education reduces risk of all-cause 4. Beck J, Greenwood DA, Blanton L, et al.; 2017 agement may include positive screening mortality in type 2 diabetes patients: a system- Standards Revision Task Force. 2017 national for overall stress related to work-life atic review and meta-analysis. Endocrine 2017; standards for diabetes self-management edu- 55:712–731 balance, DD, diabetes management dif- cation and support. Diabetes Care 2017;40:1409– 16. Thorpe CT, Fahey LE, Johnson H, Deshpande ficulties,depression,anxiety,disordered 1419 M, Thorpe JM, Fisher EB. Facilitating healthy eating, and cognitive dysfunction (see 5. Tang TS, Funnell MM, Brown MB, Kurlander coping in patients with diabetes: a systematic Table 5.2 for a complete list). It is pref- JE. Self-management support in “real-world” review. Diabetes Educ 2013;39:33–52 erable to incorporate psychosocial assess- settings: an empowerment-based intervention. 17. Fisher L, Hessler D, Glasgow RE, et al. Patient Educ Couns 2010;79:178–184 REDEEM: a pragmatic trial to reduce diabetes ment and treatment into routine care 6. Marrero DG, Ard J, Delamater AM, et al. distress. Diabetes Care 2013;36:2551–2558 rather than waiting for a specific prob- Twenty-first century behavioral medicine: a con- 18. Robbins JM, Thatcher GE, Webb DA, lem or deterioration in metabolic or text for empowering clinicians and patients Valdmanis VG. Nutritionist visits, diabetes classes, S56 Lifestyle Management Diabetes Care Volume 42, Supplement 1, January 2019

and hospitalization rates and charges: the on glycosylated hemoglobin and cardiovascular 49. Briggs Early K, Stanley K. Position of the Urban Diabetes Study. Diabetes Care 2008;31: risk factors: a meta-analysis. Diabetes Educ 2012; Academy of Nutrition and Dietetics: the role of 655–660 38:108–123 medical nutrition therapy and registered dieti- 19. Duncan I, Ahmed T, Li QE, et al. Assessing the 35. Evert AB, Boucher JL, Cypress M, et al. tian nutritionists in the prevention and treat- value of the diabetes educator. Diabetes Educ Nutrition therapy recommendations for the ment of prediabetes and type 2 diabetes. J Acad 2011;37:638–657 management of adults with diabetes. Diabetes Nutr Diet 2018;118:343–353 20. Strawbridge LM, Lloyd JT, Meadow A, Riley Care 2014;37(Suppl. 1):S120–S143 50. Franz MJ, MacLeod J, Evert A, et al. Academy GF, Howell BL. One-year outcomes of diabe- 36. Shah M, Kaselitz E, Heisler M. The role of of Nutrition and Dietetics nutrition practice tes self-management training among Medicare community health workers in diabetes: update guideline for type 1 and type 2 diabetes in adults: beneficiaries newly diagnosed with diabetes. on current literature. Curr Diab Rep 2013;13:163– systematic review of evidence for medical nu- Med Care 2017;55:391–397 171 trition therapy effectiveness and recommenda- 21. Piatt GA, Anderson RM, Brooks MM, et al. 37. Spencer MS, Kieffer EC, Sinco B, et al. tions for integration into the nutrition care 3-year follow-up of clinical and behavioral im- Outcomes at 18 months from a community process. J Acad Nutr Diet 2017;117:1659–1679 provements following a multifaceted diabetes health worker and peer leader diabetes self- 51. MacLeod J, Franz MJ, Handu D, et al. Acad- care intervention: results of a randomized con- management program for Latino adults. Dia- emy of Nutrition and Dietetics nutrition practice trolled trial. Diabetes Educ 2010;36:301–309 betes Care 2018;41:1414–1422 guideline for type 1 and type 2 diabetes in adults: 22. Glazier RH, Bajcar J, Kennie NR, Willson K. A 38. Heisler M, Vijan S, Makki F, Piette JD. Di- nutrition intervention evidence reviews and systematic review of interventions to improve abetes control with reciprocal peer support recommendations. J Acad Nutr Diet 2017;117: diabetes care in socially disadvantaged popula- versus nurse care management: a randomized 1637–1658 tions. Diabetes Care 2006;29:1675–1688 trial. Ann Intern Med 2010;153:507–515 52. Schwingshackl L, Chaimani A, Hoffmann 23. Hawthorne K, Robles Y, Cannings-John R, 39. Long JA, Jahnle EC, Richardson DM, G, Schwedhelm C, Boeing H. A network meta- Edwards AG. Culturally appropriate health edu- Loewenstein G, Volpp KG. Peer mentoring and analysis on the comparative efficacy of dif- cation for type 2 diabetes mellitus in ethnic financial incentives to improve glucose control in ferent dietary approaches on glycaemic control minority groups. Cochrane Database Syst Rev African American veterans: a randomized trial. in patients with type 2 diabetes mellitus. Eur 2008;3:CD006424 Ann Intern Med 2012;156:416–424 J Epidemiol 2018;33:157–170 24. Chodosh J, Morton SC, MojicaW, et al. Meta- 40. Fisher EB, Boothroyd RI, Elstad EA, et al. Peer 53. Maryniuk MD. From pyramids to plates to analysis: chronic disease self-management pro- support of complex health behaviors in preven- patterns: perspectives on meal planning. Diabe- grams for older adults. Ann Intern Med 2005; tion and disease management with special ref- tes Spectr 2017;30:67–70 143:427–438 erence to diabetes: systematic reviews. Clin 54. Schwingshackl L, Schwedhelm C, Hoffmann G, 25. Sarkisian CA, Brown AF, Norris KC, Wintz RL, Diabetes Endocrinol 2017;3:4 et al. Food groups and risk of all-cause mortality: Mangione CM. A systematic review of diabetes 41. Foster G, Taylor SJC, Eldridge SE, Ramsay J, a systematic review and meta-analysis of prospec- self-care interventions for older, African Amer- Griffiths CJ. Self-management education pro- tive studies. Am J Clin Nutr 2017;105:1462–1473 ican, or Latino adults. Diabetes Educ 2003;29: grammes by lay leaders for people with chronic 55. Esposito K, Maiorino MI, Ciotola M, et al. 467–479 conditions. Cochrane Database Syst Rev 2007;4: Effects of a Mediterranean-style diet on the need 26. Peyrot M, Rubin RR. Behavioral and psy- CD005108 for antihyperglycemic drug therapy in patients chosocial interventions in diabetes: a conceptual 42. Duncan I, Birkmeyer C, Coughlin S, Li QE, with newly diagnosed type 2 diabetes: a random- review. Diabetes Care 2007;30:2433–2440 Sherr D, Boren S. Assessing the value of diabetes ized trial. Ann Intern Med 2009;151:306–314 27. Naik AD, Palmer N, Petersen NJ, et al. Com- education. Diabetes Educ 2009;35:752–760 56. Boucher JL. Mediterranean eating pattern. parative effectiveness of goal setting in diabetes 43. Johnson TM, Murray MR, Huang Y. Associ- Diabetes Spectr 2017;30:72–76 mellitus group clinics: randomized clinical trial. ations between self-management education and 57. Cespedes EM, Hu FB, Tinker L, et al. Multiple Arch Intern Med 2011;171:453–459 comprehensive diabetes clinical care. Diabetes healthful dietary patterns and type 2 diabetes in 28. Duke S-AS, Colagiuri S, Colagiuri R. Individual Spectr 2010;23:41–46 the Women’s Health Initiative. Am J Epidemiol patienteducationfor peoplewithtype 2 diabetes 44. Strawbridge LM, Lloyd JT, Meadow A, Riley 2016;183:622–633 mellitus. Cochrane Database Syst Rev 2009;1: GF, Howell BL. Use of Medicare’s diabetes self- 58. Ley SH, Hamdy O, Mohan V, Hu FB. Pre- CD005268 management training benefit. Health Educ Be- vention and management of type 2 diabetes: 29. Odgers-Jewell K, Ball LE, Kelly JT, Isenring EA, hav 2015;42:530–538 dietary components and nutritional strategies. Reidlinger DP, Thomas R. Effectiveness of group- 45. Li R, Shrestha SS, Lipman R, Burrows NR, Kolb Lancet 2014;383:1999–2007 based self-management education for individu- LE, Rutledge S; Centers for Disease Control and 59. Campbell AP. DASH eating plan: an eating als with type 2 diabetes: a systematic review Prevention (CDC). Diabetes self-management pattern for diabetes management. Diabetes with meta-analyses and meta-regression. Diabet education and training among privately insured Spectr 2017;30:76–81 Med 2017;34:1027–1039 persons with newly diagnosed diabetesdUnited 60. Rinaldi S, Campbell EE, Fournier J, O’Connor 30. Pereira K, Phillips B, Johnson C, States, 2011–2012. MMWR Morb Mortal Wkly C, Madill J. A comprehensive review of the Vorderstrasse A. Internet delivered diabetes Rep 2014;63:1045–1049 literature supporting recommendations from self-management education: a review. Diabetes 46. Horigan G, Davies M, Findlay-White F, the Canadian Diabetes Association for the use Technol Ther 2015;17:55–63 Chaney D, Coates V. Reasons why patients re- of a plant-based diet for management of type 2 31. Sepah SC, Jiang L, Peters AL. Long-term ferred to diabetes education programmes diabetes. Can J Diabetes 2016;40:471–477 outcomes of a Web-based diabetes prevention choosenot toattend:asystematicreview. Diabet 61. Pawlak R. vegetarian diets in the prevention program: 2-year results of a single-arm longitu- Med 2017;34:14–26 and management of diabetes and its complica- dinal study. J Med Internet Res 2015;17:e92 47. Center For Health Law and Policy Innovation. tions. Diabetes Spectr 2017;30:82–88 32. Greenwood DA, Gee PM, Fatkin KJ, Peeples Reconsidering cost-sharing for diabetes self- 62. Saslow LR, Daubenmier JJ, Moskowitz JT, M. A systematic review of reviews evaluating management education: recommendations for et al. Twelve-month outcomes of a randomized technology-enabled diabetes self-management policy reform [Internet]. Available from: http:// trial of a moderate-carbohydrate versus very education and support. J Diabetes Sci Technol www.chlpi.org/health_library/reconsidering-cost- low-carbohydrate diet in overweight adults 2017;11:1015–1027 sharing-diabetes-self-management-education- with type 2 diabetes mellitus or prediabetes. 33. van Eikenhorst L, Taxis K, van Dijk L, de Gier H. recommendations-policy-reform/. Accessed 2 Nutr Diabetes 2017;7:304 Pharmacist-led self-management interventions November 2018 63. Hallberg SJ, McKenzie AL, Williams PT, et al. to improve diabetes outcomes. A systematic 48. Davies MJ, D’Alessio DA, Fradkin J, et al. Effectiveness and safety of a novel care model for literature review and meta-analysis. Front Phar- Management of hyperglycemia in type 2 diabe- the management of type 2 diabetes at 1 year: an macol 2017;8:891 tes, 2018. A consensus report by the American open-label, non-randomized, controlled study. 34. Tshiananga JKT, Kocher S, Weber C, Erny- Diabetes Association (ADA) and the European Diabetes Ther 2018;9:583–612 Albrecht K, Berndt K, Neeser K. The effect of Association for the Study of Diabetes (EASD). 64. Sainsbury E, Kizirian NV, Partridge SR, nurse-led diabetes self-management education Diabetes Care 2018;41:2669–2701 Gill T, Colagiuri S, Gibson AA. Effect of dietary care.diabetesjournals.org Lifestyle Management S57

carbohydrate restriction on glycemic control in 77. Gardner CD, Trepanowski JF, Del Gobbo LC, Dietary guidelines for Americans 2015-2020, adults with diabetes: a systematic review and et al. Effect of low-fat vs low-carbohydrate diet Eighth Edition [Internet], 2015. Available from meta-analysis. Diabetes Res Clin Pract 2018;139: on 12-month weight loss in overweight adults https://health.gov/dietaryguidelines/2015/ 239–252 and the association with genotype pattern or guidelines. Accessed 2 November 2018 65. U.S. Food and Drug Administration. FDA insulin secretion: the DIETFITS randomized clin- 91. Nansel TR, Lipsky LM, Liu A. Greater diet Drug Safety Communication: FDA revises labels ical trial. JAMA 2018;319:667–679 quality is associated with more optimal glycemic of SGLT2 inhibitors for diabetes to include warn- 78. Sacks FM, Bray GA, Carey VJ, et al. Com- control in a longitudinal study of youth with ings about too much acid in the blood and parison of weight-loss diets with different com- type 1 diabetes. Am J Clin Nutr 2016;104:81–87 serious urinary tract infections [Internet], positions of fat, protein, and carbohydrates. N 92. Katz ML, Mehta S, Nansel T, Quinn H, Lipsky 2015. Available from http://www.fda.gov/Drugs/ Engl J Med 2009;360:859–873 LM, Laffel LMB. Associations of nutrient intake DrugSafety/ucm475463.htm. Accessed 2 Novem- 79. de Souza RJ, Bray GA, Carey VJ, et al. Effects with glycemic control in youth with type 1 di- ber 2018 of 4 weight-loss diets differing in fat, protein, and abetes: differences by insulin regimen. Diabetes 66. Blau JE, Tella SH, Taylor SI, Rother KI. Keto- carbohydrate on fat mass, lean mass, visceral Technol Ther 2014;16:512–518 acidosis associated with SGLT2 inhibitor treat- adipose tissue, and hepatic fat: results from the 93. Rossi MCE, Nicolucci A, Di Bartolo P, et al. ment: analysis of FAERS data. Diabetes Metab POUNDS LOST trial. Am J Clin Nutr 2012;95:614– Diabetes Interactive Diary: a new telemedi- Res Rev 2017;33:e2924 625 cine system enabling flexible diet and insu- 67. Bowen ME, Cavanaugh KL, Wolff K, et al. The 80. Johnston BC, Kanters S, Bandayrel K, et al. lin therapy while improving quality of life: diabetes nutrition education study randomized Comparison of weight loss among named diet an open-label, international, multicenter, ran- controlled trial: a comparative effectiveness programs in overweight and obese adults: domized study. Diabetes Care 2010;33:109– – study of approaches to nutrition in diabetes a meta-analysis. JAMA 2014;312:923 933 115 self-management education. Patient Educ Couns 81. Fox CS, Golden SH, Anderson C, et al.; 94. Laurenzi A, Bolla AM, Panigoni G, et al. 2016;99:1368–1376 American Heart Association Diabetes Committee Effects of carbohydrate counting on glucose 68. Mudaliar U, Zabetian A, Goodman M, et al. of the Council on Lifestyle and Cardiometabolic control and quality of life over 24 weeks in adult Cardiometabolic risk factor changes observed in Health, Council on Clinical Cardiology, Council patients with type 1 diabetes on continuous diabetes prevention programs in US settings: on Cardiovascular and Stroke Nursing, Council on subcutaneous insulin infusion: a randomized, a systematic review and meta-analysis. PLoS Cardiovascular Surgery and Anesthesia, Council prospective clinical trial (GIOCAR). Diabetes – Med 2016;13:e1002095 on Quality of Care and Outcomes Research; Care 2011;34:823 827 69. Balk EM, Earley A, Raman G, Avendano EA, American Diabetes Association. Update on pre- 95. Samann¨ A, Muhlhauser¨ I, Bender R, Kloos Ch, Pittas AG, Remington PL. Combined diet and vention of cardiovascular disease in adults with Muller¨ UA. Glycaemic control and severe hypo- fl physical activity promotion programs to prevent type 2 diabetes mellitus in light of recent evi- glycaemia following training in exible, inten- fi sive insulin therapy to enable dietary freedom type 2 diabetes among persons at increased risk: dence: a scienti c statement from the American Heart Association and the American Diabetes in people with type 1 diabetes: a prospective a systematic review for the Community Preven- Association. Diabetes Care 2015;38:1777–1803 implementation study. Diabetologia 2005;48: tive Services Task Force. Ann Intern Med 2015; 82. DAFNE Study Group. Training in flexible, 1965–1970 163:437–451 intensive insulin management to enable dietary 96. Bell KJ, Barclay AW, Petocz P, Colagiuri S, 70. Franz MJ, Boucher JL, Rutten-Ramos S, freedom in people with type 1 diabetes: Dose Brand-Miller JC. Efficacy of carbohydrate count- VanWormer JJ. Lifestyle weight-loss intervention Adjustment for Normal Eating (DAFNE) random- ing in type 1 diabetes: a systematic review and outcomes in overweight and obese adults with ised controlled trial. BMJ 2002;325:746 meta-analysis. Lancet Diabetes Endocrinol 2014; type 2 diabetes: a systematic review and meta- 83. Delahanty LM, Nathan DM, Lachin JM, 2:133–140 analysis of randomized clinical trials. J Acad Nutr et al.; Diabetes Control and Complications Trial/ 97. Bell KJ, Smart CE, Steil GM, Brand-Miller JC, Diet 2015;115:1447–1463 Epidemiology of Diabetes Interventions and King B, Wolpert HA. Impact of fat, protein, and 71. Sumithran P, Prendergast LA, Delbridge E, Complications. Association of diet with glycated glycemic index on postprandial glucose control et al. Long-term persistence of hormonal adap- hemoglobin during intensive treatment of type 1 in type 1 diabetes: implications for intensive tations to weight loss. N Engl J Med 2011;365: diabetes in the Diabetes Control and Complica- diabetes management in the continuous glucose – 1597 1604 tions Trial. Am J Clin Nutr 2009;89:518–524 monitoring era. Diabetes Care 2015;38:1008– 72. Hamdy O, Mottalib A, Morsi A, et al. Long- 84. Wheeler ML, Dunbar SA, Jaacks LM, et al. 1015 term effect of intensive lifestyle intervention on Macronutrients, food groups, and eating pat- 98. Bell KJ, Toschi E, Steil GM, Wolpert HA. cardiovascular risk factors in patients with di- terns in the management of diabetes: a system- Optimized mealtime insulin dosing for fat and abetes in real-world clinical practice: a 5-year atic review of the literature, 2010. Diabetes Care proteinintype1diabetes:applicationofamodel- longitudinal study. BMJ Open Diabetes Res Care 2012;35:434–445 based approach to derive insulin doses for open- 2017;5:e000259 85. Thomas D, Elliott EJ. Low glycaemic index, or loop diabetes management. Diabetes Care 2016; 73. Lean ME, Leslie WS, Barnes AC, et al. Primary low glycaemic load, diets for diabetes mellitus. 39:1631–1634 care-led weight management for remission of Cochrane Database Syst Rev 2009;1:CD006296 99. Paterson MA, Smart CEM, Lopez PE, et al. type 2 diabetes (DiRECT): an open-label, cluster- 86. Snorgaard O, Poulsen GM, Andersen HK, Influence of dietary protein on postprandial randomised trial. Lancet 2018;391:541–551 Astrup A. Systematic review and meta-analysis blood glucose levels in individuals with type 1 74. Mottalib A, Salsberg V, Mohd-Yusof B-N, of dietary carbohydrate restriction in patients diabetes mellitus using intensive insulin therapy. et al. Effects of nutrition therapy on HbA1c with type 2 diabetes. BMJ Open Diabetes Res Diabet Med 2016;33:592–598 and cardiovascular disease risk factors in over- Care 2017;5:e000354 100. Tuttle KR, Bakris GL, Bilous RW, et al. Di- weight and obese patients with type 2 diabetes. 87. van Wyk HJ, Davis RE, Davies JS. A critical abetic kidney disease: a report from an ADA Nutr J 2018;17:42 review of low-carbohydrate diets in people with Consensus Conference. Diabetes Care 2014;37: 75. Estruch R, Ros E, Salas-Salvado´ J, et al.; type 2 diabetes. Diabet Med 2016;33:148–157 2864–2883 PREDIMED Study Investigators. Primary preven- 88. Meng Y, Bai H, Wang S, Li Z, Wang Q, Chen L. 101. Pan Y, Guo LL, Jin HM. Low-protein diet for tion of cardiovascular disease with a Mediter- Efficacy of low carbohydrate diet for type 2 diabetic nephropathy: a meta-analysis of ran- ranean diet supplemented with extra-virgin olive diabetes mellitus management: a systematic re- domized controlled trials. Am J Clin Nutr 2008; oil or nuts. N Engl J Med 2018;378:e34 viewandmeta-analysisofrandomized controlled 88:660–666 76. EmadianA,AndrewsRC,EnglandCY,Wallace trials. Diabetes Res Clin Pract 2017;131:124–131 102. Robertson L, Waugh N, Robertson A. Pro- V, Thompson JL. The effect of macronutrients on 89. Tay J, Luscombe-Marsh ND, Thompson CH, tein restriction for diabetic renal disease. Co- glycaemic control: a systematic review of dietary et al. Comparison of low- and high-carbohydrate chrane Database Syst Rev 2007;4:CD002181 randomised controlled trials in overweight and diets for type 2 diabetes management: a ran- 103. Layman DK, Clifton P, Gannon MC, Krauss obese adults with type 2 diabetes in which there domized trial. Am J Clin Nutr 2015;102:780–790 RM, Nuttall FQ. Protein in optimal health: heart was no difference in weight loss between treat- 90. U.S. Department of Agriculture and U.S. disease and type 2 diabetes. Am J Clin Nutr 2008; ment groups. Br J Nutr 2015;114:1656–1666 Department of Health and Human Services. 87:1571S–1575S S58 Lifestyle Management Diabetes Care Volume 42, Supplement 1, January 2019

104. Institute of Medicine. Dietary reference Omega-3 EE90 Risk Reduction in Diabetes Association Task Force on Practice Guidelines. intakes for energy, carbohydrate, fiber, fat, fatty (AFORRD): a randomised controlled trial. Diabe- Circulation 2013;129(Suppl.):S76–S99 acids, cholesterol, protein, and amino acids tologia 2009;52:50–59 132. Johnson RK, Lichtenstein AH, Anderson [Internet], 2005. Washington, DC, National 117. KromhoutD, GeleijnseJM, deGoede J, et al. CAM, et al.; American Heart Association Nutrition Academies Press. Available from http:// n-3 fatty acids, ventricular arrhythmia-related Committee of the Council on Lifestyle and Car- www.nationalacademies.org/hmd/Reports/ events, and fatal myocardial infarction in post- diometabolic Health; Council on Cardiovascular 2002/Dietary-Reference-Intakes-for-Energy- myocardial infarction patients with diabetes. and Stroke Nursing; Council on Clinical Cardiol- Carbohydrate-Fiber-Fat-Fatty-Acids-Cholesterol- Diabetes Care 2011;34:2515–2520 ogy; Council on Quality of Care and Outcomes Protein-and-Amino-Acids.aspx. Accessed 2 118. Bosch J, Gerstein HC, Dagenais GR, et al.; Research; Stroke Council. Low-calorie sweetened November 2018 ORIGIN Trial Investigators. n-3 fatty acids and beverages and cardiometabolic health: a science 105. Ros E. Dietary cis-monounsaturated fatty cardiovascular outcomes in patients with dys- advisory from the American Heart Association. acids and metabolic control in type 2 diabetes. glycemia. N Engl J Med 2012;367:309–318 Circulation 2018;138:e126–e140 Am J Clin Nutr 2003;78(Suppl.):617S–625S 119. Thomas MC, Moran J, Forsblom C, et al.; 133. 2018 Physical Activity Guidelines Advisory 106. Forouhi NG, Imamura F, Sharp SJ, et al. FinnDianeStudy Group. Theassociationbetween Committee. 2018 Physical Activity Guidelines Association of plasma phospholipid n-3 and n-6 dietary sodium intake, ESRD, and all-cause mor- Advisory Committee Scientific Report. Washing- polyunsaturated fatty acids with type 2 diabetes: tality in patients with type 1 diabetes. Diabetes ton, DC, U.S. Department of Health and Human the EPIC-InterAct case-cohort study. PLoS Med Care 2011;34:861–866 Services, 2018 2016;13:e1002094 120. Ekinci EI,Clarke S,Thomas MC,et al. Dietary 134. Bazargan-Hejazi S, Arroyo JS, Hsia S, Brojeni 107. Wang DD, Li Y, Chiuve SE, et al. Association salt intake and mortality in patients with type 2 NR, Pan D. A racial comparison of differences fi – of speci c dietary fats with total and cause- diabetes. Diabetes Care 2011;34:703 709 between self-reported and objectively measured fi speci c mortality. JAMA Intern Med 2016;176: 121. Lennon SL, DellaValle DM, Rodder SG, et al. physical activity among US adults with diabetes. – 1134 1145 2015 Evidence Analysis Library evidence-based Ethn Dis 2017;27:403–410 108. Brehm BJ, Lattin BL, Summer SS, et al. One- nutrition practice guideline for the management 135. Sluik D, Buijsse B, Muckelbauer R, et al. – year comparison of a high monounsaturated of hypertension in adults. J Acad Nutr Diet 2017; Physical activity and mortality in individuals – fat diet with a high-carbohydrate diet in 117:1445 1458.e17 with diabetes mellitus: a prospective study and – fl type 2 diabetes. Diabetes Care 2009;32:215 220 122. Maillot M, Drewnowski A. A con ict be- meta-analysis. Arch Intern Med 2012;172:1285– 109. Shai I, Schwarzfuchs D, Henkin Y, et al.; tween nutritionally adequate diets and meeting 1295 Dietary Intervention Randomized Controlled the 2010 dietary guidelines for sodium. Am J Prev 136. Tikkanen-Dolenc H, Waden´ J, Forsblom C, – Trial (DiRECT) Group. Weight loss with a low- Med 2012;42:174 179 et al.; FinnDiane Study Group. Physical activity carbohydrate, Mediterranean, or low-fat diet. 123. Aroda VR, Edelstein SL, Goldberg RB, et al.; reduces risk of premature mortality in patients N Engl J Med 2008;359:229–241 Diabetes Prevention Program Research Group. with type 1 diabetes with and without kidney 110. Brunerova L, Smejkalova V, Potockova J, Long-term metformin use and vitamin B12 de- disease. Diabetes Care 2017;40:1727–1732 Andel M. A comparison of the influence of a high- ficiency in the Diabetes Prevention Program 137. Boule´ NG, Haddad E, Kenny GP, Wells GA, fat diet enriched in monounsaturated fatty acids Outcomes Study. J Clin Endocrinol Metab Sigal RJ. Effects of exercise on glycemic control and conventional diet on weight loss and met- 2016;101:1754–1761 and body mass in type 2 diabetes mellitus: abolic parameters in obese non-diabetic and 124. Allen RW, Schwartzman E, Baker WL, a meta-analysis of controlled clinical trials. type 2 diabetic patients. Diabet Med 2007;24: Coleman CI, Phung OJ. Cinnamon use in type 2 JAMA 2001;286:1218–1227 533–540 diabetes: an updated systematic review and 138. Colberg SR, Riddell MC. Physical activity: 111. Bloomfield HE, Koeller E, Greer N, meta-analysis. Ann Fam Med 2013;11:452–459 regulation of glucose metabolism, clinical man- MacDonald R, Kane R, Wilt TJ. Effects on health 125. Mitri J, Pittas AG. Vitamin D and diabetes. outcomes of a Mediterranean diet with no re- Endocrinol Metab Clin North Am 2014;43: agement strategies, and weight control. In Amer- striction on fat intake: a systematic review and 205–232 ican Diabetes Association/JDRF Type 1 Diabetes meta-analysis. Ann Intern Med 2016;165:491– 126. Mozaffarian D. Dietary and policy priorities Sourcebook. Peters A, Laffel L, Eds. Alexandria, 500 for cardiovascular disease, diabetes, and obesity: VA, American Diabetes Association, 2013 112. Sacks FM, Lichtenstein AH, Wu JHY, et al.; a comprehensive review. Circulation 2016;133: 139. Ostman C, Jewiss D, King N, Smart NA. American Heart Association. Dietary fats and 187–225 Clinical outcomes to exercise training in type 1 cardiovascular disease: a presidential advisory 127. Grotz VL, Pi-Sunyer X, Porte D Jr, Roberts A, diabetes: a systematic review and meta-analysis. – from the American Heart Association. Circulation Richard Trout J. A 12-week randomized clinical Diabetes Res Clin Pract 2018;139:380 391 2017;136:e1–e23 trial investigating the potential for sucralose to 140. Boule´ NG, Kenny GP, Haddad E, Wells GA, 113. Jacobson TA, Maki KC, Orringer CE, et al.; affect glucose homeostasis. Regul Toxicol Phar- Sigal RJ. Meta-analysis of the effect of structured fi NLA Expert Panel. National Lipid Association macol 2017;88:22–33 exercise training on cardiorespiratory tness in recommendations for patient-centered manage- 128. Miller PE, Perez V. Low-calorie sweeteners type 2 diabetes mellitus. Diabetologia 2003;46: ment of dyslipidemia: part 2. J Clin Lipidol 2015;9 and body weight and composition: a meta- 1071–1081 (Suppl.):S1–S122.e1 analysis of randomized controlled trials and 141. Rejeski WJ, Ip EH, Bertoni AG, et al.; Look 114. Harris WS, Mozaffarian D, Rimm E, et al. prospective cohort studies. Am J Clin Nutr AHEAD Research Group. Lifestyle change and Omega-6 fatty acids and risk for cardiovascular 2014;100:765–777 mobility in obese adults with type 2 diabetes. N disease: a science advisory from the American 129. Rogers PJ, Hogenkamp PS, de Graaf C, et al. Engl J Med 2012;366:1209–1217 Heart Association Nutrition Subcommittee of the Does low-energy sweetener consumption affect 142. Colberg SR, Sigal RJ, Yardley JE, et al. Council on Nutrition, Physical Activity, and Me- energy intake and body weight? A systematic Physical activity/exercise and diabetes: a posi- tabolism; Council on Cardiovascular Nursing; review, including meta-analyses, of the evidence tion statement of the American Diabetes Asso- and Council on Epidemiology and Prevention. from human and animal studies. Int J Obes 2016; ciation. Diabetes Care 2016;39:2065–2079 Circulation 2009;119:902–907 40:381–394 143. Janssen I, Leblanc AG. Systematic review of 115. Crochemore ICC, Souza AFP, de Souza 130. Azad MB, Abou-Setta AM, Chauhan BF, the health benefits of physical activity and fit- ACF, Rosado EL. v-3 polyunsaturated fatty acid et al. Nonnutritive sweeteners and cardiometa- ness in school-aged children and youth. Int J supplementation does not influence body bolic health: a systematic review and meta- Behav Nutr Phys Act 2010;7:40 composition, insulin resistance, and lipemia in analysis of randomized controlled trials and 144. Riddell MC, Gallen IW, Smart CE, et al. women with type 2 diabetes and obesity. Nutr prospective cohort studies. CMAJ 2017;189: Exercise management in type 1 diabetes: a con- Clin Pract 2012;27:553–560 E929–E939 sensus statement. Lancet Diabetes Endocrinol 116. Holman RR, Paul S, Farmer A, Tucker L, 131. EckelRH,JakicicJM,ArdJD,etal.2013AHA/ 2017;5:377–390 Stratton IM, Neil HA; Atorvastatin in Factorial ACC guideline on lifestyle management to reduce 145. Anderson BJ, Laffel LM, Domenger C, et al. with Omega-3 EE90 Risk Reduction in Diabetes cardiovascular risk: a report of the Ameri- Factors associated with diabetes-specific health- Study Group. Atorvastatin in Factorial with can College of Cardiology/American Heart related quality of life in youth with type 1 care.diabetesjournals.org Lifestyle Management S59

diabetes: the global TEENs study. Diabetes Care 162. Pop-Busui R, Evans GW, Gerstein HC, et al.; 177. Voulgari C, Katsilambros N, Tentolouris N. 2017;40:1002–1009 Action to Control Cardiovascular Risk in Diabetes Smoking cessation predicts amelioration of 146. Jelleyman C, Yates T, O’Donovan G, et al. Study Group. Effects of cardiac autonomic dys- microalbuminuria in newly diagnosed type 2 The effects of high-intensity interval training on function on mortality risk in the Action to Control diabetes mellitus: a 1-year prospective study. glucose regulationand insulin resistance:a meta- Cardiovascular Risk in Diabetes (ACCORD) trial. Metabolism 2011;60:1456–1464 analysis. Obes Rev 2015;16:942–961 Diabetes Care 2010;33:1578–1584 178. Huerta TR, Walker DM, Mullen D, Johnson 147. Little JP, Gillen JB, Percival ME, et al. Low- 163. Suarez L, Barrett-Connor E. Interaction be- TJ, Ford EW. Trends in e-cigarette awareness volume high-intensity interval training reduces tween cigarette smoking and diabetes mellitus and perceived harmfulness in the U.S. Am J Prev hyperglycemia and increases muscle mitochon- in the prediction of death attributed to cardio- Med 2017;52:339–346 drial capacity in patients with type 2 diabetes. J vascular disease. Am J Epidemiol 1984;120:670– 179. Pericot-Valverde I, Gaalema DE, Priest JS, Appl Physiol (1985) 2011;111:1554–1560 675 Higgins ST. E-cigarette awareness, perceived 148. U.S. Department of Health and Human 164. Stanton CA, Keith DR, Gaalema DE, et al. harmfulness, and ever use among U.S. adults. Services. 2008 physical activity guidelines for Trends in tobacco use among US adults with Prev Med 2017;104:92–99 Americans [Internet], 2008. Available from chronic health conditions: National Survey on 180. Leventhal AM, Strong DR, Kirkpatrick MG, https://health.gov/paguidelines/guidelines/default Drug Use and Health 2005–2013. Prev Med 2016; et al. Association of electronic cigarette use with .aspx. Accessed 2 November 2018 92:160–168 initiation of combustible tobacco product smok- 149. Willey KA, Singh MAF. Battling insulin re- 165. Bae J. Differences in cigarette use behaviors ing in early adolescence. JAMA 2015;314:700– sistance in elderly obese people with type 2 by age at the time of diagnosis with diabetes from 707 diabetes: bring on the heavy weights. Diabetes young adulthood to adulthood: results from 181. Leventhal AM, Stone MD, Andrabi N, et al. Care 2003;26:1580–1588 the National Longitudinal Study of Adolescent Association of e-cigarette vaping and progres- 150. Katzmarzyk PT, Church TS, Craig CL, Health. J Prev Med Public Health 2013;46: sion to heavier patterns of cigarette smoking. Bouchard C. Sitting time and mortality from 249–260 JAMA 2016;316:1918–1920 all causes, cardiovascular disease, and cancer. 166. Sliwi´ nska-Mosso´ n´ M, Milnerowicz H. The 182. Hartmann-Boyce J, McRobbie H, Bullen C, Med Sci Sports Exerc 2009;41:998–1005 impact of smoking on the development of di- Begh R, Stead LF, Hajek P. Electronic cigarettes 151. Dempsey PC, Larsen RN, Sethi P, et al. abetes and its complications. Diab Vasc Dis Res for smoking cessation. Cochrane Database Syst Beneﬁts for type 2 diabetes of interrupting 2017;14:265–276 Rev 2016;9:CD010216 prolonged sitting with brief bouts of light walking 167. Kar D, Gillies C, Zaccardi F, et al. Relation- 183. Halpern SD, Harhay MO, Saulsgiver K, or simple resistance activities. Diabetes Care ship of cardiometabolic parameters in non- Brophy C, Troxel AB, Volpp KG. A pragmatic trial 2016;39:964–972 smokers, current smokers, and quitters in diabetes: of e-cigarettes, incentives, and drugs for smoking 152. Cui J, Yan J-H, Yan L-M, Pan L, Le J-J, Guo Y-Z. a systematic review and meta-analysis. Cardio- cessation. N Engl J Med 2018;378:2302–2310 Effects of yoga in adults with type 2 diabetes vasc Diabetol 2016;15:158 184. Schraufnagel DE, Blasi F, Drummond MB, mellitus: a meta-analysis. J Diabetes Investig 168. Jankowich M, Choudhary G, Taveira TH, Wu et al.; Forum of International Respiratory Soci- 2017;8:201–209 W-C. Age-, race-, and gender-speciﬁc prevalence eties. Electronic cigarettes. A position statement 153. Lee MS, Jun JH, Lim H-J, Lim H-S. A sys- of diabetes among smokers. Diabetes Res Clin of the Forum of International Respiratory Soci- tematic review and meta-analysis of tai chi for Pract 2011;93:e101–e105 eties. Am J Respir Crit Care Med 2014;190:611– treating type 2 diabetes. Maturitas 2015;80:14–23 169. Akter S, Goto A, Mizoue T. Smoking and the 618 154. Colberg SR, Sigal RJ, Fernhall B, et al.; risk of type 2 diabetes in Japan: a systematic 185. Bam TS, Bellew W, Berezhnova I, et al.; American College of Sports Medicine; American review and meta-analysis. J Epidemiol 2017;27: Tobacco Control Department International Union Diabetes Association. Exercise and type 2 di- 553–561 Against Tuberculosis and Lung Disease. Position abetes. The American College of Sports Medicine 170. Liu X, Bragg F, Yang L, et al.; China Kadoorie statement on electronic cigarettes or electronic and the American Diabetes Association: joint Biobank Collaborative Group. Smoking and nicotine delivery systems. Int J Tuberc Lung Dis position statement executive summary. Diabe- smoking cessation in relation to risk of diabetes 2014;18:5–7 tes Care 2010;33:2692–2696 in Chinese men and women: a 9-year prospective 186. Bhatnagar A, Whitsel LP, Ribisl KM, et al.; 155. Church TS, Blair SN, Cocreham S, et al. study of 0.5 million people. Lancet Public Health American Heart Association Advocacy Coordi- Effects of aerobic and resistance training on 2018;3:e167–e176 nating Committee, Council on Cardiovascular hemoglobin A1c levels in patients with type 2 171. Yeh HC, Duncan BB, Schmidt MI, Wang NY, and Stroke Nursing, Council on Clinical Cardiol- diabetes: a randomized controlled trial. JAMA Brancati FL. Smoking, smoking cessation, and ogy, and Council on Quality of Care and Out- 2010;304:2253–2262 risk for type 2 diabetes mellitus: a cohort study. comes Research. Electronic cigarettes: a policy 156. Bax JJ, Young LH, Frye RL, Bonow RO, Ann Intern Med 2010;152:10–17 statement from the American Heart Association. Steinberg HO, Barrett EJ; ADA. Screening for 172. Tonstad S, Lawrence D. Varenicline in Circulation 2014;130:1418–1436 coronary artery disease in patients with diabe- smokers with diabetes: a pooled analysis 187. Young-Hyman D, de Groot M, Hill-Briggs F, tes. Diabetes Care 2007;30:2729–2736 of 15 randomized, placebo-controlled studies Gonzalez JS, Hood K, Peyrot M. Psychosocial care 157. Peters A, Laffel L (Eds.). American Diabetes of varenicline. J Diabetes Investig 2017;8:93– for people with diabetes: a position statement of Association/JDRF Type 1 Diabetes Sourcebook. 100 the American Diabetes Association. Diabetes Alexandria, VA, American Diabetes Association, 173. West R. Tobacco smoking: health impact, Care 2016;39:2126–2140 2013 prevalence, correlates and interventions. Psy- 188. Anderson RJ, Grigsby AB, Freedland KE, 158. Colberg SR. Exercise and Diabetes: A Clini- chol Health 2017;32:1018–1036 et al. Anxiety and poor glycemic control: cian’s Guide to Prescribing Physical Activity. 174. Ranney L, Melvin C, Lux L, McClain E, Lohr a meta-analytic review of the literature. Int J Alexandria, VA, American Diabetes Association, 2013 KN. Systematic review: smoking cessation in- Psychiatry Med 2002;32:235–247 159. Lemaster JW, Reiber GE, Smith DG, Heagerty tervention strategies for adults and adults in 189. Delahanty LM, Grant RW, Wittenberg E, PJ, Wallace C. Daily weight-bearing activity does special populations. Ann Intern Med 2006;145: et al. Association of diabetes-related emotional not increase the risk of diabetic foot ulcers. Med 845–856 distress with diabetes treatment in primary care Sci Sports Exerc 2003;35:1093–1099 175. Tian J, Venn A, Otahal P, Gall S. The patients with type 2 diabetes. Diabet Med 2007; 160. Smith AG, Russell J, Feldman EL, et al. association between quitting smoking and 24:48–54 Lifestyle intervention for pre-diabetic neuropa- weight gain: a systematic review and meta- 190. Anderson RJ, Freedland KE, Clouse RE, thy. Diabetes Care 2006;29:1294–1299 analysis of prospective cohort studies. Obes Lustman PJ. The prevalence of comorbid de- 161. Spallone V, Ziegler D, Freeman R, et al.; Rev 2015;16:883–901 pression in adults with diabetes: a meta-analysis. Toronto Consensus Panel on Diabetic Neuropa- 176. Clair C, Rigotti NA, Porneala B, et al. As- Diabetes Care 2001;24:1069–1078 thy. Cardiovascular autonomic neuropathy in sociation of smoking cessation and weight 191. Kovacs Burns K, Nicolucci A, Holt RIG, et al.; diabetes: clinical impact, assessment, diagnosis, change with cardiovascular disease among adults DAWN2 Study Group. Diabetes Attitudes, Wishes and management. Diabetes Metab Res Rev with and without diabetes. JAMA 2013;309:1014– and Needs second study (DAWN2Ô): cross- 2011;27:639–653 1021 national benchmarking indicators for family S60 Lifestyle Management Diabetes Care Volume 42, Supplement 1, January 2019

members living with people with diabetes. Dia- 195. Fisher L, Glasgow RE, Strycker LA. The 199. Gary TL, Safford MM, Gerzoff RB, et al. bet Med 2013;30:778–788 relationship between diabetes distress and clin- Perception of neighborhood problems, health 192. Harkness E, Macdonald W, Valderas J, ical depression with glycemic control among behaviors, and diabetes outcomes among Coventry P, Gask L, Bower P. Identifying psycho- patients with type 2 diabetes. Diabetes Care adults with diabetes in managed care: the social interventions that improve both physical 2010;33:1034–1036 TranslatingResearchIntoActionforDiabe- – and mental health in patients with diabetes: 196. Aikens JE. Prospective associations betes (TRIAD) study. Diabetes Care 2008;31:273 a systematic review and meta-analysis. Diabetes tween emotional distress and poor outcomes 278 Care 2010;33:926–930 200. Beverly EA, Hultgren BA, Brooks KM, in type 2 diabetes. Diabetes Care 2012;35:2472– 193. Nicolucci A, Kovacs Burns K, Holt RIG, Ritholz MD, Abrahamson MJ, Weinger K. Un- 2478 et al.; DAWN2 Study Group. Diabetes Attitudes, derstanding physicians’ challenges when treat- 197. Fisher L, Skaff MM, Mullan JT, et al. Clinical Wishes and Needs second study (DAWN2Ô): ing type 2 diabetic patients’ social and emotional cross-national benchmarking of diabetes-related depression versus distress among patients with difﬁculties: a qualitative study. Diabetes Care psychosocial outcomes for people with diabetes. type 2 diabetes: not just a question of semantics. 2011;34:1086–1088 Diabet Med 2013;30:767–777 Diabetes Care 2007;30:542–548 201. Huang Y, Wei X, Wu T, Chen R, Guo A. 194. Fisher L, Hessler DM, Polonsky WH, Mullan 198. Snoek FJ, Bremmer MA, Hermanns N. Con- Collaborative care for patients with depres- J. When is diabetes distress clinically mean- structs of depression and distress in diabetes: sion and diabetes mellitus: a systematic review ingful?: establishing cut points for the Diabetes time for an appraisal. Lancet Diabetes Endocrinol and meta-analysis. BMC Psychiatry 2013;13: Distress Scale. Diabetes Care 2012;35:259–264 2015;3:450–460 260 Diabetes Care Volume 42, Supplement 1, January 2019 S61

6. Glycemic Targets: Standards of American Diabetes Association Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S61–S70 | https://doi.org/10.2337/dc19-S006

ASSESSMENT OF GLYCEMIC CONTROL Glycemic management is primarily assessed with the A1C test, which was the measure studied in clinical trials demonstrating the beneﬁts of improved glycemic control. Patient self-monitoring of blood glucose (SMBG) may help with self-management and medication adjustment, particularly in individuals taking insulin. Continuous glucose monitoring (CGM) also has an important role in assessing the effectiveness and safety of treatment in many patients with type 1 diabetes, and limited data suggest it may also be helpful in selected patients with type 2 diabetes, such as those on intensive insulin regimens (1).

A1C Testing

Recommendations 6.1 Perform the A1C test at least two times a year in patients who are meeting treatment goals (and who have stable glycemic control). E 6.2 Perform the A1C test quarterly in patients whose therapy has changed or who are not meeting glycemic goals. E 6.3 Point-of-care testing for A1C provides the opportunity for more timely treatment changes. E

A1C reflects average glycemia over approximately 3 months. The performance of the fi test is generally excellent for NGSP-certi ed assays (www.ngsp.org). The test is the Suggested citation: American Diabetes Associa- major tool for assessing glycemic control and has strong predictive value for diabetes tion. 6. Glycemic targets: Standards of Medical complications (1–3). Thus, A1C testing should be performed routinely in all patients Care in Diabetesd2019. Diabetes Care 2019; with diabetesdat initial assessment and as part of continuing care. Measurement 42(Suppl. 1):S61–S70 approximately every 3 months determines whether patients’ glycemic targets have © 2018 by the American Diabetes Association. been reached and maintained. The frequency of A1C testing should depend on the Readers may use this article as long as the work ’ is properly cited, the use is educational and not clinical situation, the treatment regimen, and the clinician s judgment. The use of for profit, and the work is not altered. More infor- point-of-care A1C testing may provide an opportunity for more timely treatment mation is available at http://www.diabetesjournals changes during encounters between patients and providers. Patients with type 2 .org/content/license. S62 Glycemic Targets Diabetes Care Volume 42, Supplement 1, January 2019

diabetes with stable glycemia well A1C and Mean Glucose significant interference may explain a within target may do well with A1C Table 6.1 shows the correlation between report that for any level of mean glyce- testing only twice per year. Unstable A1C levels and mean glucose levels based mia, African Americans heterozygous for or intensively managed patients (e.g., on two studies: the international A1C- the common hemoglobin variant HbS pregnant women with type 1 diabetes) Derived Average Glucose (ADAG) study, had lower A1C by about 0.3 percentage may require testing more frequently which assessed the correlation between points when compared with those with- than every 3 months (4). A1C and frequent SMBG and CGM in out the trait (10,11). Another genetic 507 adults (83% non-Hispanic whites) variant, X-linked glucose-6-phosphate A1C Limitations with type 1, type 2, and no diabetes (6), dehydrogenase G202A, carried by 11% The A1C test is an indirect measure of and an empirical study of the average of African Americans, was associated average glycemia and, as such, is subject blood glucose levels at premeal, post- with a decrease in A1C of about 0.8% to limitations. As with any laboratory meal, and bedtime associated with spec- in hemizygous men and 0.7% in homo- test, there is variability in the measure- ified A1C levels using data from the ADAG zygous women compared with those ment of A1C. Although such variability trial (7). The American Diabetes Associ- without the trait (12). is less on an intraindividual basis than ation (ADA) and the American Associa- A small study comparing A1C to CGM that of blood glucose measurements, clini- tion for Clinical Chemistry have determined data in children with type 1 diabetes cians should exercise judgment when that the correlation (r 5 0.92) in the ADAG found a highly statistically significant using A1C as the sole basis for assessing trial is strong enough to justify reporting correlation between A1C and mean glycemic control, particularly if the result both the A1C result and the estimated blood glucose, although the correla- is close to the threshold that might average glucose (eAG) result when a cli- tion (r 5 0.7) was significantly lower prompt a change in medication therapy. nician orders the A1C test. Clinicians than in the ADAG trial (13). Whether Conditions that affect red blood cell should note that the mean plasma glu- there are clinically meaningful differ- turnover (hemolytic and other anemias, cose numbers in the table are based on ences in how A1C relates to average glucose-6-phosphate dehydrogenase ;2,700 readings per A1C in the ADAG glucose in children or in different deficiency, recent blood transfusion, trial. In a recent report, mean glucose ethnicities is an area for further study use of drugs that stimulate erythropoesis, measured with CGM versus central (8,14,15). Until further evidence is end-stage kidney disease, and pregnancy) laboratory–measured A1C in 387 par- available, it seems prudent to estab- may result in discrepancies between ticipants in three randomized trials lish A1C goals in these populations the A1C result and the patient’strue demonstrated that A1C may underesti- with consideration of both individual- mean glycemia. Hemoglobin variants mate or overestimate mean glucose (5). ized SMBG and A1C results. must be considered, particularly when Thus, as suggested, a patient’s CGM the A1C result does not correlate with profile has considerable potential for Glucose Assessment the patient’sSMBGlevels.However, optimizing his or her glycemic manage- For many people with diabetes, glucose most assays in use in the U.S. are accurate ment (5). monitoring is key for the achievement of in individuals heterozygous for the most glycemic targets. Major clinical trials of common variants (www.ngsp.org/interf A1C Differences in Ethnic Populations and insulin-treated patients have included .asp). Other measures of average gly- Children SMBG as part of multifactorial inter- cemia such as fructosamine and 1,5- In the ADAG study, there were no sig- ventions to demonstrate the benefitof anhydroglucitol are available, but their nificant differences among racial and intensive glycemic control on diabetes translation into average glucose levels ethnic groups in the regression lines complications (16). SMBG is thus an in- and their prognostic significance are not between A1C and mean glucose, al- tegral component of effective therapy of as clear as for A1C. Though some vari- though the study was underpowered patients taking insulin. In recent years, ability in the relationship between av- to detect a difference and there was CGM has emerged as a complementary erage glucose levels and A1C exists a trend toward a difference between method for the assessment of glucose among different individuals, generally the African/African American and non- levels. Glucose monitoring allows pa- the association between mean glucose Hispanic white cohorts, with higher tients to evaluate their individual re- and A1C within an individual correlates A1C values observed in Africans/African sponse to therapy and assess whether over time (5). Americans compared with non-Hispanic glycemic targets are being safely A1C does not provide a measure of whites for a given mean glucose. Other achieved. Integrating results into diabe- glycemic variability or hypoglycemia. For studies have also demonstrated higher tes management can be a useful tool patients prone to glycemic variability, A1C levels in African Americans than in for guiding medical nutrition therapy especially patients with type 1 diabetes whites at a given mean glucose concen- and physical activity, preventing hypo- or type 2 diabetes with severe insulin tration (8,9). glycemia, and adjusting medications (par- deficiency, glycemic control is best eval- A1C assays are available that do not ticularly prandial insulin doses). The uated by the combination of results from demonstrate a statistically significant patient’s specific needs and goals should SMBG or CGM and A1C. A1C may also difference in individuals with hemoglo- dictate SMBG frequency and timing or inform the accuracy of the patient’s bin variants. Other assays have statisti- the consideration of CGM use. Please meter (or the patient’s reported SMBG cally significant interference, but the refer to Section 7 “Diabetes Technology” results) and the adequacy of the SMBG difference is not clinically significant. for a fuller discussion of the use of SMBG testing schedule. Use of an assay with such statistically and CGM. care.diabetesjournals.org Glycemic Targets S63 a .2(6). 0.92 was aai aetee ersn 5 I nesohrientd acltrfrcnetn 1 eut noeG nete gd rmo/,i availabl is mmol/L, or mg/dL either in eAG, into results A1C converting for calculator of A data noted. ADAG otherwise on unless based CI, are 95% represent parentheses in Data 2(0)28(240 298 (108) 12 mo/o)m/Lmo/ gd mlLm/Lmo/ gd mlLm/Lmmol/L mg/dL mmol/L glucose bedtime Mean mg/dL mmol/L glucose postmeal Mean mg/dL (217 269 glucose premeal Mean mmol/L (147 183 (97) 11 glucose fasting mg/dL Mean (123 154 8.0 (64) 8 mmol/L 7.5 (100 126 glucose* 7.0 plasma Mean (53) 7 6.5 mg/dL 5.5 (42) 6 (mmol/mol) % A1C 6.1 Table 0(6 4 (193 240 (170 212 (86) 10 (75) 9 A1C GOALS – – – – –

. (64 8.5 (58 7.99 (53 7.49 (47 6.99 (37 6.49 For glycemic goals in older adults, please refer to Section 12 “Older Adults.” For —

– glycemic goals in children, please refer to 9 7 (164 178 69) – – – – enguoelvl o speci for levels glucose Mean 4 6 (157 167 (143 152 (135 142 (117 122 64) 58) 53) 47) Section 13 “Children and Adolescents.” For glycemic goals in pregnant women, please refer to Section 14 “Management of Diabetes in Pregnancy.” ; – – – – – – – 4)1. (13.3 16.5 347) 1)1. (12.0 14.9 314) (8.1 10.2 217) (6.8 8.6 185) (5.5 7.0 152) 8)1. (10.7 13.4 (9.4 11.8 282) 249) ,0 lcs esrmnsoe otsprACmaueeti 0 dlsw adults 507 in measurement A1C per months 3 over measurements glucose 2,700 Recommendations 6.4 A reasonable A1C goal for many nonpregnant adults is ,7% (53 mmol/mol). A 6.5 Providers might reasonably sug- fi – – – – dAClvl (6,7) levels A1C ed 12.1) 10.3) 8.5) 13.9) – – – 19.3) 17.5) 15.7) gest more stringent A1C goals (such as ,6.5% [48 mmol/mol]) for selected individual patients if this can be achieved without significant hypoglycemia or other – – – – – adverse effects of treatment 7)93(8.7 9.3 (7.9 8.4 177) 162) (7.5 7.9 (6.5 6.8 150) 127) 9)99(9.1 9.9 192) (i.e., polypharmacy). Appropriate patients might include those with short duration of diabetes, type 2 diabetes treated with lifestyle or – – – – – metformin only, long life expec- .)15(148 155 (147 152 9.8) 9.0) (134 139 (115 118 8.3) 7.0) 07 7 (167 179 10.7) tancy, or no significant cardiovascular disease. C 6.6 Less stringent A1C goals (such as ,8% [64 mmol/mol]) may be appropriate for patients – – – – – 6)86(8.2 8.6 (8.2 8.4 161) 157) (7.4 7.7 (6.4 6.5 144) 121) 9)99(9.3 9.9 191) with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, exten- t ye1 ye2 n odaee.The diabetes. no and 2, type 1, type ith sive comorbid conditions, or – – – – – .)19(180 189 (170 176 8.9) 8.7) (159 164 (139 144 8.0) 6.7) 06 0 (195 206 10.6) long-standing diabetes in whom the goal is difficult to achieve despite diabetes self-management education, appropriate glucose monitoring, and effective doses – – – – – 9)1. (10.0 10.5 (9.4 9.8 197) 183) (8.8 9.1 (7.7 8.0 169) 148) 1)1. (10.8 11.4 217) of multiple glucose-lowering agents including insulin. B

tht:/rfsinldaee.r/A.*hs estimates *These http://professional.diabetes.org/eAG. at e 6.7 Reassess glycemic targets over time based on the criteria in Fig. 6.1 or, in older adults, Table

– – – 12.1. E 02 7 (166 177 10.2) (145 153 (131 136 9.4) 8.2) – – orlto ewe 1 n average and A1C between correlation 09 7 (163 175 10.9) 20 2 (197 222 12.0)

A1C and Microvascular Complications Hyperglycemia deﬁnes diabetes, and glycemic control is fundamental to diabetes – – – – – 8)97(9.0 9.7 (9.2 9.8 188) 188) (8.0 8.5 (7.3 7.5 161) 141) 4)1. (10.9 12.3 248) management. The Diabetes Control and Complications Trial (DCCT) (16), a prospective randomized controlled trial of intensive (mean A1C about 7% [53 mmol/mol]) versus standard (mean

– – – – A1C about 9% [75 mmol/mol]) glycemic 10.4) 10.4) 8.9) 7.8) – 13.8) glucose control in patients with type 1 diabetes, showed deﬁnitively that better glycemic control is associated with 50–76% S64 Glycemic Targets Diabetes Care Volume 42, Supplement 1, January 2019

Figure 6.1—Depicted are patient and disease factors used to determine optimal A1C targets. Characteristics and predicaments toward the left justify more stringent efforts to lower A1C; those toward the right suggest less stringent efforts. A1C 7% 5 53 mmol/mol. Adapted with permission from Inzucchi et al. (40).

reductions in rates of development and instituted early in the course of dis- MR Controlled Evaluation [ADVANCE], and progression of microvascular (retinopa- ease. Epidemiologic analyses of the Veterans Affairs Diabetes Trial [VADT]) thy, neuropathy, and diabetic kidney DCCT (16) and UKPDS (23) demonstrate were conducted to test the effects of disease) complications. Follow-up of the a curvilinear relationship between A1C near normalization of blood glucose on DCCT cohorts in the Epidemiology of and microvascular complications. Such cardiovascular outcomes in individuals Diabetes Interventions and Complica- analyses suggest that, on a population with long-standing type 2 diabetes and tions (EDIC) study (17,18) demonstrated level, the greatest number of complica- either known cardiovascular disease persistence of these microvascular ben- tions will be averted by taking patients (CVD) or high cardiovascular risk. These efits over two decades despite the fact from very poor control to fair/good con- trials showed that lower A1C levels were that the glycemic separation between trol. These analyses also suggest that associated with reduced onset or pro- the treatment groups diminished and further lowering of A1C from 7% to gression of some microvascular compli- disappeared during follow-up. 6% [53 mmol/mol to 42 mmol/mol] is cations (24–26). The Kumamoto Study (19) and UK associated with further reduction in The concerning mortality findings in Prospective Diabetes Study (UKPDS) the risk of microvascular complications, the ACCORD trial (27), discussed be- (20,21) confirmed that intensive glyce- although the absolute risk reductions low, and the relatively intense efforts mic control significantly decreased rates become much smaller. Given the sub- required to achieve near euglycemia of microvascular complications in pa- stantially increased risk of hypoglycemia should also be considered when setting tients with short-duration type 2 diabe- in type 1 diabetes trials and with poly- glycemic targets for individuals with long- tes. Long-term follow-up of the UKPDS pharmacy in type 2 diabetes, the risks standing diabetes such as those stud- cohorts showed enduring effects of early of lower glycemic targets may outweigh ied in ACCORD, ADVANCE, and VADT. glycemic control on most microvascular the potential benefits on microvascular Findings from these studies suggest complications (22). complications. caution is needed in treating diabetes Therefore, achieving A1C targets of Three landmark trials (Action to Con- aggressively to near-normal A1C goals ,7% (53 mmol/mol) has been shown trol Cardiovascular Risk in Diabetes in people with long-standing type 2 di- to reduce microvascular complications [ACCORD], Action in Diabetes and Vas- abetes with or at significant risk of CVD. of type 1 and type 2 diabetes when cular Disease: Preterax and Diamicron However, on the basis of physician care.diabetesjournals.org Glycemic Targets S65

judgment and patient preferences, select more advanced type 2 diabetes than or advanced age/frailty may benefitfrom patients, especially those with little co- UKPDS participants. All three trials were less aggressive targets (36,37). morbidity and long life expectancy, may conducted in relatively older participants As discussed further below, severe benefit from adopting more intensive with longer known duration of diabetes hypoglycemia is a potent marker of glycemic targets (e.g., A1C target ,6.5% (mean duration 8–11 years) and either high absolute risk of cardiovascular [48 mmol/mol]) if they can achieve it CVD or multiple cardiovascular risk fac- events and mortality (38). Providers safely without hypoglycemia or signifi- tors. The target A1C among intensive- should be vigilant in preventing hypo- cant therapeutic burden. control subjects was ,6% (42 mmol/mol) glycemia and should not aggressively in ACCORD, ,6.5% (48 mmol/mol) in attempt to achieve near-normal A1C ADVANCE, and a 1.5% reduction in A1C levels in patients in whom such targets A1C and Cardiovascular Disease compared with control subjects in VADT, cannot be safely and reasonably achieved. Outcomes with achieved A1C of 6.4% vs. 7.5% As discussed in Section 9 “Pharmaco- Cardiovascular Disease and Type 1 Diabetes (46 mmol/mol vs. 58 mmol/mol) in logic Approaches to Glycemic Treatment,” CVD is a more common cause of death ACCORD, 6.5% vs. 7.3% (48 mmol/mol addition of specific sodium–glucose co- than microvascular complications in pop- vs. 56 mmol/mol) in ADVANCE, and 6.9% transporter 2 inhibitors (SGLT2i) or ulations with diabetes. There is evidence vs. 8.4% (52 mmol/mol vs. 68 mmol/mol) glucagon-like peptide 1 receptor ago- fi for a cardiovascular bene t of intensive in VADT. Details of these studies are nists (GLP-1 RA) to improve cardiovascular glycemic control after long-term follow- reviewed extensively in “Intensive Gly- outcomes in patients with established up of cohorts treated early in the course cemic Control and the Prevention of CVD is indicated with consideration of of type 1 diabetes. In the DCCT, there Cardiovascular Events: Implications of glycemic goals. If the patient is not at A1C was a trend toward lower risk of CVD the ACCORD, ADVANCE, and VA Diabe- target, continue metformin unless con- events with intensive control. In the tes Trials” (31). traindicated and add SGLT2i or GLP-1 RA 9-year post-DCCT follow-up of the EDIC The glycemic control comparison in with proven cardiovascular benefit. If the cohort, participants previously random- ACCORD was halted early due to an patient is meeting A1C target, consider ized to the intensive arm had a sig- increased mortality rate in the intensive one of three strategies (39): fi ni cant 57% reduction in the risk of compared with the standard treatment nonfatal myocardial infarction (MI), stroke, arm (1.41% vs. 1.14% per year; hazard 1. If already on dual therapy or multiple or cardiovascular death compared with ratio 1.22 [95% CI 1.01–1.46]), with a glucose-lowering therapies and not those previously randomized to the stan- similar increase in cardiovascular deaths. on an SGLT2i or GLP-1 RA, consider fi dard arm (28). The bene t of intensive Analysis of the ACCORD data did not switching to one of these agents with glycemic control in this cohort with type 1 identify a clear explanation for the excess proven cardiovascular benefit. diabetes has been shown to persist for mortality in the intensive treatment arm 2. Reconsider/lower individualized A1C several decades (29) and to be associated (27). target and introduce SGLT2i or GLP-1 with a modest reduction in all-cause Longer-term follow-up has shown no RA. mortality (30). evidence of cardiovascular benefitor 3. Reassess A1C at 3-month intervals and Cardiovascular Disease and Type 2 Diabetes harm in the ADVANCE trial (32). The add SGLT2i or GLP-1 RA if A1C goes In type 2 diabetes, there is evidence that end-stage renal disease rate was lower above target. more intensive treatment of glycemia in in the intensive treatment group over newly diagnosed patients may reduce follow-up. However, 10-year follow-up Setting and Modifying A1C Goals long-term CVD rates. During the UKPDS, of the VADT cohort (33) showed a reduc- Numerous factors must be considered there was a 16% reduction in CVD events tion in the risk of cardiovascular events when setting glycemic targets. The ADA (combined fatal or nonfatal MI and sud- (52.7 [control group] vs. 44.1 [intervention proposes general targets appropriate den death) in the intensive glycemic group] events per 1,000 person-years) for many patients but emphasizes the control arm that did not reach statistical with no benefit in cardiovascular or over- importance of individualization based significance (P 5 0.052), and there was all mortality. Heterogeneity of mortality on key patient characteristics. Glycemic no suggestion of benefit on other CVD effects across studies was noted, which targets must be individualized in the outcomes (e.g., stroke). However, after may reflect differences in glycemic tar- context of shared decision making to 10 years of observational follow-up, gets, therapeutic approaches, and pop- address the needs and preferences of those originally randomized to inten- ulation characteristics (34). each patient and the individual charac- sive glycemic control had significant Mortality findings in ACCORD (27) and teristics that influence risks and benefits long-term reductions in MI (15% with subgroup analyses of VADT (35) suggest of therapy for each patient. sulfonylurea or insulin as initial pharma- that the potential risks of intensive gly- The factors to consider in individual- cotherapy, 33% with metformin as initial cemic control may outweigh its benefits izing goals are depicted in Fig. 6.1. Figure pharmacotherapy) and in all-cause mor- in higher-risk patients. In all three trials, 6.1 is not designed to be applied rigidly tality (13% and 27%, respectively) (22). severe hypoglycemia was significantly but to be used as a broad construct to ACCORD, ADVANCE, and VADT sug- more likely in participants who were guide clinical decision making (40) in both gested no significant reduction in CVD randomly assigned to the intensive gly- type 1 and type 2 diabetes. More strin- outcomes with intensive glycemic con- cemic control arm. Those patients with gent control (such as an A1C of 6.5% [48 trol in participants followed for shorter long duration of diabetes, a known history mmol/mol] or ,7% [53 mmol/mol]) may durations (3.5–5.6 years) and who had of hypoglycemia, advanced atherosclerosis, be recommended if it can be achieved S66 Glycemic Targets Diabetes Care Volume 42, Supplement 1, January 2019

safely and with acceptable burden of preprandial versus postprandial SMBG may be relaxed without undermining therapy and if life expectancy is sufficient targets is complex (41). Elevated post- overall glycemic control as measured to reap benefits of tight control. Less challenge (2-h oral glucose tolerance by A1C. These data prompted the re- stringent control (A1C up to 8% [64 test)glucosevalues have beenassociated vision in the ADA-recommended premeal mmol/mol]) may be recommended if with increased cardiovascular risk inde- glucose target to 80–130 mg/dL (4.4– the life expectancy of the patient is pendent of fasting plasma glucose in 7.2 mmol/L) but did not affect the def- such that the benefits of an intensive some epidemiologic studies, but inter- inition of hypoglycemia. goal may not be realized, or if the risks vention trials have not shown postpran- and burdens outweigh the potential dial glucose to be a cardiovascular risk HYPOGLYCEMIA benefits. Severe or frequent hypoglyce- factor independent of A1C. In subjects mia is an absolute indication for the with diabetes, surrogate measures of Recommendations 6.8 Individuals at risk for hypogly- modification of treatment regimens, in- vascular pathology, such as endothelial cemia should be asked about cluding setting higher glycemic goals. dysfunction, are negatively affected by symptomatic and asymptom- Diabetes is a chronic disease that postprandial hyperglycemia. It is clear atic hypoglycemia at each en- progresses over decades. Thus, a goal that postprandial hyperglycemia, like counter. C that might be appropriate for an indi- preprandial hyperglycemia, contributes 6.9 Glucose(15–20g)isthepreferred vidual early in the course of the disease to elevated A1C levels, with its relative treatment for the conscious in- may change over time. Newly diag- contribution being greater at A1C levels dividual with blood glucose nosed patients and/or those without that are closer to 7% (53 mmol/mol). ,70 mg/dL [3.9 mmol/L]), comorbidities that limit life expectancy However, outcome studies have clearly although any form of carbo- may benefit from intensive control shown A1C to be the primary predictor hydrate that contains glucose proven to prevent microvascular compli- of complications, and landmark trials of may be used. Fifteen minutes cations. Both DCCT/EDIC and UKPDS glycemic control such as the DCCT and after treatment, if SMBG shows demonstrated metabolic memory, or a UKPDS relied overwhelmingly on pre- continued hypoglycemia, the legacy effect, in which a finite period of prandial SMBG. Additionally, a random- treatment should be repeated. intensive control yielded benefits that ized controlled trial in patients with Once SMBG returns to normal, extended for decades after that control known CVD found no CVD benefitof the individual should consume ended. Thus, a finite period of intensive insulin regimens targeting postprandial a meal or snack to prevent re- control to near-normal A1C may yield glucose compared with those targeting currence of hypoglycemia. E enduring benefits even if control is preprandial glucose (42). Therefore, it is 6.10 Glucagon should be prescribed subsequently deintensified as patient reasonable for postprandial testing to be for all individuals at increased characteristics change. Over time, co- recommended for individuals who have risk of level 2 hypoglycemia, morbidities may emerge, decreasing premeal glucose values within target but defined as blood glucose ,54 life expectancy and the potential to have A1C values above target. Mea- mg/dL (3.0 mmol/L), so it is reap benefits from intensive control. suring postprandial plasma glucose available should it be needed. Also, with longer duration of disease, 1–2 h after the start of a meal and Caregivers, school personnel, diabetes may become more difficult to using treatments aimed at reducing or family members of these control, with increasing risks and bur- postprandial plasma glucose values individuals should know where dens of therapy. Thus, A1C targets to ,180 mg/dL (10.0 mmol/L) may it is and when and how to ad- should be reevaluated over time to help to lower A1C. minister it. Glucagon administra- balance the risks and benefits as pa- An analysis of data from 470 partici- tion is not limited to health care tient factors change. pants in the ADAG study (237 with type 1 professionals. E Recommended glycemic targets for diabetes and 147 with type 2 diabetes) 6.11 Hypoglycemia unawareness or many nonpregnant adults are shown found that actual average glucose levels one or more episodes of level in Table 6.2. The recommendations in- associated with conventional A1C targets 3 hypoglycemia should trigger clude blood glucose levels that appear to were higher than older DCCT and ADA reevaluation of the treatment correlate with achievement of an A1C targets (Table 6.1) (7,43). These findings regimen. E of ,7% (53 mmol/mol). The issue of support that premeal glucose targets 6.12 Insulin-treated patients with hypoglycemia unawareness or an Table 6.2—Summary of glycemic recommendations for many nonpregnant episode of level 2 hypoglycemia adults with diabetes should be advised to raise their A1C ,7.0% (53 mmol/mol)* glycemic targets to strictly avoid Preprandial capillary plasma glucose 80–130 mg/dL* (4.4–7.2 mmol/L) hypoglycemia for at least several Peak postprandial capillary plasma glucose† ,180 mg/dL* (10.0 mmol/L) weeks in order to partially re- *More or less stringent glycemic goals may be appropriate for individual patients. Goals should verse hypoglycemia unaware- be individualized based on duration of diabetes, age/life expectancy, comorbid conditions, ness and reduce risk of future known CVD or advanced microvascular complications, hypoglycemia unawareness, and individual episodes. A patient considerations. †Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial glucose goals. Postprandial glucose measurements should be made 1–2h 6.13 Ongoing assessment of cogni- after the beginning of the meal, generally peak levels in patients with diabetes. tive function is suggested with care.diabetesjournals.org Glycemic Targets S67

Table 6.3—Classification of hypoglycemia (44) are noted as particularly vulnerable to Level Glycemic criteria/description hypoglycemia because of their reduced ability to recognize hypoglycemic symp- , $ Level 1 Glucose 70 mg/dL (3.9 mmol/L) and glucose 54 mg/dL toms and effectively communicate their (3.0 mmol/L) needs. Individualized glucose targets, Level 2 Glucose ,54 mg/dL (3.0 mmol/L) patient education, dietary intervention Level 3 A severe event characterized by altered mental and/or (e.g., bedtime snack to prevent overnight physical status requiring assistance hypoglycemia when specifically needed to treat low blood glucose), exercise management, medication adjustment, glucose monitoring, and routine clinical cohort of older black and white adults with surveillance may improve patient out- increased vigilance for hypogly- type 2 diabetes include insulin use, poor or comes (54). CGM with automated low cemia by the clinician, patient, moderate versus good glycemic control, glucose suspend has been shown to be and caregivers if low cognition or albuminuria, and poor cognitive function effective in reducing hypoglycemia in declining cognition is found. B (46). type 1 diabetes (55). For patients with Symptoms of hypoglycemia include, type 1 diabetes with level 3 hypoglyce- Hypoglycemia is the major limiting fac- but are not limited to, shakiness, irrita- mia and hypoglycemia unawareness that tor in the glycemic management of bility, confusion, tachycardia, and hun- persists despite medical treatment, type 1 and type 2 diabetes. Recommen- ger. Hypoglycemia may be inconvenient human islet transplantation may be an dations regarding the classification of or frightening to patients with diabetes. option, but the approach remains ex- hypoglycemia are outlined in Table 6.3 Level 3 hypoglycemia may be recognized perimental (56,57). (44). Level 1 hypoglycemia is defined as a or unrecognized and can progress to loss In 2015, the ADA changed its prepran- measurable glucose concentration ,70 of consciousness, seizure, coma, or dial glycemic target from 70–130 mg/dL mg/dL (3.9 mmol/L) but $54 mg/dL death. It is reversed by administration (3.9–7.2 mmol/L) to 80–130 mg/dL (4.4– (3.0 mmol/L). A blood glucose concentra- of rapid-acting glucose or glucagon. Hy- 7.2 mmol/L). This change reflects the tion of 70 mg/dL (3.9 mmol/L) has been poglycemia can cause acute harm to the results of the ADAG study, which dem- recognized as a threshold for neuroen- person with diabetes or others, espe- onstrated that higher glycemic targets docrine responses to falling glucose in cially if it causes falls, motor vehicle corresponded to A1C goals (7). An ad- people without diabetes. Because many accidents, or other injury. A large cohort ditional goal of raising the lower range of people with diabetes demonstrate im- study suggested that among older adults the glycemic target was to limit over- paired counterregulatory responses to with type 2 diabetes, a history of level 3 treatment and provide a safety margin in hypoglycemia and/or experience hypo- hypoglycemia was associated with greater patients titrating glucose-lowering drugs glycemia unawareness, a measured glu- risk of dementia (48). Conversely, in a such as insulin to glycemic targets. cose level ,70 mg/dL (3.9 mmol/L) is substudy of the ACCORD trial, cognitive considered clinically important, indepen- impairment at baseline or decline in dent of the severity of acute hypoglycemic cognitive function during the trial was Hypoglycemia Treatment symptoms. Level 2 hypoglycemia (de- significantly associated with subsequent Providers should continue to counsel fined as a blood glucose concentra- episodes of level 3 hypoglycemia (49). patients to treat hypoglycemia with tion ,54 mg/dL [3.0 mmol/L]) is the Evidence from DCCT/EDIC, which involved fast-acting carbohydrates at the hy- threshold at which neuroglycopenic adolescents and younger adults with type 1 poglycemia alert value of 70 mg/dL symptoms begin to occur and requires diabetes, found no association between (3.9 mmol/L) or less. Hypoglycemia treat- immediate action to resolve the hypo- frequency of level 3 hypoglycemia and ment requires ingestion of glucose- or glycemic event. Lastly, level 3 hypogly- cognitive decline (50), as discussed in carbohydrate-containing foods. The acute cemia is defined as a severe event Section 13 “Children and Adolescents.” glycemic response correlates better with characterized by altered mental and/or Level 3 hypoglycemia was associated the glucose content of food than with physical functioning that requires assis- withmortalityinparticipantsinboththe the carbohydrate content of food. Pure tance from another person for recovery. standard and the intensive glycemia arms glucose is the preferred treatment, but Studies of rates of level 3 hypoglyce- of the ACCORD trial, but the relationships any form of carbohydrate that contains mia that rely on claims data for hospi- between hypoglycemia, achieved A1C, glucose will raise blood glucose. Added talization, emergency department visits, and treatment intensity were not straight- fat may retard and then prolong the and ambulance use substantially under- forward. An association of level 3 hypo- acute glycemic response. In type 2 di- estimate rates of level 3 hypoglycemia glycemia with mortality was also found in abetes, ingested protein may increase (45), yet find high burden of hypoglyce- the ADVANCE trial (51). An association insulin response without increasing mia in adults over 60 years of age in the between self-reported level 3 hypoglyce- plasma glucose concentrations (58). community (46). African Americans are mia and 5-year mortality has also been Therefore, carbohydrate sources high at substantially increased risk of level 3 reported in clinical practice (52) in protein should not be used to treat hypoglycemia (46,47). In addition to age Young children with type 1 diabetes or prevent hypoglycemia. Ongoing in- and race, other important risk factors and the elderly, including those with sulin activity or insulin secretagogues found in a community-based epidemiologic type 1 and type 2 diabetes (48,53), may lead to recurrent hypoglycemia S68 Glycemic Targets Diabetes Care Volume 42, Supplement 1, January 2019

unless more food is ingested after re- clinically significant hypoglycemia may 5. Beck RW, Connor CG, Mullen DM, Wesley covery. Once the glucose returns to benefit from at least short-term relaxa- DM, Bergenstal RM. The fallacy of average: normal, the individual should be coun- tion of glycemic targets. how using HbA1c alone to assess glycemic control can be misleading. Diabetes Care seled to eat a meal or snack to prevent 2017;40:994–999 recurrent hypoglycemia. INTERCURRENT ILLNESS 6. Nathan DM, Kuenen J, Borg R, Zheng H, For further information on management Schoenfeld D, Heine RJ; A1c-Derived Average Glucagon of patients with hyperglycemia in the Glucose Study Group. Translating the A1C assay The use of glucagon is indicated for the into estimated average glucose values. Diabetes hospital, please refer to Section 15 – treatment of hypoglycemia in people Care 2008;31:1473 1478 “Diabetes Care in the Hospital.” 7. Wei N, Zheng H, Nathan DM. Empirically unable or unwilling to consume carbo- Stressful events (e.g., illness, trauma, establishing blood glucose targets to achieve – hydrates by mouth. Those in close con- surgery, etc.) may worsen glycemic con- HbA1c goals. Diabetes Care 2014;37:1048 1051 tact with, or having custodial care of, trol and precipitate diabetic ketoacidosis 8. Selvin E. Are there clinical implications of racial differences in HbA ? A difference, to people with hypoglycemia-prone diabe- or nonketotic hyperglycemic hyper- 1c tes (family members, roommates, school be a difference, must make a difference. Diabe- osmolar state, life-threatening conditions tes Care 2016;39:1462–1467 personnel, child care providers, correc- that require immediate medical care to 9. Bergenstal RM, Gal RL, Connor CG, et al.; T1D tional institution staff, or coworkers) prevent complications and death. Any Exchange Racial Differences Study Group. Racial should be instructed on the use of glu- condition leading to deterioration in gly- differences in the relationship of glucose con- cagon kits, including where the kit is and centrations and hemoglobin A1c levels. Ann In- cemic control necessitates more frequent – when and how to administer glucagon. tern Med 2017;167:95 102 monitoring of blood glucose; ketosis-prone 10. Lacy ME, Wellenius GA, Sumner AE, et al. An individual does not need to be a health patients also require urine or blood ketone Association of sickle cell trait with hemoglobin – care professional to safely administer monitoring. If accompanied by ketosis, A1c in African Americans. JAMA 2017;317:507 glucagon. Care should be taken to ensure vomiting,oralterationinthelevelof 515 11. Rohlfing C, Hanson S, Little RR. Measure- that glucagon kits are not expired. consciousness, marked hyperglycemia re- ment of hemoglobin A1c in patients with sickle quires temporary adjustment of the treat- cell trait. JAMA 2017;317:2237 Hypoglycemia Prevention ment regimen and immediate interaction 12. Wheeler E, Leong A, Liu C-T, et al.; EPIC-CVD Hypoglycemia prevention is a critical withthediabetescareteam.Thepatient Consortium; EPIC-InterAct Consortium; Lifelines component of diabetes management. treated with noninsulin therapies or med- Cohort Study. Impact of common genetic determinants of hemoglobin A1c on type 2 diabetes SMBG and, for some patients, CGM ical nutrition therapy alone may require risk and diagnosis in ancestrally diverse pop- are essential tools to assess therapy insulin. Adequate fluid and caloric intake ulations: a transethnic genome-wide meta- and detect incipient hypoglycemia. Pa- must be ensured. Infection or dehydra- analysis. PLoS Med 2017;14:e1002383 tients should understand situations that tion is more likely to necessitate hospital- 13. Wilson DM, Kollman; Diabetes Research in increase their risk of hypoglycemia, such ization of the person with diabetes than Children Network (DirecNet) Study Group. Re- lationship of A1C to glucose concentrations in as when fasting for tests or procedures, the person without diabetes. children with type 1 diabetes: assessments by when meals are delayed, during and after A physician with expertise in diabetes high-frequency glucose determinations by sen- the consumption of alcohol, during and management should treat the hospital- sors. Diabetes Care 2008;31:381–385 after intense exercise, and during sleep. ized patient. For further information on 14. Buse JB, Kaufman FR, Linder B, Hirst K, El Hypoglycemia may increase the risk of the management of diabetic ketoacido- Ghormli L, Willi S; HEALTHY Study Group. Di- abetes screening with hemoglobin A1c versus harm to self or others, such as with sis and the nonketotic hyperglycemic fasting plasma glucose in a multiethnic middle- driving. Teaching people with diabetes hyperosmolar state, please refer to school cohort. Diabetes Care 2013;36:429–435 to balance insulin use and carbohydrate the ADA consensus report “Hyper- 15. Kamps JL, Hempe JM, Chalew SA. Racial intake and exercise are necessary, but glycemic Crises in Adult Patients With disparity in A1C independent of mean blood these strategies are not always sufficient Diabetes” (60). glucose in childrenwith type 1 diabetes.Diabetes Care 2010;33:1025–1027 for prevention. 16. Diabetes Control and Complications Trial In type 1 diabetes and severely insulin- References Research Group. The effect of intensive treat- deficient type 2 diabetes, hypoglycemia 1. Laiteerapong N, Ham SA, Gao Y, et al. The ment of diabetes on the development and unawareness (or hypoglycemia-associated legacy effect in type 2 diabetes: impact of early progression of long-term complications in autonomic failure) can severely com- glycemic control on future complications (the insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986 promise stringent diabetes control and Diabetes & Aging Study). Diabetes Care. In press 2. Stratton IM, Adler AI, Neil HAW, et al. Asso- 17. Diabetes Control and Complications Trial quality of life. This syndrome is charac- ciation of glycaemia with macrovascular and (DCCT)/Epidemiology of Diabetes Interventions terized by deficient counterregulatory microvascular complications of type 2 diabetes and Complications (EDIC) Research Group. Effect hormone release, especially in older (UKPDS 35): prospective observational study. of intensive diabetes therapy on the progression adults, and a diminished autonomic re- BMJ 2000;321:405–412 of diabetic retinopathy in patients with type 1 fi diabetes: 18 years of follow-up in the DCCT/EDIC. sponse, which both are risk factors for, 3. Little RR, Rohl ng CL, Sacks DB; National Glycohemoglobin Standardization Program (NGSP) Diabetes 2015;64:631–642 and caused by, hypoglycemia. A corollary Steering Committee. Status of hemoglobin A1c 18. Lachin JM, Genuth S, Cleary P, Davis MD, to this “vicious cycle” is that several measurement and goals for improvement: from Nathan DM; Diabetes Control and Complications weeks of avoidance of hypoglycemia chaos to order for improving diabetes care. Clin Trial/Epidemiology of Diabetes Interventions hasbeendemonstratedtoimprove Chem 2011;57:205–214 and Complications Research Group. Retinopathy 4. Jovanovicˇ L, Savas H, Mehta M, Trujillo A, and nephropathy in patients with type 1 diabetes counterregulation and hypoglycemia Pettitt DJ. Frequent monitoring of A1C during four years after a trial of intensive therapy awareness in many patients (59). Hence, pregnancy as a treatment tool to guide therapy. [published correction appears in N Engl J Med patients with one or more episodes of Diabetes Care 2011;34:53–54 2000;342:1376]. N Engl J Med 2000;342:381–389 care.diabetesjournals.org Glycemic Targets S69

19. Ohkubo Y, Kishikawa H, Araki E, et al. In- College of Cardiology Foundation; American Complications (EDIC) study. Diabetes Care tensive insulin therapy prevents the progres- Heart Association. Intensive glycemic control 2010;33:1090–1096 sion of diabetic microvascular complications in and the prevention of cardiovascular events: im- 44. Agiostratidou G, Anhalt H, Ball D, et al. Japanese patients with non-insulin-dependent plications of the ACCORD, ADVANCE, and VA dia- Standardizing clinically meaningful outcome diabetes mellitus: a randomized prospective betes trials: a position statement of the American measures beyond HbA1c for type 1 diabetes: 6-year study. Diabetes Res Clin Pract 1995;28: Diabetes Association and a scientiﬁc statement of a consensus report of the American Association 103–117 the American College of Cardiology Foundation and of Clinical Endocrinologists, the American Asso- 20. UK Prospective Diabetes Study (UKPDS) the American Heart Association. Diabetes Care ciation of Diabetes Educators, the American Group. Effect of intensive blood-glucose control 2009;32:187–192 Diabetes Association, the Endocrine Society, with metformin on complications in overweight 32.ZoungasS,ChalmersJ,NealB,etal.; JDRF International, The Leona M. and Harry B. patients with type 2 diabetes (UKPDS 34). Lancet ADVANCE-ON Collaborative Group. Follow-up Helmsley Charitable Trust, the Pediatric Endo- 1998;352:854–865 of blood-pressure lowering and glucose control crine Society, and the T1D Exchange. Diabetes 21. UK Prospective Diabetes Study (UKPDS) in type 2 diabetes. N Engl J Med 2014;371:1392– Care 2017;40:1622–1630 Group. Intensive blood-glucose control with 1406 45. Karter AJ, Moffet HH, Liu JY, Lipska KJ. sulphonylureas or insulin compared with con- 33. Hayward RA, Reaven PD, Wiitala WL, et al.; Surveillance of hypoglycemiadlimitations of ventional treatment and risk of complications in VADT Investigators. Follow-up of glycemic con- emergency department and hospital utilization patients with type 2 diabetes (UKPDS 33). Lancet trol and cardiovascular outcomes in type 2 di- data. JAMA Intern Med 2018;178:987–988 1998;352:837–853 abetes. N Engl J Med 2015;372:2197–2206 46. Lee AK, Lee CJ, Huang ES, Sharrett AR, Coresh 22. Holman RR, Paul SK, Bethel MA, Matthews 34. Turnbull FM, Abraira C, Anderson RJ, et al.; J, Selvin E. Risk factors for severe hypoglycemia DR, Neil HAW. 10-year follow-up of intensive Control Group. Intensive glucose control and in black and white adults with diabetes: the glucose control in type 2 diabetes. N Engl J macrovascular outcomes in type 2 diabetes Atherosclerosis Risk in Communities (ARIC) Med 2008;359:1577–1589 [published correction appears in Diabetologia study. Diabetes Care 2017;40:1661–1667 23. Adler AI, Stratton IM, Neil HAW, et al. 2009;52:2470]. Diabetologia 2009;52:2288–2298 47. Karter AJ, Lipska KJ, O’Connor PJ, et al.; Association of systolic blood pressure with 35. Duckworth WC, Abraira C, Moritz TE, et al.; SUPREME-DM Study Group. High rates of severe macrovascular and microvascular complications Investigators of the VADT. The duration of di- hypoglycemia among African American patients of type 2 diabetes (UKPDS 36): prospective abetes affects the response to intensive glucose with diabetes: the SUrveillance, PREvention, and observational study. BMJ 2000;321:412–419 control in type 2 subjects: the VA Diabetes Trial. ManagEment of Diabetes Mellitus (SUPREME-DM) 24. Duckworth W, Abraira C, Moritz T, et al.; J Diabetes Complications 2011;25:355–361 network. J Diabetes Complications 2017;31: VADT Investigators. Glucose control and vascular 36. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, 869–873 complications in veterans with type 2 diabetes. Steinman MA. Potential overtreatment of di- 48. Whitmer RA, Karter AJ, Yaffe K, Quesenberry N Engl J Med 2009;360:129–139 abetes mellitus in older adults with tight CP Jr, Selby JV. Hypoglycemic episodes and risk of 25. Patel A, MacMahon S, Chalmers J, et al.; glycemic control. JAMA Intern Med 2015;175: dementia in older patients with type 2 diabetes ADVANCE Collaborative Group. Intensive blood 356–362 mellitus. JAMA 2009;301:1565–1572 glucose control and vascular outcomes in pa- 37. Vijan S, Sussman JB, Yudkin JS, Hayward 49. Punthakee Z, Miller ME, Launer LJ, et al.; tients with type 2 diabetes. N Engl J Med 2008; RA. Effect of patients’ risks and preferences ACCORD Group of Investigators; ACCORD-MIND 358:2560–2572 on health gains with plasma glucose level lowering Investigators. Poor cognitive function and 26. Ismail-Beigi F, Craven T, Banerji MA, et al.; in type 2 diabetes mellitus. JAMA Intern Med risk of severe hypoglycemia in type 2 dia- ACCORD trial group. Effect of intensive treat- 2014;174:1227–1234 betes: post hoc epidemiologic analysis of ment of hyperglycaemia on microvascular 38. Lee AK, Warren B, Lee CJ, et al. The asso- the ACCORD trial. Diabetes Care 2012;35: outcomes in type 2 diabetes: an analysis of ciation of severe hypoglycemia with incident 787–793 the ACCORD randomised trial. Lancet 2010; cardiovascular events and mortality in adults 50. Jacobson AM, Musen G, Ryan CM, et al.; 376:419–430 with type 2 diabetes. Diabetes Care 2018;41: Diabetes Control and Complications Trial/ 27. Gerstein HC, Miller ME, Byington RP, et al.; 104–111 Epidemiology of Diabetes Interventions and Action to Control Cardiovascular Risk in Diabe- 39. Davies MJ, D’Alessio DA, Fradkin J, et al. Complications Study Research Group. Long- tes Study Group. Effects of intensive glucose Management of hyperglycemia in type 2 diabe- term effect of diabetes and its treatment on lowering in type 2 diabetes. N Engl J Med 2008; tes, 2018. A consensus report by the American cognitive function. N Engl J Med 2007;356: 358:2545–2559 Diabetes Association (ADA) and the European 1842–1852 28. Nathan DM, Cleary PA, Backlund J-YC, Association for the Study of Diabetes (EASD). 51. Zoungas S, Patel A, Chalmers J, et al.; et al.; Diabetes Control and Complications Trial/ Diabetes Care 2018;41:2669–2701 ADVANCE Collaborative Group. Severe hypo- Epidemiology of Diabetes Interventions and 40. Inzucchi SE, Bergenstal RM, Buse JB, et al. glycemia and risks of vascular events and death. Complications (DCCT/EDIC) Study Research Management of hyperglycemia in type 2 diabe- N Engl J Med 2010;363:1410–1418 Group. Intensive diabetes treatment and car- tes, 2015: a patient-centered approach: update 52. McCoy RG, Van Houten HK, Ziegenfuss JY, diovascular disease in patients with type 1 di- to a position statement of the American Diabetes Shah ND, Wermers RA, Smith SA. Increased abetes. N Engl J Med 2005;353:2643–2653 Association and the European Association for the mortality of patients with diabetes reporting 29. Nathan DM, Zinman B, Cleary PA, et al.; Study of Diabetes. Diabetes Care 2015;38:140– severe hypoglycemia. Diabetes Care 2012;35: Diabetes Control and Complications Trial/ 149 1897–1901 Epidemiology of Diabetes Interventions and 41. American Diabetes Association. Postpran- 53. DuBose SN, Weinstock RS, Beck RW, et al. Complications (DCCT/EDIC) Research Group. dial blood glucose. Diabetes Care 2001;24:775– Hypoglycemia in older adults with type 1 di- Modern-day clinical course of type 1 diabetes 778 abetes. Diabetes Technol Ther 2016;18:765– mellitus after 30 years’ duration: the Diabetes 42. Raz I, Wilson PWF, Strojek K, et al. Effects 771 Control and Complications Trial/Epidemiology of of prandial versus fasting glycemia on cardio- 54. Seaquist ER, Anderson J, Childs B, et al. Diabetes Interventions and Complications and vascular outcomes in type 2 diabetes: the Hypoglycemia and diabetes: a report of a work- Pittsburgh Epidemiology of Diabetes Complica- HEART2D trial. Diabetes Care 2009;32:381– group of the American Diabetes Association and tions experience (1983–2005). Arch Intern Med 386 the Endocrine Society. Diabetes Care 2013;36: 2009;169:1307–1316 43. Albers JW, Herman WH, Pop-Busui R, et al.; 1384–1395 30. Orchard TJ, Nathan DM, Zinman B, et al.; Diabetes Control and Complications Trial/Epide- 55. Bergenstal RM, Klonoff DC, Garg SK, et al.; Writing Group for the DCCT/EDIC Research miology of Diabetes Interventions and Compli- ASPIRE In-Home Study Group. Threshold- Group. Association between 7 years of intensive cations Research Group. Effect of prior intensive based insulin-pump interruption for reduction treatment of type 1 diabetes and long-term insulin treatment during the Diabetes Control of hypoglycemia. N Engl J Med 2013;369:224– mortality. JAMA 2015;313:45–53 and Complications Trial (DCCT) on peripheral 232 31. Skyler JS, Bergenstal R, Bonow RO, et al.; neuropathy in type 1 diabetes during the Epi- 56. Hering BJ, Clarke WR, Bridges ND, et al.; American Diabetes Association; American demiology of Diabetes Interventions and Clinical Islet Transplantation Consortium. S70 Glycemic Targets Diabetes Care Volume 42, Supplement 1, January 2019

Phase 3 trial of transplantation of human islets caveat emptor. Diabetes Care 2016;39:1072– 59. Cryer PE. Diverse causes of hypoglycemia- in type 1 diabetes complicated by severe hy- 1074 associated autonomic failure in diabetes. N Engl J poglycemia. Diabetes Care 2016;39:1230– 58. Layman DK, Clifton P, Gannon MC, Krauss Med 2004;350:2272–2279 1240 RM, Nuttall FQ. Protein in optimal health: heart 60. Kitabchi AE, Umpierrez GE, Miles JM, Fisher 57. Harlan DM. Islet transplantation for hy- disease and type 2 diabetes. Am J Clin Nutr 2008; JN. Hyperglycemic crises in adult patients with poglycemia unawareness/severe hypoglycemia: 87:1571S–1575S diabetes. Diabetes Care 2009;32:1335–1343 Diabetes Care Volume 42, Supplement 1, January 2019 S71

7. Diabetes Technology: Standards American Diabetes Association of Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S71–S80 | https://doi.org/10.2337/dc19-S007

Diabetes technology is the term used to describe the hardware, devices, and software that people with diabetes use to help manage blood glucose levels, stave off diabetes complications, reduce the burden of living with diabetes, and improve quality of life. Historically, diabetes technology has been divided into two main categories: insulin administered by syringe, pen, or pump, and blood glucose monitoring as assessed by meter or continuous glucose monitor. More recently, diabetes technology has expanded to include hybrid devices that both monitor glucose and deliver insulin, some automatically, as well as software that serves as a medical device, providing diabetes self-management support. Diabetes technology, when applied appropriately, can improve the lives and health of people with diabetes; however, the complexity and rapid change of the diabetes technology landscape can also be a barrier to patient and provider implementation. To provide some additional clarity in the diabetes technology space, the American Diabetes Association is, for the ﬁrst time, adding a dedicated section on diabetes technology to the “Standards of Medical Care in Diabetes.” For this ﬁrst writing, the section will focus on insulin delivery and glucose monitoring with the most common devices currently in use. In future years, this section will be expanded to include software as a medical device, privacy, cost, technology-enabled diabetes education and support, telemedicine, and other issues that providers and patients encounter with the use of technology in modern diabetes care.

INSULIN DELIVERY

Insulin Syringes and Pens Suggested citation: American Diabetes Associa- Recommendations tion. 7. Diabetes technology: Standards of Med- d 7.1 ical Care in Diabetes 2019. Diabetes Care 2019;42 For people with diabetes who require insulin, insulin syringes or insulin pens (Suppl. 1):S71–S80 may be used for insulin delivery with consideration of patient preference, B © 2018 by the American Diabetes Association. insulin type and dosing regimen, cost, and self-management capabilities. Readers may use this article as long as the work 7.2 Insulin pens or insulin injection aids may be considered for patients with is properly cited, the use is educational and not dexterity issues or vision impairment to facilitate the administration of for proﬁt, and the work is not altered. More infor- accurate insulin doses. C mation is available at http://www.diabetesjournals .org/content/license. S72 Diabetes Technology Diabetes Care Volume 42, Supplement 1, January 2019

Injecting insulin with a syringe or pen is quickly, while a thinner needle may cause based upon the individual characteristics the insulin delivery method used by most less pain. Needle length ranges from 4 to of the patient and which is most likely to people with diabetes (1,2), with the re- 12.7 mm, with some evidence suggesting benefit him or her. Newer systems, such mainder using insulin pumps or auto- shorter needles may lower the risk of as sensor-augmented pumps and automated insulin delivery devices (see intramuscular injection. When reused, matic insulin delivery systems, are dis- sections on those topics below). For needles may be duller and thus injection cussed elsewhere in this section. patients with diabetes who use insulin, more painful. Proper insulin technique is Adoption of pump therapy in the U.S. insulin syringes and pens are both able a requisite to obtain the full benefits of shows geographical variations, which to deliver insulin safely and effectively insulin injection therapy, and concerns with may be related to provider prefer- for the achievement of glycemic tar- technique and using the proper technique ence or center characteristics (10,11) gets. When choosing between a syringe are outlined in Section 9 “Pharmacologic and socioeconomic status, as pump ther- and a pen, patient preferences, cost, Approaches to Glycemic Treatment.” apy is more common in individuals of insulin type and dosing regimen, and Another insulin delivery option is a higher socioeconomic status as re- self-management capabilities should disposable patch-like device, which pro- flected by race/ethnicity, private health be considered. It is important to note vides a continuous, subcutaneous infu- insurance, family income, and education that while many insulin types are avail- sion of rapid-acting insulin (basal), as (11,12). Given the additional barriers to able for purchase as either pens or vials, well as 2-unit increments of bolus insulin optimal diabetes care observed in dis- others may only be available in one form at the press of a button (7). advantaged groups (13), addressing the or the other and there may be significant differences in access to insulin pumps cost differences between pens and vials and other diabetes technology may con- (see Table 9.3 for a list of insulin product Insulin Pumps tribute to fewer health disparities. costs with dosage forms). Insulin pens Recommendations Pump therapy can be successfully may allow people with vision impairment 7.3 Individuals with diabetes who started at the time of diagnosis (14,15). or dexterity issues to dose insulin accu- have been successfully using con- Practical aspects of pump therapy initi- rately (3–5), while insulin injection aids tinuous subcutaneous insulin ination include: assessment of patient and are also available to help with these fusion should have continued family readiness, (although there is no con- issues (http://main.diabetes.org/dforg/ access across third-party payers. E sensus on which factors to consider in pdfs/2018/2018-cg-injection-aids.pdf). 7.4 Most adults, children, and adoles- adults (16) or pediatrics), selection of pump The most common syringe sizes are cents with type 1 diabetes should type and initial pump settings, patient/ 1 mL, 0.5 mL, and 0.3 mL, allowing doses of be treated with intensive insulin family education of potential pump com- up to 100 units, 50 units, and 30 units of therapy with either multiple daily plications (e.g., diabetic ketoacidosis [DKA] U-100 insulin, respectively. In a few parts injections or an insulin pump. A with infusion set failure), transition from of the world, insulin syringes still have 7.5 Insulin pump therapy may be con- MDI,andintroductionofadvancedpump U-80 and U-40 markings for older insulin sideredasanoptionforallchil- settings (e.g., temporary basal rates, concentrations and veterinary insulin, and dren and adolescents, especially in extended/square/dual wave bolus). U-500 syringes are available for the use of children under 7 years of age. C Complications of the pump can be U-500 insulin. Syringes are generally used caused by issues with infusion sets once but may be reused by the same in- Continuous subcutaneous insulin injec- (dislodgement, occlusion), which place dividual in resource-limited settings with tion (CSII) or insulin pumps have been patients at risk for ketosis and DKA and appropriate storage and cleansing (6). available in the U.S. for 40 years. These thus must be recognized and managed Insulin pens offer added convenience devices deliver rapid-acting insulin early (17); lipohypertrophy or, less fre- by combining the vial and syringe into a throughout the day to help manage quently, lipoatrophy (18,19); and pump single device. Insulin pens, allowing push- blood glucose levels. Most insulin pumps site infection (20). Discontinuation of button injections, come as disposable use tubing to deliver insulin through a pump therapy is relatively uncommon pens with prefilled cartridges or reusable cannula, while a few attach directly to today; the frequency has decreased over insulin pens with replaceable insulin car- the skin, without tubing. the past decades and its causes have tridges. Some reusable pens include a Most studies comparing multiple daily changed (20,21). Current reasons for memory function, which can recall dose injections (MDI) with CSII have been attrition are problems with cost, wear- amounts and timing. “Smart” pens that relatively small and of short duration. ability, disliking the pump, suboptimal can be programmed to calculate insulin However, a recent systematic review and glycemic control, or mood disorders (e.g., doses and provide downloadable data meta-analysis concluded that pump ther- anxiety or depression) (22). reports are also available. Pens also apy has modest advantages for lower- vary with respect to dosing increment ing A1C (–0.30% [95% CI 20.58 to 20.02]) Insulin Pumps in Pediatrics and minimal dose, which can range from and for reducing severe hypoglycemia The safety of insulin pumps in youth has half-unit doses to 2-unit dose increments. rates in children and adults (8). There is been established for over 15 years (23). Needle thickness (gauge) and length is no consensus to guide choosing which Studying the effectiveness of CSII in low- another consideration. Needle gauges form of insulin administration is best for a ering A1C has been challenging because range from 22 to 33, with higher gauge given patient, and research to guide this of the potential selection bias of obser- indicating a thinner needle. A thicker decision making is needed (9). Thus, the vational studies. Participants on CSII may needle can give a dose of insulin more choice of MDI or an insulin pump is often have a higher socioeconomic status that care.diabetesjournals.org Diabetes Technology S73

may facilitate better glycemic control provider, to ensure that data are used in an postprandially, prior to exercise, (24) versus MDI. In addition, the fast effective and timely manner. For patients when they suspect low blood pace of development of new insulins with type 1 diabetes using CGM, the great- glucose, after treating low blood and technologies quickly renders com- est predictor of A1C lowering for all age- glucose until they are normogly- parisons obsolete. However, randomized groups was frequency of sensor use, which cemic, and prior to critical tasks controlled trials (RCTs) comparing CSII was highest in those aged $25 years and such as driving. B and MDI with insulin analogs demon- lower in younger age-groups (41). Simi- 7.7 When prescribed as part of a strate a modest improvement in A1C in larly, for SMBG in patients with type 1 broad educational program, self- participants on CSII (25,26). Observational diabetes, there is a correlation between monitoring of blood glucose may studies, registry data, and meta-analysis greater SMBG frequency and lower A1C help to guide treatment decisions have also suggested an improvement of (42). Among patients who check their and/or self-management for pa- glycemic control in participants on CSII blood glucose at least once daily, many tients taking less frequent insu- (27–29). Although hypoglycemia was a report taking no action when results are lin injections. B major adverse effect of intensified insu- high or low (43). Patients should betaught 7.8 When prescribing self-monitoring lin regimen in the Diabetes Control and how to use SMBG and/or CGM data to of blood glucose, ensure that pa- Complications Trial (DCCT) (30), data sug- adjust food intake, exercise, or pharma- tients receive ongoing instruction gests that CSII may reduce the rates of cologic therapy to achieve specific goals. and regular evaluation of tech- severe hypoglycemia compared with MDI The ongoing need for and frequency of nique, results, and their ability to (29,31–33). There is also evidence that SMBG should be reevaluated at each use data from self-monitoring CSII may reduce DKA risk (29,34) and routine visit to avoid overuse, particularly of blood glucose to adjust ther- diabetes complications, in particular, ret- if SMBG is not being used effectively for apy. Similarly, continuous glu- inopathy and peripheral neuropathy in self-management (43–45). cose monitoring use requires youth, compared with MDI (35). Finally, robust and ongoing diabetes ed- For Patients on Intensive Insulin treatment satisfaction and quality-of-life ucation, training, and support. E Regimens measures improved on CSII compared SMBG or CGM is especially important for with MDI (36,37). Therefore, CSII can Major clinical trials of insulin-treated insulin-treated patients to monitor for be used safely and effectively in youth patients have included self-monitoring of and prevent hypoglycemia and hypergly- with type 1 diabetes to assist with achiev- blood glucose (SMBG) as part of multifac- cemia. Most patients using intensive in- ing targeted glycemic control while re- torial interventions to demonstrate the sulin regimens (MDI or insulin pump ducing the risk of hypoglycemia and DKA, benefit of intensive glycemic control on therapy) should assess glucose levels using improving quality of life and prevent- diabetes complications (40). SMBG is thus SMBG or a CGM prior to meals and snacks, ing long-term complications. Based on an integral component of effective therapy at bedtime, occasionally postprandially, patient-provider shared decision making, of patients taking insulin. In recent years, prior to exercise, when they suspect low insulin pumps may be considered in all continuous glucose monitoring (CGM) has blood glucose, after treating low blood pediatric patients. In particular, pump emerged as a complementary method for glucose until they are normoglycemic, and therapy may be the preferred mode of the assessment of glucose levels (discussed prior to critical tasks such as driving. For insulin delivery for children under 7 years below). Glucose monitoring allows patients many patients using SMBG, this will require of age (38). Because of a paucity of data in to evaluate their individual response to testingupto6–10 times daily, although adolescents and youths with Type 2 di- therapy and assess whether glycemic tar- individual needs may vary. A database abetes, there is insufficient evidence to gets are being safely achieved. Integrating study of almost 27,000 children and ado- make recommendations. results into diabetes management can be lescents with type 1 diabetes showed that, Commonbarrierstopumptherapy a useful tool for guiding medical nutrition after adjustment for multiple confounders, adoption in children and adolescents are therapy and physical activity, preventing increased daily frequency of SMBG was concerns regarding the physical interfer- hypoglycemia, and adjusting medications significantly associated with lower A1C ence of the device, discomfort with idea of (particularly prandial insulin doses). The (–0.2% per additional test per day) and having a device on the body therapeutic patient’sspecific needs and goals should with fewer acute complications (46). effectiveness, and financial burden (27,39). dictate SMBG frequency and timing or the consideration of CGM use. For Patients Using Basal Insulin and/or SELF-MONITORING OF BLOOD Oral Agents GLUCOSE The evidence is insufficient regarding Optimizing Self-monitoring of Blood when to prescribe SMBG and how often Recommendations testing is needed for insulin-treated pa- 7.6 Most patients using intensive in- Glucose and Continuous Glucose tients who do not use intensive insulin sulin regimens (multiple daily in- Monitor Use SMBG and CGM accuracy is dependent on regimens, such as those with type 2 di- jections or insulin pump therapy) the instrument and user, so it is important abetes using basal insulin with or without should assess glucose levels us- to evaluate each patient’s monitoring tech- oral agents. However, for patients using ing self-monitoring of blood nique, both initially and at regular intervals basal insulin, assessing fasting glucose glucose (or continuous glucose thereafter. Optimal use of SMBG and CGM with SMBG to inform dose adjustments monitoring) prior to meals and requires proper review and interpretation to achieve blood glucose targets results in snacks, at bedtime, occasionally of the data, by both the patient and the lower A1C (47,48). S74 Diabetes Technology Diabetes Care Volume 42, Supplement 1, January 2019

In people with type 2 diabetes not Oxygen. Currently available glucose mon- with glucose meter accuracy and using insulin, routine glucose monitoring itors utilize an enzymatic reaction linked choose appropriate devices for may be of limited additional clinical ben- to an electrochemical reaction, either their patients based on these fac- efit. For some individuals, glucose moni- glucose oxidase or glucose dehydroge- tors. E toring can provide insight into the impact nase (58). Glucose oxidase monitors are of diet, physical activity, and medication sensitive to the oxygen available and Glucose meters meeting U.S. Food and management on glucose levels. Glucose should only be used with capillary blood Drug Administration (FDA) guidance for monitoring may also be useful in assessing in patients with normal oxygen saturation. meter accuracy provide the most reliable hypoglycemia, glucose levels during inter- Higher oxygen tensions (i.e., arterial blood data for diabetes management. There current illness, or discrepancies between or oxygen therapy) may result in false low- are several current standards for accu- measured A1C and glucose levels when glucosereadings, and low oxygentensions racy of blood glucose monitors, but the there is concern an A1C result may not (i.e., high altitude, hypoxia, or venous two most used are those of the Inter- be reliable in specific individuals. How- blood readings) may lead to false high- national Organization for Standardiza- ever, several randomized trials have called glucose readings. Glucose dehydrogenase tion (ISO 15197:2013) and the FDA. into question the clinical utility and monitors are not sensitive to oxygen. The current ISO and FDA standards are cost-effectiveness of routine SMBG in compared in Table 7.1. In Europe, currently Temperature. Because the reaction is sen- noninsulin-treated patients (49–52). In a marketed monitors must meet current ISO sitive to temperature, all monitors have year-long study of insulin-naive patients standards. In the U.S., currently marketed an acceptable temperature range (58). with suboptimal initial glycemic control, monitors must meet the standard under Most will show an error if the temper- a group trained in structured SMBG (a which they were approved, which may ature is unacceptable, but a few will paper tool was used at least quarterly to not be the current standard. Moreover, provide a reading and a message indi- collect and interpret seven-point SMBG the monitoring of current accuracy is left cating that the value may be incorrect. profiles taken on 3 consecutive days) re- to the manufacturer and not routinely Interfering Substances. There are a few duced their A1C by 0.3% more than the checked by an independent source. physiologic and pharmacologic factors control group (53). A trial of once-daily Patients assume their glucose monitor that interfere with glucose readings. SMBG that included enhanced patient is accurate because it is FDA cleared, Most interfere only with glucose oxidase feedback through messaging found no but often that is not the case. There is systems (58). They are listed in Table 7.2. clinically or statistically significant change substantial variation in the accuracy of in A1C at 1 year (52). Meta-analyses have widely used blood glucose monitor- suggested that SMBG can reduce A1C by CONTINUOUS GLUCOSE ing systems. The Diabetes Technol- 0.25–0.3% at 6 months (54–56), but the MONITORS ogy Society Blood Glucose Monitoring effect was attenuated at 12 months in one System Surveillance Program provides Recommendations analysis (54). Reductions in A1C were greater information on the performance of 7.10 Sensor-augmented pump ther- (20.3%) in trials where structured SMBG devices used for SMBG (https://www apy may be considered for chil- data were used to adjust medications but .diabetestechnology.org/surveillance dren, adolescents, and adults to not significant without such structured di- .shtml). In a recent analysis,theprogram improve glycemic control with- abetes therapy adjustment (56). A key con- found that only 6 of the top 18 glucose out an increase in hypoglycemia sideration is that performing SMBG alone meters met the accuracy standard or severe hypoglycemia. Bene- does not lower blood glucose levels. To be (57). fits correlate with adherence to useful, the information must be integrated ongoing use of the device. A into clinical and self-management plans. 7.11 When prescribing continuous Factors Limiting Accuracy glucose monitoring, robust di- Counterfeit Strips. Patients should be ad- Glucose Meter Accuracy abetes education, training, and vised against purchasing or reselling Recommendation support are required for opti- preowned or second-hand test strips, 7.9 Health care providers should be mal continuous glucose moni- as these may give incorrect results. aware of the medications and tor implementation and ongoing Only unopened vials of glucose test strips other factors that can interfere use. E should be used to ensure SMBG accuracy.

Table 7.1—Comparison of ISO 15197 and FDA blood glucose meter accuracy standards Setting FDA125,126 ISO 15197-2013127 Home use 95% within 15% for all BG in the usable BG range† 99% within 20% for all BG in the usable BG range† 95% within 15% for BG $100 mg/dL Hospital use 95% within 12% for BG $75 mg/dL 95% within 15 mg/dL for BG ,100 mg/dL 95% within 12 mg/dL for BG ,75 mg/dL 99% in A or B region of Consensus Error Grid‡ 98% within 15% for BG $75 mg/dL 98% within 15 mg/dL for BG ,75 mg/dL BG, blood glucose. To convert mg/dL to mmol/L, see http://www.endmemo.com/medical/unitconvert/Glucose.php. †The range of BG values for which the meter has been proven accurate and will provide readings (other than low, high, or error). ‡Values outside of the “clinically acceptable” A and B regions are considered “outlier” readings and may be dangerous to use for therapeutic decisions128. care.diabetesjournals.org Diabetes Technology S75

Table 7.2—Interfering substances (62). To make these metrics more action- provided data on real-time CGM use Glucose oxidase monitors able, standardized reports with visual in the youngest age groups (68–70). Uric acid cues, such as an ambulatory glucose Finally, while limited by the observa- Galactose profile (62), may help the patient and the tional nature, registry data provide Xylose provider interpret the data and use it to some evidence of real-world use of Acetaminophen guide treatment decisions. the technologies (71,72). L-dopa In addition, while A1C is well estab- Ascorbic acid lished as an important risk marker for Glucose dehydrogenase monitors Impact on Glycemic Control Icodextrin (used in peritoneal dialysis) diabetes complications, with the increas- When data from adult and pediatric ing use of CGM to help facilitate safe participants is analyzed together, CGM and effective diabetes management, it is use in RCTs has been associated with important to understand how CGM met- 7.12 People who have been success- reduction in A1C levels (64–66). Yet, in rics, such as mean glucose and A1C corre- fully using continuous glucose the JDRF CGM trial, when youth were late. Estimated A1C (eA1C) is a measure monitors should have contin- analyzed by age-group (8- to 14-year- converting the mean glucose from CGM or ued access across third-party olds and 15- to 24-year-olds), no change self-monitored blood glucose readings, us- payers. E in A1C was seen, likely due to poor CGM ing a formula derived from glucose read- adherence (41). Indeed, in a secondary ings from a population of individuals, analysis of that RCT’s data in both pedi- CGM measures interstitial glucose (which into an estimate of a simultaneously atric cohorts, those who utilized the correlates well with plasma glucose). measured laboratory A1C. Recently, the sensor $6 days/week had an improve- There are two types of CGM devices. eA1C was renamed the glucose management in their glycemic control (73). Most CGM devices are real-time CGM, ment indicator (GMI), and a new formula One critical component to success with which continuously report glucose lev- was generated for converting CGM- CGM is near-daily wearing of the device els and include alarms for hypoglyce- derived mean glucose to GMI based on (64,74–76). mic and hyperglycemic excursions. The recent clinical trials using the most ac- Though data from small observational other type of device is intermittently curate CGM systems available. This pro- studies demonstrate that CGM can be scanning CGM (isCGM), which is ap- vided a new way to use CGM data to worn by patients ,8 years old and the proved for adult use only. isCGM, dis- estimate A1C (63). use of CGM provides insight to glycemic cussed more fully below, does not have patterns (68,69), an RCT in children aged alarms and does not communicate con- 4 to 9 years did not demonstrate im- tinuously, only on demand. It is reported Real-time Continuous Glucose Monitor Use in Youth provements in glycemic control following to have a lower cost than systems with 6 months of CGM use (67). However, ob- automatic alerts. Recommendation servational feasibility studies of toddlers For some CGM systems, SMBG is re- 7.13 Real-time continuous glucose demonstrated a high degree of parental quired to make treatment decisions, al- monitoring should be consid- satisfaction and sustained use of the de- though a randomized controlled trial of eredin children and adolescents vices despite the inability to change the 226 adults suggested that an enhanced with type 1 diabetes, whether degree of glycemic control attained (70). CGM device could be used safely and using multiple daily injections or Registry data has also shown an asso- effectively without regular confirmatory continuous subcutaneous insu- ciation between CGM use and lower A1C SMBG in patients with well-controlled lin infusion, as an additional tool levels (71,72), even when limiting as- type 1 diabetes at low risk of severe to help improve glucose control sessment of CGM use to participants hypoglycemia (59). Two CGM devices are and reduce the risk of hypogly- on injection therapy (72). now approved by the FDA for making cemia. Benefits of continuous treatment decisions without SMBG con- glucose monitoring correlate with Impact on Hypoglycemia firmation, sometimes called adjunctive adherence to ongoing use of the Apart from the Sensing With Insu- use (60,61). device. B lin pump Therapy to Control HbA1c The abundance of data provided by (SWITCH) study, which showed a signif- CGM offers opportunities to analyze Data regarding use of real-time CGM icant effect of adding CGM to insulin patient data more granularly than was in youth consist of findings from RCTs pump therapy on time spent in hypogly- previously possible, providing additional and small observational studies, as cemia (64), most studies focusing on information to aid in achieving glycemic well as analysis of data collected by glycemic management overall failed to targets. A variety of metrics have been registries. Some of the RCTs have in- demonstrate a significant or relevant re- proposed (62). As recently reported, the cluded both adult and pediatric partic- duction in level 1 hypoglycemia (41,65– metrics may include: 1) average glucose; 2) ipants (41,64–66), while others have 67,77). Notably, RCTs primarily aimed at percentage of time in hypoglycemic only included pediatric participants hypoglycemia prevention did demon- ranges, i.e., ,54 mg/dL (level 2), 54–70 (67) or limited the analysis of larger strate a significant reduction in mild hy- mg/dL (level 1) (62); 3) percentage of studies to just the pediatric participants poglycemia in terms of reducing the time time in target range, i.e., 70–180 mg/dL (41). Given the feasibility problems of spent in hypoglycemia by approximately (3.9–9.9 mmol/L); 4) percentage of time performing RCTs in very young children, 40% and reducing the number of level 1 in hyperglycemic range, i.e., $180 mg/dL small observational studies have also hypoglycemia events per day (78,79). S76 Diabetes Technology Diabetes Care Volume 42, Supplement 1, January 2019

Real-time Continuous Glucose Primary Outcome: A1C Reduction predicted to go low within the next Monitor Use in Adults In general, A1C reduction was shown in 30minhavebeenapprovedbytheFDA. studies where the baseline A1C was The Automation to Simulate Pancreatic Recommendations higher. In two larger studies in adults Insulin Response (ASPIRE) trial of 247 7.14 When used properly, real-time with type 1 diabetes that assessed the patients with type 1 diabetes and doc- continuous glucose monitoring benefit of CGM in patients on MDI, umented nocturnal hypoglycemia showed in conjunction with intensive there were significant reductions in that sensor-augmented insulin pump insulin regimens is a useful A1C: 20.6% in one (80,81) and 20.43% therapy with a low-glucose suspend func- tool to lower A1C in adults in the other (82). No reduction in A1C tion significantly reduced nocturnal with type 1 diabetes who are was seen in a small study performed in hypoglycemia over 3 months without not meetingglycemic targets. A underserved, less well-educated adults increasing A1C levels (66). In a different 7.15 Real-time continuous glucose with type 1 diabetes (83). In the adult sensor-augmented pump, predictive low- monitoring may be a useful tool subset of the JDRF CGM study, there was glucose suspend reduced time spent in those with hypoglycemia un- asignificant reduction in A1C of 20.53% with glucose ,70 mg/dL from 3.6% awareness and/or frequent hy- (71) in patients who were primarily at baseline to 2.6% (3.2% with sensor- poglycemic episodes. B treated with insulin pump therapy. Better augmented pump therapy without pre- 7.16 Real-time continuous glucose adherence in wearing the CGM device dictive low glucose suspend) without monitoring should be used as resulted in a greater likelihood of an im- rebound hyperglycemia during a 6- close to daily as possible for provement in glycemic control (41,84). week randomized crossover trial (95a). maximal benefit. A Studies in people with type 2 diabetes These devices may offer the opportunity 7.17 Real-time continuous glucose are heterogeneous in designdin two, to reduce hypoglycemia for those with a monitoring may be used ef- participants were using basal insulin history of nocturnal hypoglycemia. fectively to improve A1C lev- with oral agents or oral agents alone els and neonatal outcomes in (65,95); in one, individuals were on Real-time Continuous Glucose pregnant women with type 1 MDI alone (92); and in another, par- Monitor Use in Pregnancy diabetes. B ticipants were on CSII or MDI (79). The One well-designed RCT showed a reduc- 7.18 Sensor-augmented pump ther- findings in studies with MDI alone (92) tion in A1C levels in adult women with apy with automatic low-glucose and in two studies in people using oral type 1 diabetes on MDI or CSII who were suspend may be considered agents with or without insulin (93,95) pregnant (96). Neonatal outcomes were for adults with type 1 diabetes showed significant reductions in A1C better when the mother used CGM at high risk of hypoglycemia levels. during pregnancy (80). Two studies em- to prevent episodes of hypo- ploying intermittent use of real-time glycemia and reduce their se- CGMshowednodifferenceinneonatal verity. B Primary Outcome: Hypoglycemia In studies in adults where reduction in outcomes in women with type 1 diabe- episodes of hypoglycemia was the pri- tes (97) or gestational diabetes mellitus Data exist to support the use of CGM mary end point, significant reductions (98). in adults, both those on MDI and on were seen in individuals with type 1 CSII. In terms of randomized controlled diabetes on MDI or CSII (85–87). In Intermittently Scanned Continuous trials in people with type 1 diabetes, one study in patients who were at Glucose Monitor Use there are four studies in adults with higher risk for episodes of hypoglyce- Recommendation A1C as the primary outcome (80–84), mia (87), there was a reduction in rates 7.19 Intermittently scanned contin- three studies in adults with hypogly- of all levels of hypoglycemia (see Sec- uous glucose monitor use may cemia as the primary outcome (85–87), tion 6 “Glycemic Targets” for hypogly- be considered as a substitute four studies in adults and children cemia definitions). The Multiple Daily for self-monitoring of blood with A1C as the primary outcome Injections and Continuous Glucose Mon- glucose in adults with diabetes (41,64–66), and three studies in adults itoring in Diabetes (DIAMOND) study in requiring frequent glucose test- andchildrenwithhypoglycemiaasa people with type 2 diabetes on MDI did ing. C primary outcome (41,78,88). There are not show a reduction in hypoglycemia three studies in adults with type 1 or (92). Studies in individuals with type 2 isCGM (sometimes referred to as “flash” type 2 diabetes (89–91) and four studies diabetes on oral agents with or without CGM) is a CGM that measures glucose with adults with type 2 diabetes (92–95). insulin did not show reductions in rates in interstitial fluid through a ,0.4 mm– Finally, there are three studies that have of hypoglycemia (93,95). CGM may be thick filament that is inserted under the been done in pregnant women with particularly useful in insulin-treated pa- skin. It has been available in Europe prepregnancy diabetes or gestational tients with hypoglycemia unawareness since 2014 and was approved by the diabetes mellitus (96–98). Overall, ex- and/or frequent hypoglycemic episodes, FDA for use in adults in the U.S. in 2017. cluding studies evaluating pediatric pa- although studies have not shown consis- The personal version of isCGM has a re- tients alone or pregnant women, 2,984 tent reductions in severe hypoglycemia ceiver that, after scanning over the sensor people with type 1 or type 2 diabetes (41,64,65). by the individual, displays real-time glu- have been studied to assess the benefits Sensor-augmented pumps that sus- cose values and glucose trend arrows. of CGM. pend insulin when glucose is low or The data can be uploaded and a report care.diabetesjournals.org Diabetes Technology S77

created using available software. In the and safety for individuals with type 1 124) demonstrated safety (122) and professional version, the patient does and type 2 diabetes, based on data improved A1C in adults (reduction from not carry a receiver; the data are blinded available until January 2017 (114). The 7.360.9%to6.860.6%)andadolescents to the patient and the device is down- authors concluded that, although there (7.7 6 0.8% to 7.1 6 0.6%) (123). loaded in the diabetes care provider’s were few quality data available at the time To date, the longest outpatient RCTs office using the provider’s receiver and of the report, isCGM may increase treat- lasted 12 weeks and compared HCL the software. The isCGM sensor is smaller ment satisfaction, increase time in range, treatment (a system that is not currently than those of other systems and is wa- and reduce frequency of nocturnal hypo- FDA approved) to sensor-augmented ter resistant. In the U.S., the FDA now glycemia, without differences in A1C or pumps in adults and children as young requires a 1-h start-up time after activation quality of life or serious adverse events. as 6 years of age (n 5 86) with A1C levels of the system, and it can be worn up to The Canadian Agency for Drugs and above target at baseline. Compared with 14 days. The isCGM does not require Technologies in Health reviewed existing sensor-augmented pump therapy, the calibration with SMBG because it is fac- data on isCGM performance and accu- HCL system reduced the risk for hypogly- tory calibrated. Acetaminophen does racy, hypoglycemia, effect on A1C, and cemia and improved glucose control in not cause interference with glucose patient satisfaction and quality of life A1C levels (124). readings. The mean absolute relative and concluded that the system could difference reported by the manufac- replace SMBG in particular in patients turer is 9.4%. It measures glucose every who require frequent testing (115). The Future Systems minute, records measurements every last review published at the time of this A multitude of other automated insulin 15 min, and displays up to 8 h of data. report (116) also supported the use of delivery systems are currently being in- As opposed to real-time CGM systems, isCGM as a more affordable alternative vestigated, including those with dual isCGM has no alarms. The direct costs to real-time CGM systems for individ- hormones (insulin and glucagon or insulin of isCGM are lower than those of real- uals with diabetes who are on intensive and pramlintide). Furthermore, some time CGM systems. In general, both insulin therapy. patients have created do-it-yourself the consumer and professional versions systems through guidance from online are covered by most commercial in- communities, although these are not FDA surance carriers and eligible Medicare AUTOMATED INSULIN DELIVERY approved or recommended. programs. Information on Medicaid cov- Recommendation References erage was not available at the time of 7.20 Automated insulin delivery sys- 1. Lasalvia P, Barahona-Correa JE, Romero- this writing. tems may be considered in chil- Alvernia DM, et al. Pen devices for insulin Studies in adults with diabetes indicate dren (.7 years) and adults with self-administration compared with needle and isCGM has acceptable accuracy when type 1 diabetes to improve gly- vial: systematic review of the literature and compared with SMBG (99–102), al- cemic control. B meta-analysis. J Diabetes Sci Technol 2016;10: – though the accuracy may be lower at 959 966 2. Hanas R, de Beaufort C, Hoey H, Anderson B. high and/or low glucose levels (103,104). To provide physiologic insulin deliv- Insulin delivery by injection in children and Studies comparing the accuracy of isCGM ery, insulin doses need to be adjusted adolescents with diabetes. Pediatr Diabetes with real-time CGM show conflicting based on glucose values, which is now 2011;12:518–526 results (102,104,105). isCGM may de- feasible with automated insulin deliv- 3. Pfutzner¨ A, Schipper C, Niemeyer M, et al. Comparison of patient preference for two insulin crease the risk of hypoglycemia in indi- ery systems consisting of three compo- injection pen devices in relation to patient viduals with type 1 (85) or type 2 diabetes nents: an insulin pump, a continuous dexterity skills. J Diabetes Sci Technol 2012;6: (94). There are a growing number of glucose sensor, and an algorithm that 910–916 studies suggesting similar good perfor- determines insulin delivery. With these 4. Williams AS, Schnarrenberger PA. A compar- mance and potential for benefitinspecial systems, insulin delivery cannot only be ison of dosing accuracy: visually impaired and sighted people using insulin pens. J Diabetes Sci populations, including pregnant women suspended but also increased or de- Technol 2010;4:514–521 with diabetes (106), individuals with creased based on sensor glucose values. 5. Reinauer KM, Joksch G, Renn W, Eggstein M. type 1 diabetes and hypoglycemia un- Emerging evidence suggests such sys- Insulin pens in elderly diabetic patients. Diabetes awareness(107),andchildren (108–110), tems may lower the risk of exercise- Care 1990;13:1136–1137 although accuracy (mean absolute rela- related hypoglycemia (117) and may 6. Thomas DR, Fischer RG, Nicholas WC, fi – Beghe C, Hatten KW, Thomas JN. Disposable tive difference) could be decreased in have psychosocial bene ts (118 121). insulin syringe reuse and aseptic practices in younger children (109). Contact derma- While eventually insulin delivery in diabetic patients. J Gen Intern Med 1989;4:97– titis has been reported and linked to the closed-loop systems may be truly auto- 100 presence of isobornyl acrylate, a struc- mated, meals must currently be an- 7. Winter A, Lintner M, Knezevich E. V-Go insulin tural plastic of the device, which is a skin nounced. A so-called hybrid approach, delivery system versus multiple daily insulin injections for patients with uncontrolled type 2 sensitizer and can cause an additional hybrid closed-loop (HCL), has been diabetes mellitus. J Diabetes Sci Technol 2015; spreading allergic reaction (111–113). adopted in first-generation closed- 9:1111–1116 There are several published reviews of loop systems and requires users to bolus 8. Yeh H-C, Brown TT, Maruthur N, et al. Com- data available on isCGM (114–116). The for meals and snacks. The FDA has ap- parative effectiveness and safety of methods fi of insulin delivery and glucose monitoring for Norwegian Institute for Public Health proved the rst HCL system for use in those diabetes mellitus: a systematic review and conducted an assessment of isCGM clin- as young as 7 years of age. A 3-month meta-analysis. Ann Intern Med 2012;157: ical effectiveness, cost-effectiveness, noncontrolled trial using this device (n 5 336–347 S78 Diabetes Technology Diabetes Care Volume 42, Supplement 1, January 2019

9. Pickup JC. The evidence base for diabetes 24. Redondo MJ, Connor CG, Ruedy KJ, et al.; childrenwith type 1 diabetes:a randomized open technology: appropriate and inappropriate Pediatric Diabetes Consortium. Pediatric Diabe- crossover trial. Pediatrics 2003;112:559–564 meta-analysis. J Diabetes Sci Technol 2013;7: tes Consortium Type 1 Diabetes New Onset 37. Opipari-Arrigan L, Fredericks EM, Burkhart 1567–1574 (NeOn) Study: factors associated with HbA1c N, Dale L, Hodge M, Foster C. Continuous sub- 10. Blackman SM, Raghinaru D, Adi S, et al. levels one year after diagnosis. Pediatr Diabetes cutaneous insulin infusion benefits quality of Insulin pump use in young children in the T1D 2014;15:294–302 life in preschool-age children with type 1 di- Exchange clinic registry is associated with lower 25. Doyle EA, Weinzimer SA, Steffen AT, Ahern abetes mellitus. Pediatr Diabetes 2007;8:377– hemoglobin A1c levels than injection therapy. JAH, Vincent M, Tamborlane WVA. A randomized, 383 Pediatr Diabetes 2014;15:564–572 prospective trial comparing the efficacy of con- 38. Sundberg F, Barnard K, Cato A, et al. ISPAD 11. Lin MH, Connor CG, Ruedy KJ, et al.; Pedi- tinuous subcutaneous insulin infusion with mul- Guidelines. Managing diabetes in preschool chil- atric Diabetes Consortium. Race, socioeconomic tiple daily injections using insulin glargine. dren. Pediatr Diabetes 2017;18:499–517 status, and treatment center are associated with Diabetes Care 2004;27:1554–1558 39. Commissariat PV, Boyle CT, Miller KM, et al. insulin pump therapy in youth in the first year 26. Alemzadeh R, Ellis JN, Holzum MK, Parton EA, Insulin pump use in young children with type 1 following diagnosis of type 1 diabetes. Diabetes Wyatt DT. Beneficial effects of continuous sub- diabetes: sociodemographic factors and parent- Technol Ther 2013;15:929–934 cutaneous insulin infusion and flexible multiple reported barriers. Diabetes Technol Ther 2017; 12. Willi SM, Miller KM, DiMeglio LA, et al.; T1D daily insulin regimen using insulin glargine in 19:363–369 Exchange Clinic Network. Racial-ethnic dis- type 1 diabetes. Pediatrics 2004;114:e91–e95 40. Nathan DM, Genuth S, Lachin J, et al.; Di- parities in management and outcomes among 27. Sherr JL, Hermann JM, Campbell F, et al.; T1D abetes Control and Complications Trial Research children with type 1 diabetes. Pediatrics 2015; Exchange Clinic Network, the DPV Initiative, and Group. The effect of intensive treatment of 135:424–434 the National Paediatric Diabetes Audit and the diabetes on the development and progression 13. Redondo MJ, Libman I, Cheng P, et al.; Royal College of Paediatrics and Child Health of long-term complications in insulin-dependent Pediatric Diabetes Consortium. Racial/ethnic registries. Use of insulin pump therapy in children diabetes mellitus. N Engl J Med 1993;329:977– minority youth with recent-onset type 1 di- and adolescents with type 1 diabetes and its 986 abetes have poor prognostic factors. Diabetes impact on metabolic control: comparison of 41. Tamborlane WV, Beck RW, Bode BW, et al.; Care 2018;41:1017–1024 results from three large, transatlantic paediatric Juvenile Diabetes Research Foundation Con- 14. Ramchandani N, Ten S, Anhalt H, et al. Insulin registries. Diabetologia 2016;59:87–91 tinuous Glucose Monitoring Study Group. pump therapy from the time of diagnosis of type 1 28. Jeitler K, Horvath K, Berghold A, et al. Con- Continuous glucose monitoring and intensive diabetes. Diabetes Technol Ther 2006;8:663–670 tinuous subcutaneous insulin infusion versus treatment of type 1 diabetes. N Engl J Med 15. Berghaeuser MA, Kapellen T, Heidtmann B, multiple daily insulin injections in patients with 2008;359:1464–1476 Haberland H, Klinkert C, Holl RW; DPV-Science- diabetes mellitus: systematic review and meta- 42. Miller KM, Beck RW, Bergenstal RM, et al.; Initiative and the German working group for analysis. Diabetologia 2008;51:941–951 T1D Exchange Clinic Network. Evidence of a insulin pump treatment in paediatric patients. 29. Karges B, Schwandt A, Heidtmann B, et al. strong association between frequency of self- Continuous subcutaneous insulin infusion in Association of insulin pump therapy vs insulin monitoring of blood glucose and hemoglobin toddlers starting at diagnosis of type 1 diabetes injection therapy with severe hypoglycemia, A1c levels in T1D Exchange clinic registry partic- mellitus. A multicenter analysis of 104 patients ketoacidosis, and glycemic control among chil- ipants. Diabetes Care 2013;36:2009–2014 from 63 centres in Germany and Austria. Pediatr dren, adolescents, and young adults with type 1 43. Grant RW, Huang ES, Wexler DJ, et al. Diabetes 2008;9:590–595 diabetes. JAMA 2017;318:1358–1366 Patients who self-monitor blood glucose and 16. Peters AL, Ahmann AJ, Battelino T, et al. 30. The DCCT Research Group. Epidemiology their unused testing results. Am J Manag Care Diabetes technologydcontinuous subcutane- of severe hypoglycemia in the Diabetes Control 2015;21:e119–e129 ous insulin infusion therapy and continuous and Complications Trial. Am J Med 1991;90:450–459 44. Gellad WF, Zhao X, Thorpe CT, Mor MK, Good glucose monitoring in adults: an Endocrine So- 31. Haynes A, Hermann JM, Miller KM, et al. CB, Fine MJ. Dual use of Department of Veterans ciety clinical practice guideline. J Clin Endocrinol Severe hypoglycemia rates are not associated Affairs and Medicare benefits and use of test Metab 2016;101:3922–3937 with HbA1c: a cross-sectional analysis of 3 con- strips in veterans with type 2 diabetes mellitus. 17. Wheeler BJ, Heels K, Donaghue KC, Reith DM, temporary pediatric diabetes registry databases. JAMA Intern Med 2015;175:26–34 Ambler GR. Insulin pump-associated adverse Pediatr Diabetes 2017;18:643–650 45. Endocrine Society and Choosing Wisely. eventsinchildrenandadolescentsdaprospective 32. Pickup JC, Sutton AJ. Severe hypoglycaemia Five things physicians and patients should ques- study. Diabetes Technol Ther 2014;16:558–562 and glycaemic control in type 1 diabetes: meta- tion [Internet]. Available from http://www 18. Kordonouri O, Lauterborn R, Deiss D. Lipo- analysis of multiple daily insulin injections com- .choosingwisely.org/societies/endocrine-society/. hypertrophy in young patients with type 1 di- pared with continuous subcutaneous insulin Accessed 12 November 2018 abetes. Diabetes Care 2002;25:634 infusion. Diabet Med 2008; 25:765–774 46. Ziegler R, Heidtmann B, Hilgard D, Hofer S, 19. Kordonouri O, Biester T, Schnell K, et al. 33. Birkebaek NH, Drivvoll AK, Aakeson K, et al. Rosenbauer J, Holl R; DPV-Wiss-Initiative. Fre- Lipoatrophy in children with type 1 diabetes: an Incidence of severe hypoglycemia in children quency of SMBG correlates with HbA1c and increasing incidence? J Diabetes Sci Technol with type 1 diabetes in the Nordic countries in acute complications in children and adolescents 2015;9:206–208 the period 2008–2012: association with hemo- with type 1 diabetes. Pediatr Diabetes 2011;12: 20. Guinn TS, Bailey GJ, Mecklenburg RS. Factors globin A1c and treatment modality. BMJ Open 11–17 related to discontinuation of continuous sub- Diabetes Res Care 2017;5:e000377 47. Rosenstock J, Davies M, Home PD, Larsen J, cutaneous insulin-infusion therapy. Diabetes 34. Maahs DM, Hermann JM, Holman N, et al.; Koenen C, Schernthaner G. A randomised, 52-week, Care 1988;11:46–51 National Paediatric Diabetes Audit and the Royal treat-to-target trial comparing insulin detemir 21. Wong JC, Boyle C, DiMeglio LA, et al.; T1D College of Paediatrics and Child Health, the DPV with insulin glargine when administered as add- Exchange Clinic Network. Evaluation of pump dis- Initiative, and the T1D Exchange Clinic Network. on to glucose-lowering drugs in insulin-naive continuation and associated factors in the T1D Rates of diabetic ketoacidosis: international people with type 2 diabetes. Diabetologia 2008; Exchange clinic registry. J Diabetes Sci Technol comparison with 49,859 pediatric patients 51:408–416 2017;11:224–232 with type 1 diabetes from England, Wales, the 48. Garber AJ. Treat-to-target trials: uses, in- 22. Wong JC, Dolan LM, Yang TT, Hood KK. U.S., Austria, and Germany. Diabetes Care 2015; terpretation and review of concepts. Diabetes Insulin pump use and glycemic control in ado- 38:1876–1882 Obes Metab 2014;16:193–205 lescents with type 1 diabetes: predictors of 35. Zabeen B, Craig ME, Virk SA, et al. Insulin 49. Farmer A, Wade A, Goyder E, et al. Impact of change in method of insulin delivery across pump therapy is associated with lower rates of self monitoring of blood glucose in the manage- two years. Pediatr Diabetes 2015;16:592–599 retinopathy and peripheral nerve abnormality. ment of patients with non-insulin treated di- 23. Plotnick LP, Clark LM, Brancati FL, Erlinger T. PLoS One 2016;11:e0153033 abetes: open parallel group randomised trial. Safety and effectiveness of insulin pump therapy 36. Weintrob N, Benzaquen H, Galatzer A, et al. BMJ 2007;335:132 in children and adolescents with type 1 diabetes. Comparison of continuous subcutaneous insulin 50. O’Kane MJ, Bunting B, Copeland M, Coates Diabetes Care 2003;26:1142–1146 infusion and multiple daily injection regimens in VE; ESMON study group. Efficacy of self care.diabetesjournals.org Diabetes Technology S79

monitoring of blood glucose in patients with term for estimating A1C from continuous glu- continuous glucose monitoring compared with newly diagnosed type 2 diabetes (ESMON study): cose monitoring. Diabetes Care 2018;41:2275– self monitoring of blood glucose: meta-analysis randomised controlled trial. BMJ 2008;336: 2280 of randomised controlled trials using individual 1174–1177 64. Battelino T, Conget I, Olsen B, et al.; SWITCH patient data. BMJ 2011;343:d3805 51. Simon J, Gray A, Clarke P, Wade A, Neil A, Study Group. The use and efficacy of continuous 77. Riveline J-P, Schaepelynck P, Chaillous L, Farmer A; Diabetes Glycaemic Education and glucose monitoring in type 1 diabetes treated et al.; EVADIAC Sensor Study Group. Assessment Monitoring Trial Group. Cost effectiveness of with insulin pump therapy: a randomised con- of patient-led or physician-driven continuous self monitoring of blood glucose in patients with trolled trial. Diabetologia 2012;55:3155–3162 glucose monitoring in patients with poorly con- non-insulin treated type 2 diabetes: economic 65. Deiss D, Bolinder J, Riveline J-P, et al. Im- trolled type 1 diabetes using basal-bolus insulin evaluation of data from the DiGEM trial. BMJ proved glycemic control in poorly controlled regimens: a 1-year multicenter study. Diabetes 2008;336:1177–1180 patients with type 1 diabetes using real-time Care 2012;35:965–971 52. Young LA, Buse JB, Weaver MA, et al.; continuous glucose monitoring. Diabetes Care 78. Battelino T, Phillip M, Bratina N, Nimri R, Monitor Trial Group. Glucose self-monitoring 2006;29:2730–2732 Oskarsson P, Bolinder J. Effect of continuous in non-insulin-treated patients with type 2 di- 66. O’Connell MA, Donath S, O’Neal DN, et al. glucose monitoring on hypoglycemia in type 1 abetes in primary care settings: a randomized Glycaemic impact of patient-led use of sensor- diabetes. Diabetes Care 2011;34:795–800 trial. JAMA Intern Med 2017;177:920–929 guided pump therapy in type 1 diabetes: a ran- 79. Beck RW, Hirsch IB, Laffel L, et al.; Juvenile 53. Polonsky WH, Fisher L, Schikman CH, et al. domised controlled trial. Diabetologia 2009;52: Diabetes Research Foundation Continuous Glu- Structured self-monitoring of blood glucose sig- 1250–1257 cose Monitoring Study Group. The effect of con- nificantly reduces A1C levels in poorly controlled, 67. Mauras N, Beck R, Xing D, et al.; Diabetes tinuous glucose monitoring in well-controlled noninsulin-treated type 2 diabetes: results from Research in Children Network (DirecNet) Study type 1 diabetes. Diabetes Care 2009;32:1378– the Structured Testing Program study. Diabetes Group. A randomized clinical trial to assess the 1383 Care 2011;34:262–267 efficacy and safety of real-time continuous glu- 80. Beck RW, Riddlesworth T, Ruedy K, et al.; 54. Malanda UL, Welschen LMC, Riphagen II, cose monitoring in the management of type 1 DIAMOND Study Group. Effect of continuous Dekker JM, Nijpels G, Bot SDM. Self-monitoring diabetes in young children aged 4 to ,10 years. glucose monitoring on glycemic control in adults of blood glucose in patients with type 2 diabetes Diabetes Care 2012;35:204–210 with type 1 diabetes using insulin injections: the mellitus who are not using insulin. Cochrane 68. Jeha GS, Karaviti LP, Anderson B, et al. DIAMOND randomized clinical trial. JAMA 2017; Database Syst Rev 2012;1:CD005060 Continuous glucose monitoring and the reality 317:371–378 55. Willett LR. ACP Journal Club. Meta-analysis: of metabolic control in preschool children with 81. Riddlesworth T, Price D, Cohen N, Beck RW. self-monitoring in non-insulin-treated type 2 di- type 1 diabetes. Diabetes Care 2004;27:2881– Hypoglycemic event frequency and the effect abetes improved HbA1c by 0.25%. Ann Intern 2886 of continuous glucose monitoring in adults Med 2012;156:JC6–JC12 69. Gandrud LM, Xing D, Kollman C, et al. The with type 1 diabetes using multiple daily in- 56. Mannucci E, Antenore A, Giorgino F, Scavini Medtronic Minimed Gold continuous glucose sulin injections. Diabetes Ther 2017;8:947– M. Effects of structured versus unstructured monitoring system: an effective means to dis- 951 self-monitoring of blood glucose on glucose cover hypo- and hyperglycemia in children under 82. Lind M, Polonsky W, Hirsch IB, et al. Con- control in patients with non-insulin-treated 7 years of age. Diabetes Technol Ther 2007;9: tinuous glucose monitoring vs conventional ther- type 2 diabetes: a meta-analysis of randomized 307–316 apy for glycemic control in adults with type 1 controlled trials. J Diabetes Sci Technol 2018;12: 70. Tsalikian E, Fox L, Weinzimer S, et al.; Di- diabetes treated with multiple daily insulin in- 183–189 abetes Research in Children Network Study jections: the GOLD randomized clinical trial 57. Klonoff DC, Parkes JL, Kovatchev BP, et al. Group. Feasibility of prolonged continuous glu- [published correction appears in JAMA 2017; Investigation of the accuracy of 18 marketed cose monitoring in toddlers with type 1 diabetes. 317:1912]. JAMA 2017;317:379–387 blood glucose monitors. Diabetes Care 2018;41: Pediatr Diabetes 2012;13:301–307 83. Sequeira PA, Montoya L, Ruelas V, et al. 1681–1688 71. Wong JC, Foster NC, Maahs DM, et al.; T1D Continuous glucose monitoring pilot in low- 58. Ginsberg BH. Factors affecting blood glucose Exchange Clinic Network. Real-time continuous income type 1 diabetes patients. Diabetes monitoring: sources of errors in measurement. J glucose monitoring among participants in the Technol Ther 2013;15:855–858 Diabetes Sci Technol 2009;3:903–913 T1D Exchange clinic registry. Diabetes Care 2014; 84. Tumminia A, Crimi S, Sciacca L, et al. Efficacy 59. Aleppo G, Ruedy KJ, Riddlesworth TD, et al.; 37:2702–2709 of real-time continuous glucose monitoring on REPLACE-BG Study Group. REPLACE-BG: a ran- 72. Foster NC, Miller KM, Tamborlane WV, glycaemic control and glucose variability in type domized trial comparing continuous glucose Bergenstal RM, Beck RW; T1D Exchange Clinic 1 diabetic patients treated with either insulin monitoring with and without routine blood Network. Continuous glucose monitoring in pa- pumps or multiple insulin injection therapy: glucose monitoring in adults with well-controlled tients with type 1 diabetes using insulin injec- a randomized controlled crossovertrial. Diabetes type 1 diabetes. Diabetes Care 2017;40:538–545 tions. Diabetes Care 2016;39:e81–e82 Metab Res Rev 2015;31:61–68 60. U.S. Food and Drug Administration. FDA 73. Beck RW, Buckingham B, Miller K, et al.; 85. Bolinder J, Antuna R, Geelhoed-Duijvestijn P, news release: FDA expands indication for con- Juvenile Diabetes Research Foundation Contin- Kroger¨ J, Weitgasser R. Novel glucose-sensing tinuous glucose monitoring system, first to uous Glucose Monitoring Study Group. Factors technology and hypoglycaemia in type 1 diabe- replace fingerstick testing for diabetes treat- predictive of use and of benefit from continuous tes: a multicentre, non-masked, randomised ment decisions [Internet], 2016. Available from glucose monitoring in type 1 diabetes. Diabetes controlled trial. Lancet 2016;388:2254–2263 https://www.fda.gov/newsevents/newsroom/ Care 2009;32:1947–1953 86. Hermanns N, Schumann B, Kulzer B, Haak T. pressannouncements/ucm534056.htm. Accessed 74. Juvenile Diabetes Research Foundation Con- The impact of continuous glucose monitoring on 14 September 2017 tinuous Glucose Monitoring Study Group. Effec- low interstitial glucose values and low blood 61. U.S. Food and Drug Administration. FDA tiveness of continuous glucose monitoring in a glucose values assessed by point-of-care blood news release: FDA approves first continuous clinical care environment: evidence from the glucose meters: results of a crossover trial. J glucose monitoring system for adults not re- Juvenile Diabetes Research Foundation Contin- Diabetes Sci Technol 2014;8:516–522 quiring blood sample calibration [Internet], uous Glucose Monitoring (JDRF-CGM) trial. Di- 87. van Beers CAJ, DeVries JH, Kleijer SJ, et al. 2017. Available from https://www.fda.gov/ abetes Care 2010;33:17–22 Continuous glucose monitoring for patients with NewsEvents/Newsroom/PressAnnouncements/ 75. Chase HP, Beck RW, Xing D, et al. Continuous type 1 diabetes and impaired awareness of ucm577890.htm. Accessed 2 October 2017 glucosemonitoringin youthwithtype 1diabetes: hypoglycaemia (IN CONTROL): a randomised, 62. Danne T, Nimri R, Battelino T, et al. In- 12-month follow-up of the Juvenile Diabetes open-label, crossover trial. Lancet Diabetes En- ternational consensus on use of continuous Research Foundation continuous glucose mon- docrinol 2016;4:893–902 glucose monitoring. Diabetes Care 2017;40: itoring randomized trial. Diabetes Technol Ther 88. Heinemann L, Freckmann G, Ehrmann D, 1631–1640 2010;12:507–515 et al. Real-time continuous glucose monitoring 63. Bergenstal RM, Beck RW, Close KL, et al. 76. Pickup JC, Freeman SC, Sutton AJ. Glycaemic in adults with type 1 diabetes and impaired hypo- Glucose management indicator (GMI): a new control in type 1 diabetes during real time glycaemia awareness or severe hypoglycaemia S80 Diabetes Technology Diabetes Care Volume 42, Supplement 1, January 2019

treated with multiple daily insulin injections 101. Bailey T, Bode BW, Christiansen MP, Klaff in Emerging Health Technologies. Ottawa, ON, (HypoDE): a multicentre, randomised controlled LJ, Alva S. The performance and usability of a Canadian Agency for Drugs and Technologies in trial. Lancet 2018;391:1367–1377 factory-calibrated flash glucose monitoring sys- Health, 2016 [Internet]. Available from http:// 89. Garg S, Zisser H, Schwartz S, et al. Improve- tem. Diabetes Technol Ther 2015;17:787–794 www.ncbi.nlm.nih.gov/books/NBK476439/. Ac- ment in glycemic excursions with a transcuta- 102. Aberer F, Hajnsek M, Rumpler M, et al. cessed 22 October 2018 neous, real-time continuous glucose sensor: Evaluation of subcutaneous glucose monitoring 116. Leelarathna L, Wilmot EG. Flash forward: a randomized controlled trial. Diabetes Care systems under routine environmental conditions areviewofflash glucose monitoring. Diabet 2006;29:44–50 in patients with type 1 diabetes. Diabetes Obes Med 2018;35:472–482 90. New JP, Ajjan R, Pfeiffer AFH, Freckmann G. Metab 2017;19:1051–1055 117. Sherr JL, Cengiz E, Palerm CC, et al. Reduced Continuous glucose monitoring in people with 103. Fokkert MJ, van Dijk PR, Edens MA, et al. hypoglycemia and increased time in target diabetes: the randomized controlled Glucose Performance of the FreeStyle Libre flash glucose using closed-loop insulin delivery during nights Level Awareness in Diabetes Study (GLADIS). monitoring system in patients with type 1 and with or without antecedent afternoon exercise Diabet Med 2015;32:609–617 2 diabetes mellitus. BMJ Open Diabetes Res Care in type 1 diabetes. Diabetes Care 2013;36: 91. Cooke D, Hurel SJ, Casbard A, et al. Ran- 2017;5:e000320 2909–2914 domized controlled trial to assess the impact 104. Bonora B, Maran A, Ciciliot S, Avogaro A, 118. Troncone A, Bonfanti R, Iafusco D, et al. of continuous glucose monitoring on HbA1c in Fadini GP. Head-to-head comparison between Evaluating the experience of children with type 1 insulin-treated diabetes (MITRE Study). Diabet flashand continuous glucose monitoringsystems diabetes and their parents taking part in an Med 2009;26:540–547 in outpatients with type 1 diabetes. J Endocrinol artificial pancreas clinical trial over multiple 92. Beck RW, Riddlesworth TD, Ruedy K, et al.; Invest 2016;39:1391–1399 days in a diabetes camp setting. Diabetes DIAMOND Study Group. Continuous glucose 105. Boscari F, Galasso S, Acciaroli G, et al. Head- Care 2016;39:2158–2164 monitoring versus usual care in patients with to-head comparison of the accuracy of Abbott 119. Barnard KD, Wysocki T, Allen JM, et al. type 2 diabetes receiving multiple daily insulin FreeStyle Libre and Dexcom G5 Mobile. Nutr Closing the loop overnight at home setting: injections: a randomized trial. Ann Intern Med Metab Cardiovasc Dis 2018;28:425–427 psychosocial impact for adolescents with type 2017;167:365–374 106. Scott EM, Bilous RW, Kautzky-Willer A. 1 diabetes and their parents. BMJ Open Diabetes 93. Ehrhardt NM, Chellappa M, Walker MS, Accuracy, user acceptability, and safety evalua- Res Care 2014;2:e000025 Fonda SJ, Vigersky RA. The effect of real-time tion for the FreeStyle Libre flash glucose mon- 120. Barnard KD, Wysocki T, Thabit H, et al.; continuous glucose monitoring on glycemic con- itoring system when used by pregnant women Angela Consortium. Psychosocial aspects of trol in patients with type 2 diabetes mellitus. with diabetes. Diabetes Technol Ther 2018;20: closed- and open-loop insulin delivery: closing J Diabetes Sci Technol 2011;5:668–675 180–188 the loop in adults with type 1 diabetes in the 94. Haak T, Hanaire H, Ajjan R, Hermanns N, 107. Reddy M, Jugnee N, El Laboudi A, home setting. Diabet Med 2015;32:601–608 Riveline J-P, Rayman G. Flash glucose-sensing Spanudakis E, Anantharaja S, Oliver N. A ran- 121. Weissberg-Benchell J, Hessler D, Polonsky technology as a replacement for blood glucose domized controlled pilot study of continuous WH, Fisher L. Psychosocial impact of the bionic monitoring for the management of insulin- glucose monitoring and flash glucose monitoring pancreas during summer camp. J Diabetes Sci treated type 2 diabetes: a multicenter, open- in people with type 1 diabetes and impaired Technol 2016;10:840–844 label randomized controlled trial. Diabetes Ther awareness of hypoglycaemia. Diabet Med 2018; 122. Bergenstal RM, Garg S, Weinzimer SA, et al. 2017;8:55–73 35:483–490 Safety of a hybrid closed-loop insulin delivery 95. Yoo HJ, An HG, Park SY, et al. Use of a real 108. Szadkowska A, Gawrecki A, Michalak A, system in patients with type 1 diabetes. JAMA time continuous glucose monitoring system as Zozulinska-Zi´ o´łkiewicz D, Fendler W, Młynarski 2016;316:1407–1408 a motivational device for poorly controlled type 2 W. Flash glucose measurements in children with 123. Garg SK, Weinzimer SA, Tamborlane WV, diabetes. Diabetes Res Clin Pract 2008;82:73–79 type 1 diabetes in real-life settings: to trust or et al. Glucose outcomes with the in-home use 95a. Forlenza GP, Li Z, Buckingham BA, et al. not to trust? Diabetes Technol Ther 2018;20: of a hybrid closed-loop insulin delivery system Predictive low-glucose suspend reduces hypo- 17–24 in adolescents and adults with type 1 diabetes. glycemiainadults,adolescents,andchildrenwith 109. Massa GG, Gys I, Op ’t Eyndt A, et al. Diabetes Technol Ther 2017;19:155–163 type 1 diabetes in an at-home randomized Evaluation of the FreeStyleÒ Libre flash glucose 124. Tauschmann M, Thabit H, Bally L, et al. crossover study: results of the PROLOG trial. monitoring system in children and adolescents Closed-loop insulin delivery in suboptimally con- Diabetes Care 2018;41:2155–2161 with type 1 diabetes. Horm Res Paediatr 2018; trolled type 1 diabetes: a multicentre, 12-week 96. Feig DS, Donovan LE, Corcoy R, et al.; 89:189–199 randomised trial. Lancet 2018;392:1321–1329 CONCEPTT Collaborative Group. Continuous 110. Edge J, Acerini C, Campbell F, et al. An 125. U.S. Food and Drug Adminstration. Self- glucose monitoring in pregnant women with alternative sensor-based method for glucose monitoring blood glucose test systems for over- type 1 diabetes (CONCEPTT): a multicentre in- monitoring in children and young people with the-counter use: guidance for industry and Food ternational randomised controlled trial. Lan- diabetes. Arch Dis Child 2017;102:543–549 and Drug Administration staff [Internet]. Avail- cet 2017;390:2347–2359 111. Kamann S, Aerts O, Heinemann L. Further able from https://www.fda.gov/downloads/ 97. Secher AL, Ringholm L, Andersen HU, Damm evidence of severe allergic contact dermatitis MedicalDevices/DeviceRegulationandGuidance/ P, Mathiesen ER. The effect of real-time contin- from isobornyl acrylate while using a continuous GuidanceDocuments/UCM380327.pdf. Accessed uous glucose monitoring in pregnant women glucose monitoring system. J Diabetes Sci Tech- 14 November 2018 with diabetes: a randomized controlled trial. nol 2018;12:630–633 126. U.S. Food and Drug Administration. Blood Diabetes Care 2013;36:1877–1883 112. Aerts O, Herman A, Bruze M, Goossens A, glucose monitoring test systems for prescription 98. Wei Q, Sun Z, Yang Y, Yu H, Ding H, Wang S. Mowitz M. FreeStyle Libre: contact irritation point-of-dare use: guidance for industry and Effect of a CGMS and SMBG on maternal and versus contact allergy. Lancet 2017;390:1644 Food and Drug Administration staff [Internet]. neonatal outcomes in gestational diabetes mel- 113. Herman A, Aerts O, Baeck M, et al. Allergic Available from https://www.fda.gov/downloads/ litus: a randomized controlled trial. Sci Rep 2016; contact dermatitis caused by isobornyl acrylate MedicalDevices/DeviceRegulationandGuidance/ 6:19920 in FreestyleÒ Libre, a newly introduced glucose GuidanceDocuments/UCM380325.pdf. Accessed 99. Olafsd´ ottir´ AF, Attvall S, Sandgren U, et al. A sensor. Contact Dermat 2017;77:367–373 14 November 2018 clinical trial of the accuracy and treatment ex- 114. Norwegian Institute of Public Health. 127. International Standards Organization. ISO perience of the flash glucose monitor FreeStyle FreeStyle Libre flash glucose self-monitoring 15197:2013 [Internet]. Available from https:// Libre in adults with type 1 diabetes. Diabetes system: a single-technology assessment [Internet], www.iso.org/standard/54976.html. Accessed 14 Technol Ther 2017;19:164–172 2017. Available from http://www.fhi.no/en/publ/ November 2018 100. Ji L, Guo X, Guo L, Ren Q, Yu N, Zhang J. A 2017/freestyle-libre-systemet-for-egenmaling-av- 128. Parkes JL, Slatin SL, Pardo S, Ginsberg BH. multicenter evaluation of the performance and blodsukker-en-hurtigmetodevurder/. Accessed A new consensus error grid to evaluate the clin- usability of a novel glucose monitoring system in 22 October 2018 ical significance of inaccuracies in the measure- Chinese adults with diabetes. J Diabetes Sci 115. Palylyk-Colwell E, Ford C. Flash glucose ment of blood glucose. Diabetes Care 2000;23: Technol 2017;11:290–295 monitoring system for diabetes. In CADTH Issues 1143–1148 Diabetes Care Volume 42, Supplement 1, January 2019 S81

8. Obesity Management for the American Diabetes Association Treatment of Type 2 Diabetes: Standards of Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S81–S89 | https://doi.org/10.2337/dc19-S008 .OEIYMNGMN O H RAMN FTP DIABETES 2 TYPE OF TREATMENT THE FOR MANAGEMENT OBESITY 8.

There is strong and consistent evidence that obesity management can delay the progression from prediabetes to type 2 diabetes (1–5) and is beneﬁcial in the treatment of type 2 diabetes (6–17). In patients with type 2 diabetes who are overweight or obese, modest and sustained weight loss has been shown to improve glycemic control and to reduce the need for glucose-lowering medications (6–8). Small studies have demonstrated that in patients with type 2 diabetes and obesity, more extreme dietary energy restriction with very low-calorie diets can reduce A1C to ,6.5% (48 mmol/mol) and fasting glucose to ,126 mg/dL (7.0 mmol/L) in the absence of pharmacologic therapy or ongoing procedures (10,18,19). Weight loss– induced improvements in glycemia are most likely to occur early in the natural history of type 2 diabetes when obesity-associated insulin resistance has caused reversible b-cell dysfunction but insulin secretory capacity remains relatively preserved (8,11,19,20). The goal of this section is to provide evidence-based recommendations for weight-loss therapy, including diet, behavioral, pharmacologic, and surgical interventions, for obesity management as treatment for hyperglycemia in type 2 diabetes.

Suggested citation: American Diabetes Associa- ASSESSMENT tion. 8. Obesity management for the treatment of type 2 diabetes: Standards of Medical Care in Recommendation Diabetesd2019. Diabetes Care 2019;42(Suppl. 1): 8.1 At each patient encounter, BMI should be calculated and documented in the S81–S89 medical record. B © 2018 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not At each routine patient encounter, BMI should be calculated as weight divided by ﬁ 2 for pro t, and the work is not altered. More infor- height squared (kg/m ) (21). BMI should be classiﬁed to determine the presence of mation is available at http://www.diabetesjournals overweight or obesity, discussed with the patient, and documented in the patient .org/content/license. S82 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 42, Supplement 1, January 2019

record. In Asian Americans, the BMI reduced cardiovascular events in adults should provide at least monthly cutoff points to define overweight and with type 2 diabetes who were over- contact and encourage ongo- obesity are lower than in other popula- weight or obese (26), it did show the ing monitoring of body weight tions (Table 8.1) (22,23). Providers feasibility of achieving and maintaining (weekly or more frequently) should advise patients who are over- long-term weight loss in patients with and/or other self-monitoring weight or obese that, in general, higher type 2 diabetes. In the Look AHEAD strategies, such as tracking in- BMIs increase the risk of cardiovascular intensive lifestyle intervention group, take, steps, etc.; continued con- disease and all-cause mortality. Pro- mean weight loss was 4.7% at 8 years sumption of a reduced-calorie viders should assess each patient’s read- (27). Approximately 50% of intensive diet; and participation in high iness to achieve weight loss and jointly lifestyle intervention participants lost levels of physical activity (200– determine weight-loss goals and inter- and maintained $5% and 27% lost 300 min/week). A vention strategies. Strategies may in- and maintained $10% of their initial 8.6 To achieve weight loss of .5%, clude diet, physical activity, behavioral body weight at 8 years (27). Participants short-term (3-month) interven- therapy, pharmacologic therapy, and randomly assigned to the intensive life- tions that use very low-calorie metabolic surgery (Table 8.1). The latter style group achieved equivalent risk fac- diets (#800 kcal/day) and total two strategies may be prescribed for tor control but required fewer glucose-, meal replacements may be pre- carefully selected patients as adjuncts blood pressure–, and lipid-lowering scribed for carefully selected pa- to diet, physical activity, and behavioral medications than those randomly as- tients by trained practitioners in therapy. signed to standard care. Secondary anal- medical care settings with close yses of the Look AHEAD trial and other medical monitoring. To main- large cardiovascular outcome studies DIET, PHYSICAL ACTIVITY, AND tain weight loss, such programs document other benefits of weight BEHAVIORAL THERAPY must incorporate long-term com- loss in patients with type 2 diabetes, prehensive weight-maintenance Recommendations including improvements in mobility, 8.2 Diet, physical activity, and behav- counseling. B physical and sexual function, and ioral therapy designed to achieve health-related quality of life (28). A and maintain .5% weight loss Among patients with type 2 diabetes who post hoc analysis of the Look AHEAD should be prescribed for patients are overweight or obese and have inade- study suggests that heterogeneous treat- with type 2 diabetes who are quate glycemic, blood pressure, and lipid ment effects may have been present. overweight or obese and ready control and/or other obesity-related med- Participants who had moderately or to achieve weight loss. A ical conditions, lifestyle changes that re- poorly controlled diabetes (A1C $6.8% 8.3 Such interventions should be sult in modest and sustained weight loss [51 mmol/mol]) as well as both those high intensity ($16 sessions in produce clinically meaningful reductions with well-controlled diabetes (A1C 6 months) and focus on diet, in blood glucose, A1C, and triglycerides ,6.8% [51 mmol/mol]) and good self- physical activity, and behavioral (6–8). Greater weight loss produces reported health were found to have strategies to achieve a 500–750 even greater benefits, including reduc- significantly reduced cardiovascular kcal/day energy deficit. A tions in blood pressure, improvements events with intensive lifestyle interven- 8.4 Diets should be individualized, in LDL and HDL cholesterol, and reductions tion during follow-up (29). as those that provide the same in the need for medications to control caloric restriction but differ in blood glucose, blood pressure, and lipids protein, carbohydrate, and fat (6–8,24), and may result in achievement of Lifestyle Interventions Significant weight loss can be attained content are equally effective in glycemic goals in the absence of antihyper- with lifestyle programs that achieve a achieving weight loss. A glycemia agent use in some patients (25). 500–750 kcal/day energy deficit, which 8.5 For patients who achieve short- in most cases is approximately 1,200– term weight-loss goals, long-term 1,500 kcal/day for women and 1,500– ($1 year) comprehensive weight- Look AHEAD Trial Although the Action for Health in Di- 1,800 kcal/day for men, adjusted for maintenance programs should abetes (Look AHEAD) trial did not show the individual’s baseline body weight. be prescribed. Such programs that an intensive lifestyle intervention Weight loss of 3–5% is the minimum

Table 8.1—Treatment options for overweight and obesity in type 2 diabetes BMI category (kg/m2) 25.0–26.9 30.0–34.9 35.0–39.9 Treatment (or 23.0–26.9*) 27.0–29.9 (or 27.5–32.4*) (or 32.5–37.4*) $40 (or $ 37.5*) Diet, physical activity, and behavioral therapy ††† † † Pharmacotherapy †† † † Metabolic surgery †† † *Cutoff points for Asian American individuals. †Treatment may be indicated for selected motivated patients. care.diabetesjournals.org Obesity Management for the Treatment of Type 2 Diabetes S83

necessary for any clinical benefit (21,30). intensive behavioral lifestyle interven- alternatives for medications that promote However, weight-loss benefits are pro- tions unless a long-term comprehensive weight gain. Medications associated with gressive; more intensive weight-loss weight-loss maintenance program is weight gain include antipsychotics (e.g., goals (.5%, .7%, .15%, etc.) may be provided (37,38). clozapine, olanzapine, risperidone, etc.) pursued if needed to achieve a healthy and antidepressants (e.g., tricyclic antide- weight and if they can be feasibly and PHARMACOTHERAPY pressants, selective serotonin reuptake safely attained. inhibitors, and monoamine oxidase inhib- Recommendations These diets may differ in the types of itors), glucocorticoids, injectable proges- 8.7 When choosing glucose-lowering foods they restrict (such as high-fat or tins, anticonvulsants including gabapentin, medications for overweight or high-carbohydrate foods) but are effec- and possibly sedating antihistamines and obese patients with type 2 di- tive if they create the necessary energy anticholinergics (40). abetes, consider their effect deficit (21,31–33). Use of meal replace- on weight. E ment plans prescribed by trained practi- 8.8 Whenever possible, minimize Approved Weight-Loss Medications tioners, with close patient monitoring, medications for comorbid con- The U.S. Food and Drug Administration can be beneficial. Within the intensive ditions that are associated with (FDA) has approved medications for both lifestyle intervention group of the Look weight gain. E short-term and long-term weight man- AHEAD trial, for example, use of a 8.9 Weight-loss medications are agement as adjuncts to diet, exercise, partial meal replacement plan was as- effective as adjuncts to diet, and behavioral therapy. Nearly all FDA- sociated with improvements in diet physical activity, and behavioral approved medications for weight loss quality (34). The diet choice should counseling for selected patients have been shown to improve glycemic be based on the patient’s health status with type 2 diabetes and BMI control in patients with type 2 diabetes and preferences. $27 kg/m2. Potential benefits and delay progression to type 2 diabetes Intensive behavioral lifestyle interven- must be weighed against the po- in patients at risk (41). Phentermine is tions should include $16 sessions in # tential risks of the medications. A indicated as short-term ( 12 weeks) 6 months and focus on diet, physical 8.10 If a patient’s response to weight- treatment (42). Five weight-loss medi- activity, and behavioral strategies to loss medications is ,5% weight cations (or combination medications) achieve an ;500–750 kcal/day energy loss after 3 months or if there are FDA-approved for long-term use deficit. Interventions should be provided are significant safety or tolera- (more than a few weeks) by patients by trained interventionists in either in- $ 2 bility issues at any time, the with BMI 27 kg/m with one or more dividual or group sessions (30). medication should be discon- obesity-associated comorbid conditions Patients with type 2 diabetes who tinued and alternative medica- (e.g., type 2 diabetes, hypertension, and are overweight or obese and have lost tions or treatment approaches dyslipidemia) who are motivated to lose weight during the 6-month intensive should be considered. A weight (41). Medications approved by behavioral lifestyle intervention should the FDA for the treatment of obesity and be enrolled in long-term ($1 year) com- their advantages and disadvantages are prehensive weight-loss maintenance Antihyperglycemia Therapy summarized in Table 8.2. The rationale programs that provide at least monthly Agents associated with varying degrees for weight-loss medications is to help contact with a trained interventionist of weight loss include metformin, a- patients to more consistently adhere to and focus on ongoing monitoring of glucosidase inhibitors, sodium–glucose low-calorie diets and to reinforce lifestyle body weight (weekly or more fre- cotransporter 2 inhibitors, glucagon- changes. Providers should be knowledge- quently) and/or other self-monitoring like peptide 1 receptor agonists, and able about the product label and should strategies such as tracking intake, amylin mimetics. Dipeptidyl peptidase balance the potential benefits of success- steps, etc.; continued consumption of 4 inhibitors are weight neutral. Unlike ful weight loss against the potential risks a reduced-calorie diet; and participation in these agents, insulin secretagogues, thia- of the medication for each patient. These highlevels ofphysical activity(200–300 min/ zolidinediones, and insulin often cause medications are contraindicated in women week (35). Some commercial and proprie- weight gain (see Section 9 “Pharmacologic who are pregnant or actively trying to tary weight-loss programs have shown Approaches to Glycemic Treatment”). conceive. Women of reproductive po- promising weight-loss results (36). A recent meta-analysis of 227 random- tential must be counseled regarding the When provided by trained practi- ized controlled trials of antihyperglyce- use of reliable methods of contraception. tioners in medical care settings with mia treatments in type 2 diabetes found close medical monitoring, short-term that A1C changes were not associated Assessing Efficacy and Safety (3-month) interventions that use very with baseline BMI, indicating that pa- Efficacy and safety should be assessed low-calorie diets (defined as #800 tients with obesity can benefit from the at least monthly for the first 3 months kcal/day) and total meal replacements same types of treatments for diabetes as of treatment. If a patient’s response is may achieve greater short-term weight normal-weight patients (39). deemed insufficient (weight loss ,5%) loss (10%–15%) than intensive behav- after 3 months or if there are significant ioral lifestyle interventions that typically Concomitant Medications safety or tolerability issues at any time, achieve 5% weight loss. However, weight Providers should carefully review the the medication should be discontinued regain following the cessation of very patient’s concomitant medications and, and alternative medications or treat- low-calorie diets is greater than following whenever possible, minimize or provide ment approaches should be considered. 8 bst aaeetfrteTeteto ye2Diabetes 2 Type of Treatment the for Management Obesity S84

Table 8.2—Medications approved by the FDA for the treatment of obesity 1-Year (52- or 56-week) mean weight loss (% loss from baseline) Average wholesale National Average Drug Weight loss Typical adult price (30-day Acquisition Cost (30-day (% loss from Common side effects Possible safety concerns/considerations Medication name maintenance dose supply) (100) supply) (101) Treatment arm baseline) (102–107) (102–107) Short-term treatment (£12 weeks) Phentermine (108) 8–37.5 mg q.d.* $5–$56 $4 (37.5 mg dose) 15 mg q.d.† 6.1 Dry mouth, insomnia, c Risk of severe hypertension (37.5 mg dose) 7.5 mg q.d.† 5.5 dizziness, irritability c Contraindicated for use in combination with PBO 1.7 monoamine oxidase inhibitors Long-term treatment (>12 weeks) Lipase inhibitor Orlistat (3) 60 mg t.i.d. (OTC) $41–$82 $42 120 mg t.i.d.‡ 9.6 Abdominal pain, ﬂatulence, c Potential malabsorption of fat-soluble 120 mg t.i.d. (Rx) $748 $556 PBO 5.6 fecal urgency, back pain, vitamins (A, D, E, K) and of certain headache medications (e.g., cyclosporine, thyroid hormone, anticonvulsants, etc.) c Rare cases of severe liver injury reported c Cholelithiasis c Nephrolithiasis

Selective serotonin (5-HT) 5-HT2C receptor agonist Lorcaserin (14) 10 mg b.i.d. $318 $255 10 mg b.i.d. 4.5 Headache, nausea, dizziness, c Serotonin syndrome– and neuroleptic Lorcaserin XR 20 mg q.d. $318 $254 PBO 1.5 fatigue, nasopharyngitis malignant syndrome–like reactions theoretically possible when coadministered with other serotonergic or antidopaminergic agents c Monitor for depression or suicidal thoughts c Worsening hypertension ibtsCare Diabetes c Avoid in liver and renal failure Sympathomimetic amine anorectic/antiepileptic combination Phentermine/ 7.5 mg/46 mg $223 (7.5 mg/ $178 (7.5 mg/ 15 mg/92 mg q.d.| 9.8 Constipation, paresthesia, c Birth defects topiramate q.d.§ 46 mg dose) 46 mg dose) 7.5 mg/46 mg q.d.| 7.8 insomnia, nasopharyngitis, c Cognitive impairment PBO 1.2 c Acute angle-closure glaucoma ER (109) xerostomia 2019 January 1, Supplement 42, Volume Opioid antagonist/antidepressant combination Naltrexone/ 8 mg/90 mg, $334 $267 16 mg/ 5.0 Constipation, nausea, c Contraindicated in patients with bupropion ER 2 tablets b.i.d. 180 mg b.i.d. headache, xerostomia, uncontrolled hypertension and/or seizure (15) PBO 1.8 insomnia disorders c Contraindicated for use with chronic opioid therapy c Acute angle-closure glaucoma c Black box warning: c Risk of suicidal behavior/ideation

Continued on p. S85 care.diabetesjournals.org Obesity Management for the Treatment of Type 2 Diabetes S85

MEDICAL DEVICES FOR WEIGHT LOSS Several minimally invasive medical devices have been recently approved by the FDA for short-term weight loss (43). It remains to be seen how these are used for obesity treatment. Given the high cost, extremely limited insurance cover- 107)

– age, and paucity of data in people with diabetes at this time, these are not (102 considered to be the standard of care for obesity management in people with type 2 diabetes. liable methods of contraception. Select history of MTC or MEN 2 Risk of thyroid C-cell tumors Contraindicated with personal or family c c Possible safety concerns/considerations ?Acute pancreatitis Black box warning: c c

ption; t.i.d, three times daily; XR, extended release. METABOLIC SURGERY

Recommendations Enrolled participants had normal (79%) or impaired on for each agent. b.i.d., twice daily; ER, extended release; ‡ 8.11 Metabolic surgery should be recommended as an option to 107) – treat type 2 diabetes in appro- (102 indigestion priate surgical candidates with $ 2 $ nausea, headache, BMI 40 kg/m (BMI 37.5 Common side effects kg/m2 in Asian Americans) and Hypoglycemia, constipation, in adults with BMI 35.0–39.9 kg/m2 (32.5–37.4 kg/m2 in Asian Americans) who do not achieve

baseline) durable weight loss and improve- Weight loss (% loss from ment in comorbidities (including hyperglycemia) with reasonable

baseline) nonsurgical methods. A 8.12 Metabolic surgery may be consid- PBO 2.0

1-Year (52- or 56-week) ered as an option for adults with 3.0 mg q.d. 6.0 1.8 mg q.d. 4.7

Treatment arm – mean weight loss (% loss from type 2 diabetes and BMI 30.0 Approximately 68% of enrolled participants had type 2 diabetes or impaired glucose tolerance. | 34.9 kg/m2 (27.5–32.4 kg/m2 in Asian Americans) who do not achieve durable weight loss and improvement in comorbidities (including hyperglycemia) with rea-

Duration of treatment was 28 weeks in a general obese adult population. A

supply) (101) sonable nonsurgical methods. † 8.13 Metabolic surgery should be National Average Drug Acquisition Cost (30-day performed in high-volume centers with multidisciplinary teams that understand and are experienced in the management of diabetes and gastrointestinal supply) (100) price (30-day surgery. C Average wholesale 8.14 Long-term lifestyle support and routine monitoring of micronutrient and nutritional status must be provided to patients after surgery, according to guidelines for

Typical adult postoperative management of maintenance dose metabolic surgery by national and international professional societies. C Continued

— 8.15 People presenting for metabolic surgery should receive a com- Liraglutide (16) 3 mg q.d. $1,441 $1,154 prehensive readiness and men- Glucagon-like peptide 1 receptor agonist Table 8.2 Medication name All medications are contraindicatedsafety in and women side who effectMEN are information 2, or is multiple may provided; endocrine become*Use for neoplasia pregnant. lowest a syndrome Women effective comprehensive type of dose; discussion 2; reproductive maximum of MTC, potential appropriate safety medullary must dose considerations, thyroid be is please carcinoma; counseled 37.5 refer OTC, regarding mg. to over the the the use prescribing counter; of informati PBO, re placebo; q.d., daily; Rx, prescri (21%) glucose tolerance. §Maximum dose, depending on response, is 15 mg/92 mg q.d. tal health assessment. B S86 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 42, Supplement 1, January 2019

1 to 5 years in 30%–63% of patients two decades, with continued refinement 8.16 People who undergo metabolic with Roux-en-Y gastric bypass (RYGB), of minimally invasive approaches (lapa- surgery should be evaluated to which generally leads to greater degrees roscopic surgery), enhanced training and assess the need for ongoing and lengths of remission compared with credentialing, and involvement of mul- mental health services to help other bariatric surgeries (17,62). Available tidisciplinary teams. Mortality rates with them adjust to medical and data suggest an erosion of diabetes re- metabolic operations are typically 0.1%– psychosocial changes after sur- missionover time (63): 35%–50% or more 0.5%, similar to cholecystectomy or gery. C of patients who initially achieve remis- hysterectomy (79–83). Morbidity has sion of diabetes eventually experience also dramatically declined with laparo- Several gastrointestinal (GI) operations recurrence. However, the median dis- scopic approaches. Major complications including partial gastrectomies and ease-free period among such individuals rates (e.g., venous thromboembo- bariatric procedures (35) promote dra- following RYGB is 8.3 years (64,65). With lism, need for operative reintervention) matic and durable weight loss and im- or without diabetes relapse, the majority are 2%–6%, with other minor compli- provement of type 2 diabetes in many of patients who undergo surgery main- cations in up to 15% (79–88), which patients. Given the magnitude and ra- tain substantial improvement of glyce- compare favorably with rates for other pidity of the effect of GI surgery on mic control from baseline for at least commonly performed elective opera- hyperglycemia and experimental evi- 5 (66,67) to 15 (45,46,65,68–70) years. tions (83). Empirical data suggest that dence that rearrangements of GI anat- Exceedingly few presurgical predictors proficiency of the operating surgeon is an omy similar to those in some metabolic of success have been identified, but important factor for determining mor- procedures directly affect glucose ho- younger age, shorter duration of diabe- tality, complications, reoperations, and meostasis (36), GI interventions have tes (e.g., ,8 years) (71), nonuse of insulin, readmissions (89). been suggested as treatments for type maintenance of weight loss, and better Longer-term concerns include dump- 2 diabetes, and in that context they are glycemic control are consistently associ- ing syndrome (nausea, colic, and diar- termed “metabolic surgery.” ated with higher rates of diabetes remis- rhea), vitamin and mineral deficiencies, A substantial body of evidence has sion and/or lower risk of weight regain anemia, osteoporosis, and, rarely (90), now been accumulated, including data (45,69,71,72). Greater baseline visceral severe hypoglycemia. Long-term nutri- from numerous randomized controlled fat area may also help to predict better tional and micronutrient deficiencies (nonblinded) clinical trials, demonstrat- postoperative outcomes, especially among and related complications occur with ing that metabolic surgery achieves su- Asian American patients with type 2 di- variable frequency depending on the perior glycemic control and reduction of abetes, who typically have more visceral type of procedure and require life- cardiovascular risk factors in patients fat compared with Caucasians with di- long vitamin/nutritional supplementa- with type 2 diabetes and obesity com- abetes of the same BMI (73). tion (91,92). Postprandial hypoglycemia pared with various lifestyle/medical Beyond improving glycemia, meta- is most likely to occur with RYGB interventions (17). Improvements in micro- bolic surgery has been shown to confer (92,93). The exact prevalence of symp- vascular complications of diabetes, car- additional health benefits in randomized tomatic hypoglycemia is unknown. In diovascular disease, and cancer have controlled trials, including substantial one study, it affected 11% of 450 pa- been observed only in nonrandomized reductions in cardiovascular disease risk tients who had undergone RYGB or ver- observational studies (44–53). Cohort factors (17), reductions in incidence of tical sleeve gastrectomy (90). Patients studies attempting to match surgical microvascular disease (74), and enhance- who undergo metabolic surgery may and nonsurgical subjects suggest that ments in quality of life (66,71,75). be at increased risk for substance use, the procedure may reduce longer-term Although metabolic surgery has been including drug and alcohol use and cig- mortality (45). shown to improve the metabolic profiles arette smoking. Additional potential risks On the basis of this mounting evi- of patients with type 1 diabetes and of metabolic surgery that have been dence, several organizations and govern- morbid obesity, establishing the role of described include worsening or new- ment agencies have recommended metabolic surgery in such patients will onset depression and/or anxiety, need expanding the indications for metabolic require larger and longer studies (76). for additional GI surgery, and suicidal surgery to include patients with type 2 Metabolic surgery is more expensive ideation (94–97). diabetes who do not achieve durable than nonsurgical management strate- People with diabetes presenting for weight loss and improvement in comor- gies, but retrospective analyses and mod- metabolicsurgeryalsohaveincreased bidities (including hyperglycemia) with eling studies suggest that metabolic rates of depression and other major reasonable nonsurgical methods at BMIs surgery may be cost-effective or even psychiatric disorders (98). Candidates for as low as 30 kg/m2 (27.5 kg/m2 for Asian cost-saving for patients with type 2 metabolic surgery with histories of alco- Americans) (54–61). Please refer to diabetes. However, results are largely hol, tobacco, or substance abuse; sig- “Metabolic Surgery in the Treatment dependent on assumptions about the nificant depression; suicidal ideation; or Algorithm for Type 2 Diabetes: A Joint long-term effectiveness and safety of other mental health conditions should Statement by International Diabetes Or- the procedures (77,78). therefore first be assessed by a mental ganizations” for a thorough review (17). health professional with expertise in Randomized controlled trials have Adverse Effects obesity management prior to consider- documented diabetes remission during The safety of metabolic surgery has ation for surgery (99). Surgery should be postoperative follow-up ranging from improved significantly over the past postponed in patients with alcohol or care.diabetesjournals.org Obesity Management for the Treatment of Type 2 Diabetes S87

substance abuse disorders, significant phentermine and topiramate extended release. intervention: the Look AHEAD study. Obesity depression, suicidal ideation, or other Diabetes Care 2014;37:3309–3316 (Silver Spring) 2014;22:5–13 ’ mental health conditions until these 14. O Neil PM, Smith SR, Weissman NJ, et al. 28. Wilding JPH. The importance of weight Randomized placebo-controlled clinical trial of management in type 2 diabetes mellitus. Int J conditions have been fully addressed. lorcaserin for weight loss in type 2 diabetes Clin Pract 2014;68:682–691 Individuals with preoperative psycho- mellitus: the BLOOM-DM study. Obesity (Silver 29. Baum A, Scarpa J, Bruzelius E, Tamler R, Basu pathology should be assessed regularly Spring) 2012;20:1426–1436 S, Faghmous J. Targeting weight loss interven- following metabolic surgery to optimize 15. Hollander P, Gupta AK, Plodkowski R, et al.; tions to reduce cardiovascular complications of mental health management and to en- COR-Diabetes Study Group. Effects of naltrexone type 2 diabetes: a machine learning-based sustained-release/bupropion sustained-release post-hoc analysis of heterogeneous treatment sure psychiatric symptoms do not in- combination therapy on body weight and effects in the Look AHEAD trial. Lancet Diabe- terfere with weight loss and lifestyle glycemic parameters in overweight and obese tes Endocrinol 2017;5:808–815 changes. patients with type 2 diabetes. Diabetes Care 30. Franz MJ, Boucher JL, Rutten-Ramos S, 2013;36:4022–4029 VanWormer JJ. Lifestyle weight-loss interven- References 16. Davies MJ, Bergenstal R, Bode B, et al.; tion outcomes in overweight and obese adults 1. Knowler WC, Barrett-Connor E, Fowler SE, NN8022-1922 Study Group. Efficacy of liraglutide with type 2 diabetes: a systematic review and et al.; Diabetes Prevention Program Research for weight loss among patients with type 2 meta-analysis of randomized clinical trials. Group. Reduction in the incidence of type 2 diabetes: the SCALE diabetes randomized clini- J Acad Nutr Diet 2015;115:1447–1463 diabetes with lifestyle intervention or metfor- cal trial. JAMA 2015;314:687–699 31. Sacks FM, Bray GA, Carey VJ, et al. Com- min. N Engl J Med 2002;346:393–403 17. Rubino F, Nathan DM, Eckel RH, et al.; parison of weight-loss diets with different com- 2. Garvey WT, Ryan DH, Henry R, et al. Pre- Delegates of the 2nd Diabetes Surgery Summit. positions of fat, protein, and carbohydrates. vention of type 2 diabetes in subjects with Metabolic surgery in the treatment algorithm N Engl J Med 2009;360:859–873 prediabetes and metabolic syndrome treated for type 2 diabetes: a joint statement by inter- 32. de Souza RJ, Bray GA, Carey VJ, et al. Effects with phentermine and topiramate extended national diabetes organizations. Diabetes Care of 4 weight-loss diets differing in fat, protein, and release. Diabetes Care 2014;37:912–921 2016;39:861–877 carbohydrate on fat mass, lean mass, visceral 3. Torgerson JS, Hauptman J, Boldrin MN, 18. Day JW, Ottaway N, Patterson JT, et al. A new adipose tissue, and hepatic fat: results from Sjostr¨ om¨ L. XENical in the prevention of Diabetes glucagon and GLP-1 co-agonist eliminates obe- the POUNDS LOST trial. Am J Clin Nutr 2012; in Obese Subjects (XENDOS) study: a randomized sity in rodents. Nat Chem Biol 2009;5:749–757 95:614–625 study of orlistat as an adjunct to lifestyle changes 19. Steven S, Hollingsworth KG, Al-Mrabeh A, 33. Johnston BC, Kanters S, Bandayrel K, et al. for the prevention of type 2 diabetes in obese et al. Very low-calorie diet and 6 months of Comparison of weight loss among named diet – patients. Diabetes Care 2004;27:155 161 weight stability in type 2 diabetes: pathophys- programs in overweight and obese adults: 4. le Roux CW, Astrup A, Fujioka K, et al.; SCALE iological changes in responders and nonrespond- a meta-analysis. JAMA 2014;312:923–933 Obesity Prediabetes NN8022-1839 Study Group. ers. Diabetes Care 2016;39:808–815 34. Raynor HA, Anderson AM, Miller GD, et al.; 3 years of liraglutide versus placebo for type 2 20. Schauer PR, Mingrone G, Ikramuddin S, Look AHEAD Research Group. Partial meal re- diabetes risk reduction and weight management Wolfe B. Clinical outcomes of metabolic surgery: placement plan and quality of the diet at 1 year: in individuals with prediabetes: a randomised, efficacy of glycemic control, weight loss, and Action for Health in Diabetes (Look AHEAD) Trial. double-blind trial. Lancet 2017;389:1399–1409 remission of diabetes. Diabetes Care 2016;39: J Acad Nutr Diet 2015;115:731–742 5. Booth H, Khan O, Prevost T, et al. Incidence 902–911 35. Donnelly JE, Blair SN, Jakicic JM, Manore of type 2 diabetes after bariatric surgery: 21. Jensen MD, Ryan DH, Apovian CM, et al.; MM, Rankin JW, Smith BK; American College of population-based matched cohort study. Lancet American College of Cardiology/American Heart Sports Medicine. Appropriate physical activity Diabetes Endocrinol 2014;2:963–968 Association Task Force on Practice Guidelines; intervention strategies for weight loss and pre- 6. UKPDS Group. UK Prospective Diabetes Study Obesity Society. 2013 AHA/ACC/TOS guideline vention of weight regain for adults. Med Sci 7: response of fasting plasma glucose to diet for the management of overweight and obesity Sports Exerc 2009;41:459–471 therapy in newly presenting type II diabetic in adults: a report of the American College of 36. Gudzune KA, Doshi RS, Mehta AK, et al. patients. Metabolism 1990;39:905–912 Cardiology/American Heart Association Task Efficacy of commercial weight-loss programs: 7. Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes Relat Metab Force on Practice Guidelines and The Obesity an updated systematic review. Ann Intern Med – Disord 1992;16:397–415 Society. J Am Coll Cardiol 2014;63(Suppl. 2): 2015;162:501 512 – 8. Pastors JG, Warshaw H, Daly A, Franz M, 2985 3023 37. Tsai AG, Wadden TA. The evolution of very- Kulkarni K. The evidence for the effectiveness 22. WHO Expert Consultation. Appropriate low-calorie diets: an update and meta-analysis. – of medical nutrition therapy in diabetes man- body-mass index for Asian populations and its Obesity (Silver Spring) 2006;14:1283 1293 agement. Diabetes Care 2002;25:608–613 implications for policy and intervention strate- 38. Johansson K, Neovius M, Hemmingsson E. – 9. Lim EL, Hollingsworth KG, Aribisala BS, Chen gies. Lancet 2004;363:157 163 Effects of anti-obesity drugs, diet, and exercise MJ, Mathers JC, Taylor R. Reversal of type 2 23. Araneta MR, Grandinetti A, Chang HK. Op- on weight-loss maintenance after a very-low- diabetes: normalisation of beta cell function in timum BMI cut points to screen Asian Americans calorie diet or low-calorie diet: a systematic association with decreased pancreas and liver for type 2 diabetes: the UCSD Filipino Health review and meta-analysis of randomized con- triacylglycerol. Diabetologia 2011;54:2506–2514 Study and the North Kohala Study (Abstract). trolled trials. Am J Clin Nutr 2014;99:14–23 10. Jackness C, Karmally W, Febres G, et al. Very Diabetes 2014;63(Suppl. 1):A20 39. Cai X, Yang W, Gao X, Zhou L, Han X, Ji L. low-calorie diet mimics the early beneficial effect 24. Rothberg AE, McEwen LN, Kraftson AT, et al. Baseline body mass index and the efficacy of of Roux-en-Y gastric bypass on insulin sensitivity Impact of weight loss on waist circumference and hypoglycemic treatment in type 2 diabetes: and b-cell function in type 2 diabetic patients. the components of the metabolicsyndrome.BMJ a meta-analysis. PLoS One 2016;11:e0166625 Diabetes 2013;62:3027–3032 Open Diabetes Res Care 2017;5:e000341 40. Domecq JP, Prutsky G, Leppin A, et al. Clinical 11. Rothberg AE, McEwen LN, Kraftson AT, 25. Lean ME, Leslie WS, Barnes AC, et al. Primary review: Drugs commonly associated with weight Fowler CE, Herman WH. Very-low-energy diet care-led weight management for remission of change: a systematic review and meta-analysis. for type 2 diabetes: an underutilized therapy? type 2 diabetes (DiRECT): an open-label, cluster- J Clin Endocrinol Metab 2015;100:363–370 J Diabetes Complications 2014;28:506–510 randomised trial. Lancet 2018;391:541–551 41. Kahan S, Fujioka K. Obesity pharmacother- 12. Hollander PA, Elbein SC, Hirsch IB, et al. Role 26. Wing RR, Bolin P, Brancati FL, et al.; Look apy in patients with type 2 diabetes. Diabetes of orlistat in the treatment of obese patients with AHEAD Research Group. Cardiovascular effects Spectr 2017;30:250–257 type 2 diabetes: a 1-year randomized double- of intensive lifestyle intervention in type 2 di- 42. Drugs.com. Phentermine [FDA prescribing blind study. Diabetes Care 1998;21:1288–1294 abetes. N Engl J Med 2013;369:145–154 information] [Internet], 2017. Available from: 13. Garvey WT, Ryan DH, Bohannon NJV, et al. 27. Look AHEAD Research Group. Eight-year https://www.drugs.com/pro/phentermine.html. Weight-loss therapy in type 2 diabetes: effects of weight losses with an intensive lifestyle Accessed 22 September 2017 S88 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 42, Supplement 1, January 2019

43. Sullivan S. Endoscopic medical devices for 60. Liang Z, Wu Q, Chen B, Yu P, Zhao H, Ouyang patients with a body mass index less than 35 primary obesity treatment in patients with di- X. Effect of laparoscopic Roux-en-Y gastric bypass kg/m2. Surg Obes Relat Dis 2015;11:6–11 abetes. Diabetes Spectr 2017;30:258–264 surgery on type 2 diabetes mellitus with hyper- 74. O’Brien R, Johnson E, Haneuse S, et al. 44. Sjostr¨ om¨ L, Lindroos A-K, Peltonen M, et al.; tension: a randomized controlled trial. Diabetes Microvascular outcomes in patients with diabe- Swedish Obese Subjects Study Scientific Group. Res Clin Pract 2013;101:50–56 tes after bariatric surgery versus usual care: Lifestyle, diabetes, and cardiovascular risk factors 61. Aminian A, Chang J, Brethauer SA, Kim JJ; a matched cohort study. Ann Intern Med 2018; 10 years after bariatric surgery. N Engl J Med 2004; American Society for Metabolic and Bariatric 169:300–310 351:2683–2693 Surgery Clinical Issues Committee. ASMBS up- 75. Halperin F, Ding S-A, Simonson DC, et al. 45. Sjostr¨ om¨ L, Peltonen M, Jacobson P, et al. dated position statement on bariatric surgery in Roux-en-Y gastric bypass surgery or lifestyle Association of bariatric surgery with long-term class I obesity (BMI 30–35 kg/m2). Surg Obes with intensive medical management in patients remission of type 2 diabetes and with microvas- Relat Dis 2018;14:1071–1087 with type 2 diabetes: feasibility and 1-year results cular and macrovascular complications. JAMA 62. Isaman DJM, Rothberg AE, Herman WH. of a randomized clinical trial. JAMA Surg 2014; 2014;311:2297–2304 Reconciliation of type 2 diabetes remission rates 149:716–726 46. Adams TD, Davidson LE, Litwin SE, et al. in studies of Roux-en-Y gastric bypass. Diabetes 76. Kirwan JP, Aminian A, Kashyap SR, Burguera Health benefits of gastric bypass surgery after Care 2016;39:2247–2253 B, Brethauer SA, Schauer PR. Bariatric surgery 6 years. JAMA 2012;308:1122–1131 63. Ikramuddin S, Korner J, Lee W-J, et al. Du- in obese patients with type 1 diabetes. Diabe- 47. Sjostr¨ om¨ L, Narbro K, Sjostr¨ om¨ CD, et al.; rability of addition of Roux-en-Y gastric bypass to tes Care 2016;39:941–948 Swedish Obese Subjects Study. Effects of bari- lifestyle intervention and medical management 77. Rubin JK, Hinrichs-Krapels S, Hesketh R, atric surgery on mortality in Swedish obese in achieving primary treatment goals for un- Martin A, Herman WH, Rubino F. Identify- subjects. N Engl J Med 2007;357:741–752 controlled type 2 diabetes in mild to moderate ing barriers to appropriate use of metabolic/ 48. Sjostr¨ om¨ L, Gummesson A, Sjostr¨ om¨ CD, obesity: a randomized control trial. Diabetes bariatric surgery for type 2 diabetes treatment: et al.; Swedish Obese Subjects Study. Effects Care 2016;39:1510–1518 Policy Lab results. Diabetes Care 2016;39:954– of bariatric surgery on cancer incidence in obese 64. Sjoholm¨ K, Pajunen P, Jacobson P, et al. 963 patients in Sweden (Swedish Obese Subjects Incidence and remission of type 2 diabetes in 78. Fouse T, Schauer P. The socioeconomic Study): a prospective, controlled intervention relation to degree of obesity at baseline and impact of morbid obesity and factors affecting trial. Lancet Oncol 2009;10:653–662 2 year weight change: the Swedish Obese access to obesity surgery. Surg Clin North Am 49. Sjostr¨ om¨ L, Peltonen M, Jacobson P, et al. Subjects (SOS) study. Diabetologia 2015;58: 2016;96:669–679 Bariatric surgery and long-term cardiovascular 1448–1453 79. Flum DR, Belle SH, King WC, et al.; Longi- events. JAMA 2012;307:56–65 65. Arterburn DE, Bogart A, Sherwood NE, et al. tudinal Assessment of Bariatric Surgery (LABS) 50. Adams TD, Gress RE, Smith SC, et al. Long- A multisite study of long-term remission and Consortium. Perioperative safety in the longitu- term mortality after gastric bypass surgery. N relapse of type 2 diabetes mellitus following dinal assessment of bariatric surgery. N Engl Engl J Med 2007;357:753–761 gastric bypass. Obes Surg 2013;23:93–102 J Med 2009;361:445–454 51. Arterburn DE, Olsen MK, Smith VA, et al. 66. Mingrone G, Panunzi S, De Gaetano A, et al. 80. Courcoulas AP, Christian NJ, Belle SH, et al.; Association between bariatric surgery and long- Bariatric-metabolic surgery versus conventional Longitudinal Assessment of Bariatric Surgery term survival. JAMA 2015;313:62–70 medical treatment in obese patients with type 2 (LABS) Consortium. Weight change and health 52. Adams TD, Arterburn DE, Nathan DM, Eckel diabetes: 5 year follow-up of an open-label, outcomes at 3 years after bariatric surgery RH. Clinical outcomes of metabolic surgery: single-centre, randomised controlled trial. Lan- among individuals with severe obesity. JAMA microvascular and macrovascular complications. cet 2015;386:964–973 2013;310:2416–2425 Diabetes Care 2016;39:912–923 67. Schauer PR, Bhatt DL, Kirwan JP, et al.; 81. Arterburn DE, Courcoulas AP. Bariatric sur- 53. Sheng B, Truong K, Spitler H, Zhang L, Tong X, STAMPEDE Investigators. Bariatric surgery ver- gery for obesity and metabolic conditions in Chen L. The long-term effects of bariatric sur- sus intensive medical therapy for diabetesd5- adults. BMJ 2014;349:g3961 gery on type 2 diabetes remission, microvascular year outcomes. N Engl J Med 2017;376:641– 82. Young MT, Gebhart A, Phelan MJ, Nguyen and macrovascular complications, and mortality: 651 NT. Use and outcomes of laparoscopic sleeve a systematic review and meta-analysis. Obes 68. Cohen RV, Pinheiro JC, Schiavon CA, Salles JE, gastrectomy vs laparoscopic gastric bypass: anal- Surg 2017;27:2724–2732 Wajchenberg BL, Cummings DE. Effects of gastric ysis of the American College of Surgeons NSQIP. J 54. Rubino F, Kaplan LM, Schauer PR, Cummings bypass surgery in patients with type 2 diabetes Am Coll Surg 2015;220:880–885 DE; Diabetes Surgery Summit Delegates. The and only mild obesity. Diabetes Care 2012;35: 83. Aminian A, Brethauer SA, Kirwan JP, Kashyap Diabetes Surgery Summit consensus conference: 1420–1428 SR, Burguera B, Schauer PR. How safe is meta- recommendations for the evaluation and use of 69. Brethauer SA, Aminian A, Romero-Talamas´ bolic/diabetes surgery? Diabetes Obes Metab gastrointestinal surgery to treat type 2 diabetes H, et al. Can diabetes be surgically cured? Long- 2015;17:198–201 mellitus. Ann Surg 2010;251:399–405 term metabolic effects of bariatric surgery in 84. Birkmeyer NJO, Dimick JB, Share D, et al.; 55. Cummings DE, Cohen RV. Beyond BMI: the obese patients with type 2 diabetes mellitus. Ann Michigan Bariatric Surgery Collaborative. Hospi- need for new guidelines governing the use of Surg 2013;258:628–636; discussion 636–637 tal complication rates with bariatric surgery in bariatric and metabolic surgery. Lancet Diabetes 70. Hsu C-C, Almulaifi A, Chen J-C, et al. Effect of Michigan. JAMA 2010;304:435–442 Endocrinol 2014;2:175–181 bariatric surgery vs medical treatment on type 2 85. Altieri MS, Yang J, Telem DA, et al. Lap band 56. Zimmet P, Alberti KGMM, Rubino F, Dixon diabetes in patients with body mass index lower outcomes from 19,221 patients across centers JB. IDF’s view of bariatric surgery in type 2 dia- than 35: five-year outcomes. JAMA Surg 2015; and over a decade within the state of New York. betes. Lancet 2011;378:108–110 150:1117–1124 Surg Endosc 2016;30:1725–1732 57. Kasama K, Mui W, Lee WJ, et al. IFSO-APC 71. Schauer PR, Bhatt DL, Kirwan JP, et al.; 86. Hutter MM, Schirmer BD, Jones DB, et al. consensus statements 2011. Obes Surg 2012; STAMPEDE Investigators. Bariatric surgery ver- First report from the American College of Sur- 22:677–684 sus intensive medical therapy for diabetesd geons Bariatric Surgery Center Network: lapa- 58. Wentworth JM, Burton P, Laurie C, Brown 3-year outcomes. N Engl J Med 2014;370: roscopic sleeve gastrectomy has morbidity and WA, O’Brien PE. Five-year outcomes of a ran- 2002–2013 effectiveness positioned between the band and domized trial of gastric band surgery in over- 72. Hariri K, Guevara D, Jayaram A, Kini SU, the bypass. Ann Surg 2011;254:410–420; discus- weight but not obese people with type 2 Herron DM, Fernandez-Ranvier G. Preoperative sion 420–422 diabetes. Diabetes Care 2017;40:e44–e45 insulin therapy as a marker for type 2 diabetes 87. NguyenNT,SloneJA,NguyenX-MT,Hartman 59. Cummings DE, Arterburn DE, Westbrook EO, remission in obese patients after bariatric sur- JS, Hoyt DB. A prospective randomized trial of et al. Gastric bypass surgery vs intensive life- gery. Surg Obes Relat Dis 2018;14:332–337 laparoscopic gastric bypass versus laparoscopic style and medical intervention for type 2 diabe- 73. Yu H, Di J, Bao Y, et al. Visceral fat area as a adjustable gastric banding for the treatment of tes: the CROSSROADS randomised controlled new predictor of short-term diabetes remission morbid obesity: outcomes, quality of life, and trial. Diabetologia 2016;59:945–953 after Roux-en-Y gastric bypass surgery in Chinese costs. Ann Surg 2009;250:631–641 care.diabetesjournals.org Obesity Management for the Treatment of Type 2 Diabetes S89

88. Courcoulas AP, King WC, Belle SH, et al. symptoms after gastric bypass and sleeve gastrec- 102. U.S. National Library of Medicine. Phenter- Seven-year weight trajectories and health out- tomy. Obesity (Silver Spring) 2015;23:1079–1084 mine - phentermine hydrochloride capsule [Inter- comes in the Longitudinal Assessment of Bari- 94. ConasonA, Teixeira J, Hsu C-H, PumaL, Knafo net], 2017. Available from https://dailymed.nlm atric Surgery (LABS) Study. JAMA Surg 2018;153: D, Geliebter A. Substance use following bariatric .nih.gov/dailymed/drugInfo.cfm?setid5737eef3b- 427–434 weight loss surgery. JAMA Surg 2013;148:145– 9a6b-4ab3-a25c-49d84d2a0197. Accessed 12 Sep- 89. Birkmeyer JD, Finks JF, O’Reilly A, et al.; 150 tember 2018 Michigan Bariatric Surgery Collaborative. 95. Bhatti JA, Nathens AB, Thiruchelvam D, 103. Nalpropion Pharmaceuticals. Contrave Surgical skill and complication rates after Grantcharov T, Goldstein BI, Redelmeier DA. (naltrexone HCl/bupropion HCl) extended- bariatric surgery. N Engl J Med 2013;369: Self-harm emergencies after bariatric surgery: release tablets [prescribing information] [Inter- 1434–1442 a population-based cohort study. JAMA Surg net], 2018. Available from https://contrave.com. 90. Service GJ, Thompson GB, Service FJ, 2016;151:226–232 Accessed 12 September 2018 Andrews JC, Collazo-Clavell ML, Lloyd RV. 96. Peterhansel¨ C, Petroff D, KlinitzkeG, Kersting 104. CHEPLAPHARM, H2-Pharma. Xenical (orli- Hyperinsulinemic hypoglycemia with nesidio- A, Wagner B. Risk of completed suicide after stat) capsules [prescribing information] [Inter- blastosis after gastric-bypass surgery. N Engl J bariatric surgery: a systematic review. Obes Rev net]. Available from https://xenical.com. Accessed Med 2005;353:249–254 2013;14:369–382 12 September 2018 91. Mechanick JI, Kushner RF, Sugerman HJ, 97. Jakobsen GS, Smastuen˚ MC, Sandbu R, 105. Eisai Inc. Belviq (lorcaserin HCl) tablets et al.; American Association of Clinical Endocri- Nordstrand N, Hofsø D, Lindberg M, et al. As- [prescribing information] [Internet], 2016. Avail- nologists; Obesity Society; American Society for sociation of bariatric surgery vs medical obesity able from https://www.belviq.com. Accessed 12 September 2018 Metabolic & Bariatric Surgery. American Asso- treatment with long-term medical complications 106. VIVUS, Inc. Qsymia (phentermine and top- ciation of Clinical Endocrinologists, The Obesity and obesity-related comorbidities. JAMA 2018; iramate extended-release) capsules [prescribing Society, and American Society for Metabolic & 319:291–301 information] [Internet], 2018. Available from Bariatric Surgery medical guidelines for clinical 98. Young-Hyman D, Peyrot M. Psychosocial https://qsymia.com. Accessed 12 September practice for the perioperative nutritional, met- Care for People with Diabetes. Alexandria, VA, 2018 abolic, and nonsurgical support of the bariatric American Diabetes Association, 2012 107. Novo Nordisk Inc. Saxenda (liraglutide) surgery patient. Obesity (Silver Spring) 2009;17 99. Greenberg I, Sogg S, M Perna F. Behavioral injection [prescribing information] [Internet], – (Suppl. 1):S1 S70 and psychological care in weight loss surgery: 2018. Available from https://www.saxenda. 92. Mechanick JI, Youdim A, Jones DB, et al.; best practice update. Obesity (Silver Spring) com. Accessed 12 September 2018 – American Association of Clinical Endocrinolo- 2009;17:880 884 108. Aronne LJ, Wadden TA, Peterson C, gists; Obesity Society; American Society for 100. Truven Health Analytics. Introduction to Winslow D, Odeh S, Gadde KM. Evaluation of Metabolic & Bariatric Surgery. Clinical practice RED BOOK Online [Internet], 2013. Available phentermine and topiramate versus phenter- guidelines for the perioperative nutritional, from http://www.micromedexsolutions.com/ mine/topiramate extended-release in obese metabolic, and nonsurgical support of the bari- micromedex2/4.34.0/WebHelp/RED_BOOK/ adults. Obesity (Silver Spring) 2013;21:2163– atric surgery patientd2013 update: cospon- Introduction_to_REDB_BOOK_Online.htm. Ac- 2171 sored by American Association of Clinical cessed 5 September 2018 109. Gadde KM, Allison DB, Ryan DH, et al. Endocrinologists, The Obesity Society, and 101. Data.Medicaid.gov. NADAC (National Av- Effects of low-dose, controlled-release, phenter- American Society for Metabolic & Bariatric erage Drug Acquisition Cost) [Internet], 2018. mine plus topiramate combination on weight Surgery. Obesity (Silver Spring) 2013;21(Suppl. Available from https://data.medicaid.gov/Drug- and associated comorbidities in overweight 1):S1–S27 Pricing-and-Payment/NADAC-National-Average- and obese adults (CONQUER): a randomised, 93. Lee CJ, Clark JM, Schweitzer M, et al. Preva- Drug-Acquisition-Cost-/a4y5-998d. Accessed placebo-controlled, phase 3 trial. Lancet 2011; lence of and risk factors for hypoglycemic 5 September 2018 377:1341–1352 S90 Diabetes Care Volume 42, Supplement 1, January 2019

9. Pharmacologic Approaches to American Diabetes Association Glycemic Treatment: Standards of Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S90–S102 | https://doi.org/10.2337/dc19-S009

PHARMACOLOGIC THERAPY FOR TYPE 1 DIABETES

Recommendations 9.1 Most people with type 1 diabetes should be treated with multiple daily

9. PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT injections of prandial and basal insulin, or continuous subcutaneous insulin infusion. A 9.2 Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce hypoglycemia risk. A 9.3 Consider educating individuals with type 1 diabetes on matching prandial insulin doses to carbohydrate intake, premeal blood glucose levels, and anticipated physical activity. E 9.4 Individuals with type 1 diabetes who have been successfully using continuous subcutaneous insulin infusion should have continued access to this therapy after they turn 65 years of age. E

Insulin Therapy Because the hallmark of type 1 diabetes is absent or near-absent b-cell function, insulin treatment is essential for individuals with type 1 diabetes. Insufﬁcient provision Suggested citation: American Diabetes Associa- of insulin causes not only hyperglycemia but also systematic metabolic disturbances tion. 9. Pharmacologic approaches to glyc- like hypertriglyceridemia and ketoacidosis, as well as tissue catabolism. Over the past emic treatment: Standards of Medical Care in three decades, evidence has accumulated supporting multiple daily injections of Diabetesd2019. Diabetes Care 2019;42(Suppl. insulin or continuous subcutaneous administration through an insulin pump as 1):S90–S102 providing the best combination of effectiveness and safety for people with type 1 © 2018 by the American Diabetes Association. diabetes. Readers may use this article as long as the work is properly cited, the use is educational and not for Generally, insulin requirements can be estimated based on weight, with typical proﬁt, and the work is not altered. More infor- doses ranging from 0.4 to 1.0 units/kg/day. Higher amounts are required during mation is available at http://www.diabetesjournals puberty, pregnancy, and medical illness. The American Diabetes Association/JDRF .org/content/license. care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S91

Type 1 Diabetes Sourcebook notes 0.5 the literature in adolescents and adults complications, and avoidance of intra- units/kg/day as a typical starting dose in with type 1 diabetes (10,11). Intensive muscular (IM) insulin delivery. patients with type 1 diabetes who are diabetes management using CSII and Exogenous-delivered insulin should metabolically stable, with half adminis- continuous glucose monitoring should be injected into subcutaneous tissue, not tered as prandial insulin given to control be considered in selected patients. See intramuscularly. Recommended sites for blood glucose after meals and the other Section 7 “Diabetes Technology” for a full insulin injection include the abdomen, half as basal insulin to control glycemia discussion of insulin delivery devices. thigh, buttock, and upper arm (21). Be- in the periods between meal absorp- The Diabetes Control and Complica- cause insulin absorption from IM sites tion (1); this guideline provides detailed tions Trial (DCCT) demonstrated that differs according to the activity of the information on intensification of ther- intensive therapy with multiple daily muscle, inadvertent IM injection can apy to meet individualized needs. In injections or CSII reduced A1C and was lead to unpredictable insulin absorp- addition, the American Diabetes Associ- associated with improved long-term out- tion and variable effects on glucose, ation position statement “Type 1 Diabe- comes (12–14). The study was carried with IM injection being associated tes Management Through the Life Span” out with short-acting and intermediate- with frequent and unexplained hypo- provides a thorough overview of type 1 acting human insulins. Despite better glycemia in several reports (21–23). diabetes treatment (2). microvascular, macrovascular, and all- Risk for IM insulin delivery is increased in Physiologic insulin secretion varies cause mortality outcomes, intensive ther- younger and lean patients when injecting with glycemia, meal size, and tissue apy was associated with a higher rate into the limbs rather than truncal sites demands for glucose. To approach this of severe hypoglycemia (61 episodes (abdomen and buttocks) and when using variability in people using insulin treat- per 100 patient-years of therapy). Since longer needles (24). Recent evidence ment, strategies have evolved to adjust the DCCT, rapid-acting and long-acting supports the use of short needles prandial doses based on predicted needs. insulin analogs have been developed. (e.g., 4-mm pen needles) as effective and Thus, education of patients on how to These analogs are associated with less well tolerated when compared to longer adjust prandial insulin to account for hypoglycemia, less weight gain, and needles (25,26), including a study per- carbohydrate intake, premeal glucose lower A1C than human insulins in people formed in obese adults (27). Injection levels, and anticipated activity can be with type 1 diabetes (15–17). Longer- site rotation is additionally necessary to effective and should be considered. acting basal analogs (U-300 glargine or avoid lipohypertrophy and lipoatrophy Newly available information suggests degludec) may convey a lower hypogly- (21). Lipohypertrophy can contribute that individuals in whom carbohydrate cemia risk compared with U-100 glargine to erratic insulin absorption, increased counting is effective can incorporate es- in patients with type 1 diabetes (18,19). glycemic variability, and unexplained timates of meal fat and protein content Rapid-acting inhaled insulin to be used hypoglycemic episodes (28). Patients into their prandial dosing for added before meals is now available and may and/or caregivers should receive educa- benefit(3–5). reduce rates of hypoglycemia in patients tion about proper injection site rotation Most studies comparing multiple daily with type 1 diabetes (20). and to recognize and avoid areas of injections with continuous subcutane- Postprandial glucose excursions may lipohypertrophy (21). As noted in ous insulin infusion (CSII) have been be better controlled by adjusting the tim- Table 4.1, examination of insulin injec- relatively small and of short duration. ing of prandial insulin dose administration. tion sites for the presence of lipohyper- However, a recent systematic review The optimal time to administer prandial trophy, as well as assessment of injection and meta-analysis concluded that pump insulin varies, based on the type of insulin device use and injection technique, are therapy has modest advantages for used (regular, rapid-acting analog, in- key components of a comprehensive di- lowering A1C (–0.30% [95% CI –0.58 to haled, etc.), measured blood glucose level, abetes medical evaluation and treatment –0.02]) and for reducing severe hypo- timing of meals, and carbohydrate con- plan. As referenced above, there are now glycemia rates in children and adults sumption. Recommendations for prandial numerous evidence-based insulin delivery (6). There is no consensus to guide insulin dose administration should there- recommendations that have been pub- choosing which form of insulin adminis- fore be individualized. lished. Proper insulin injection technique tration is best for a given patient, and may lead to more effective use of this research to guide this decision making is Insulin Injection Technique therapy and, as such, holds the potential needed (7). The arrival of continuous Ensuring that patients and/or caregivers for improved clinical outcomes. glucose monitors to clinical practice understand correct insulin injection tech- has proven beneficial in specific circum- nique is important to optimize glucose Noninsulin Treatments for Type 1 stances. Reduction of nocturnal hypogly- control and insulin use safety. Thus, it is Diabetes cemia in people with type 1 diabetes important that insulin be delivered into Injectable and oral glucose-lowering drugs using insulin pumps with glucose sensors the proper tissue in the right way. Rec- have been studied for their efficacy as is improved by automatic suspension of ommendations have been published adjuncts to insulin treatment of type 1 insulin delivery at a preset glucose level elsewhere outlining best practices for diabetes. Pramlintide is based on the (7–9). The U.S. Food and Drug Adminis- insulin injection (21). Proper insulin naturally occurring b-cell peptide amylin tration (FDA) has also approved the first injection technique includes injecting and is approved for use in adults with hybrid closed-loop pump system. The into appropriate body areas, injection type 1 diabetes. Results from randomized safety and efficacy of hybrid closed- site rotation, appropriate care of injec- controlled studies show variable reduc- loop systems has been supported in tion sites to avoid infection or other tions of A1C (0–0.3%) and body weight S92 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 42, Supplement 1, January 2019

(1–2 kg) with addition of pramlintide to 9.6 Once initiated, metformin should consider use of a sodium– insulin (29,30). Similarly, results have be continued as long as it is glucose cotransporter 2 inhibi- been reported for several agents currently tolerated and not contraindi- tor or glucagon-like peptide approved only for the treatment of type 2 cated; other agents, including 1 receptor agonist shown to diabetes. The addition of metformin to insulin, should be added to met- reduce risk of chronic kidney adults with type 1 diabetes caused small formin. A disease progression, cardio- reductions in body weight and lipid levels 9.7 Long-term use of metformin vascular events, or both. C but did not improve A1C (31,32). The may be associated with bio- 9.14 In most patients who need the addition of the glucagon-like peptide chemical vitamin B12 deficiency, greater glucose-lowering effect 1 (GLP-1) receptor agonists liraglutide and periodic measurement of of an injectable medication, and exenatide to insulin therapy caused vitamin B12 levels should be con- glucagon-like peptide 1 receptor small (0.2%) reductions in A1C compared sidered in metformin-treated agonists are preferred to insu- with insulin alone in people with type 1 patients, especially in those lin. B diabetes and also reduced body weight with anemia or peripheral neu- 9.15 Intensification of treatment for by ;3 kg (33). Similarly, the addition ropathy. B patients with type 2 diabetes of a sodium–glucose cotransporter 9.8 The early introduction of insulin not meeting treatment goals 2 (SGLT2) inhibitor to insulin therapy should be considered if there is should not be delayed. B has been associated with improvements evidence of ongoing catabo- 9.16 The medication regimen should in A1C and body weight when compared lism (weight loss), if symptoms be reevaluated at regular in- with insulin alone (34–36); however, of hyperglycemia are present, tervals (every 3–6 months) and SGLT2 inhibitor use is also associated or when A1C levels (.10% adjusted as needed to incorpo- with more adverse events including [86 mmol/mol]) or blood glu- rate new patient factors (Table ketoacidosis. The dual SGLT1/2 inhib- cose levels ($300 mg/dL 9.1). E itor sotagliflozin is currently under [16.7 mmol/L]) are very high. E consideration by the FDA and, if ap- 9.9 Consider initiating dual therapy The American Diabetes Association/ proved, would be the first adjunctive in patients with newly diag- European Association for the Study oral therapy in type 1 diabetes. nosed type 2 diabetes who of Diabetes consensus report “Man- The risks and benefits of adjunctive have A1C $1.5% (12.5 mmol/ agement of Hyperglycemia in Type 2 agents beyond pramlintide in type 1 mol) above their glycemic tar- Diabetes, 2018” (39) recommends a diabetes continue to be evaluated get. E patient-centered approach to choosing through the regulatory process; how- 9.10 A patient-centered approach appropriate pharmacologic treatment of ever, at this time, these adjunctive agents should be used to guide the blood glucose (Fig. 9.1). This includes are not approved in the context of type 1 choice of pharmacologic agents. consideration of efficacy and key patient diabetes (37). Considerations include comor- factors: 1) important comorbidities such bidities (atherosclerotic cardio- as atherosclerotic cardiovascular disease SURGICAL TREATMENT FOR vascular disease, heart failure, (ASCVD), chronic kidney disease (CKD), TYPE 1 DIABETES chronic kidney disease), hypo- and heart failure (HF), 2) hypoglycemia Pancreas and Islet Transplantation glycemia risk, impact on weight, risk, 3) effects on body weight, 4) side Pancreas and islet transplantation nor- cost, risk for side effects, and effects, 5) cost, and 6) patient prefer- malizes glucose levels but requires life- patient preferences. E ences. Lifestyle modifications that im- long immunosuppression to prevent 9.11 Among patients with type 2 prove health (see Section 5 “Lifestyle graft rejection and recurrence of auto- diabetes who have estab- Management”) should be emphasized immune islet destruction. Given the lished atherosclerotic cardiovas- along with any pharmacologic therapy. potential adverse effects of immuno- cular disease, sodium–glucose See Sections 12 and 13 for recommen- suppressive therapy, pancreas transplan- cotransporter 2 inhibitors, or dations specific for older adults and for tation should be reserved for patients glucagon-like peptide 1 recep- children and adolescents with type 2 with type 1 diabetes undergoing simul- tor agonists with demonstrated diabetes, respectively. taneous renal transplantation, following cardiovascular disease benefit renal transplantation, or for those with (Table 9.1) are recommended recurrent ketoacidosis or severe hypo- as part of the antihyperglyce- Initial Therapy glycemia despite intensive glycemic man- Metformin should be started at the time mic regimen. A agement (38). type 2 diabetes is diagnosed unless there 9.12 Among patients with athero- are contraindications; for most patients sclerotic cardiovascular disease this will be monotherapy in combination PHARMACOLOGIC THERAPY FOR at high risk of heart failure or in TYPE 2 DIABETES with lifestyle modifications. Metformin whom heart failure coexists, is effective and safe, is inexpensive, and Recommendations sodium–glucose cotransporter may reduce risk of cardiovascular events 9.5 Metformin is the preferred ini- 2 inhibitors are preferred. C and death (40). Metformin is available tial pharmacologic agent for the 9.13 For patients with type 2 diabe- in an immediate-release form for twice- treatment of type 2 diabetes. A tes and chronic kidney disease, daily dosing or as an extended-release Table 9.1—Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes Pharmacologic Approaches to Glycemic Treatment S93

*For agent-speciﬁc dosing recommendations, please refer to the manufacturers’ prescribing information. †FDA approved for CVD beneﬁt. CHF, congestive heart failure; CV, cardiovascular; DPP-4, dipeptidyl peptidase 4; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; GLP-1 RAs, glucagon-like peptide 1 receptor agonists; NASH, nonalcoholic steatohepatitis; SGLT2, sodium–glucose cotransporter 2; SQ, subcutaneous; T2DM, type 2 diabetes. care.diabetesjournals.org 9 hraooi prahst lcmcTreatment Glycemic to Approaches Pharmacologic S94 ibtsCare Diabetes oue4,Splmn ,Jnay2019 January 1, Supplement 42, Volume

Figure 9.1—Glucose-lowering medication in type 2 diabetes: overall approach. For appropriate context, see Fig. 4.1. ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; CVOTs, cardiovascular outcomes trials; DPP-4i, dipeptidyl peptidase 4 inhibitor; eGFR, estimated glomerular ﬁltration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; SGLT2i, sodium–glucose cotransporter 2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. Adapted from Davies et al. (39). care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S95

Figure 9.2—Intensifying to injectable therapies. For appropriate context, see Fig. 4.1. DSMES, diabetes self-management education and support; FPG, fasting plasma glucose; FRC, ﬁxed-ratio combination; GLP-1 RA, glucagon-like peptide 1 receptor agonist; max, maximum; PPG, postprandial glucose. Adapted from Davies et al. (39). S96 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 42, Supplement 1, January 2019

Table 9.2—Median monthly cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.S. Dosage strength/product Median AWP Median NADAC Maximum approved Class Compound(s) (if applicable) (min, max)† (min, max)† daily dose* Biguanides c Metformin 500 mg (IR) $84 ($4, $93) $2 2,000 mg 850 mg (IR) $108 ($6, $109) $3 2,550 mg 1,000 mg (IR) $87 ($4, $88) $2 2,000 mg 500 mg (ER) $89 ($82, $6,671) $4 ($4, $1,267) 2,000 mg 750 mg (ER) $72 ($65, $92) $4 1,500 mg 1,000 mg (ER) $1,028 ($1,028, $311 ($311, 2,000 mg $7,214) $1,321) Sulfonylureas (2nd c Glimepiride 4 mg $71 ($71, $198) $4 8 mg generation) c Glipizide 10 mg (IR) $75 ($67, $97) $5 40 mg (IR) 10 mg (XL) $48 $15 20 mg (XL) c Glyburide 6 mg (micronized) $50 ($48, $71) $10 12 mg (micronized) 5 mg $93 ($63, $103) $13 20 mg Thiazolidinediones c Pioglitazone 45 mg $348 ($283, $349) $4 45 mg c Rosiglitazone 4 mg $407 $329 8 mg a-Glucosidase inhibitors c Acarbose 100 mg $106 ($104, $106) $23 300 mg c Miglitol 100 mg $241 $311 300 mg Meglitinides (glinides) c Nateglinide 120 mg $155 $46 360 mg c Repaglinide 2 mg $878 ($162, $898) $48 16 mg DPP-4 inhibitors c Alogliptin 25 mg $234 $170 25 mg c Saxagliptin 5 mg $490 ($462, $490) $392 5 mg c Linagliptin 5 mg $494 $395 5 mg c Sitagliptin 100 mg $516 $413 100 mg SGLT2 inhibitors c Ertugliflozin 15 mg $322 $257 15 mg c Dapagliflozin 10 mg $557 $446 10 mg c Canagliflozin 300 mg $558 $446 300 mg c Empagliflozin 25 mg $558 $448 25 mg GLP-1 receptor agonists c Exenatide (extended 2 mg powder for $792 $634 2 mg** release) suspension or pen c Exenatide 10 mg pen $850 $680 20 mg c Dulaglutide 1.5/0.5 mL pen $876 $702 1.5 mg** c Semaglutide 1 mg pen $875 $704 1 mg** c Liraglutide 18 mg/3 mL pen $1,044 $835 1.8 mg Bile acid sequestrants c Colesevelam 625 mg tabs $712 ($674, $712) $354 3.75 g 3.75 g suspension $674 $598 3.75 g Dopamine-2 agonists c Bromocriptine 0.8 mg $855 $685 4.8 mg Amylin mimetics c Pramlintide 120 mg pen $2,547 $2,036 120 mg/injection††† AWP, average wholesale price; DPP-4, dipeptidyl peptidase 4; ER and XL, extended release; GLP-1, glucagon-like peptide 1; IR, immediate release; NADAC, National Average Drug Acquisition Cost; SGLT2, sodium–glucose cotransporter 2. †Calculated for 30-day supply (AWP [44] or NADAC [45] unit price 3 number of doses required to provide maximum approved daily dose 3 30 days); median AWP or NADAC listed alone when only one product and/or price. *Utilized to calculate median AWP and NADAC (min, max); generic prices used, if available commercially. **Administered once weekly. †††AWP and NADAC calculated based on 120 mg three times daily.

form that can be given once daily. Com- used in patients with reduced estimated consider a drug from another class de- pared with sulfonylureas, metformin as glomerular filtration rates (eGFR); the picted in Fig. 9.1. When A1C is $1.5% first-line therapy has beneficial effects FDA has revised the label for metformin (12.5 mmol/mol) above glycemic target on A1C, weight, and cardiovascular to reflect its safety in patients with (see Section 6 “Glycemic Targets” for mortality (41); there is little systematic eGFR $30 mL/min/1.73 m2 (42). A recent more information on selecting appropri- data available for other oral agents as randomized trial confirmed previous ob- ate targets), many patients will require initial therapy of type 2 diabetes. The servations that metformin use is associ- dual combination therapy to achieve principal side effects of metformin are ated with vitamin B12 deficiency and their target A1C level (45). Insulin has gastrointestinal intolerance due to bloat- worsening of symptoms of neuropathy the advantage of being effective where ing, abdominal discomfort, and diarrhea. (43). This is compatible with a recent other agents are not and should be The drug is cleared by renal filtration, and report from the Diabetes Prevention considered as part of any combination very high circulating levels (e.g., as a Program Outcomes Study (DPPOS) sug- regimen when hyperglycemia is severe, result of overdose or acute renal fail- gesting periodic testing of vitamin B12 especially if catabolic features (weight ure) have been associated with lactic (44). loss, hypertriglyceridemia, ketosis) are acidosis. However, the occurrence of In patients with contraindications or present. Consider initiating insulin ther- this complication is now known to be intolerance of metformin, initial therapy when blood glucose is $300 mg/dL very rare, and metformin may be safely apy should be based on patient factors; (16.7 mmol/L) or A1C is $10% (86 mmol/ care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S97

Table 9.3—Median cost of insulin products in the U.S. calculated as AWP (44) and NADAC (45) per 1,000 units of specified dosage form/product Median AWP Median NADAC Insulins Compounds Dosage form/product (min, max)* (min, max)* Rapid-acting analogs c Lispro biosimilar U-100 vial $280 $226 U-100 prefilled pen $361 $289 c Glulisine U-100 vial $324 $260 U-100 prefilled pen $417 $334 c Lispro U-100 vial $330 $264 U-100 3 mL cartridges $408 $326 U-100 prefilled pen; U-200 $424 $340 prefilled pen c Aspart U-100 vial $347 $278 U-100 3 mL cartridges $430 $343 U-100 prefilled pen $447 $358 c Inhaled insulin Inhalation cartridges $993 $606 Short-acting c Human Regular U-100 vial $165 ($165, $178) $135 ($135, $146) Intermediate-acting c Human NPH U-100 vial $165 ($165, $178) $135 ($135, $144) U-100 prefilled pen $377 $304 Concentrated Human c U-500 Human Regular U-500 vial $178 $142 Regular insulin insulin U-500 prefilled pen $230 $184 Basal analogs c Glargine biosimilar U-100 prefilled pen $261 $209 c Glargine U-100 vial; U-100 prefilled pen $323 $259 U-300 prefilled pen $331 $266 c Detemir U-100 vial; U-100 prefilled pen $353 $281 c Degludec U-100 prefilled pen; U-200 $388 $310 prefilled pen Premixed insulin products c NPH/Regular 70/30 U-100 vial $165 ($165, $178) $135 ($135, $144) U-100 prefilled pen $377 $306 c Lispro 50/50 U-100 vial $342 $274 U-100 prefilled pen $424 $340 c Lispro 75/25 U-100 vial $342 $273 U-100 prefilled pen $424 $340 c Aspart 70/30 U-100 vial $360 $288 U-100 prefilled pen $447 $358 Premixed insulin/GLP-1 c Degludec/Liraglutide 100/3.6 prefilled pen $793 $638 receptor agonist products c Glargine/Lixisenatide 100/33 prefilled pen $537 $431 AWP, average wholesale price; GLP-1, glucagon-like peptide 1; NADAC, National Average Drug Acquisition Cost. *AWP or NADAC calculated as in Table 9.2; median listed alone when only one product and/or price.

mol) or if the patient has symptoms of preferred six treatment options: sulfo- considerations are applied in patients hyperglycemia (i.e., polyuria or polydip- nylurea, thiazolidinedione, dipeptidyl who require a third agent to achieve sia), even at diagnosis or early in the peptidase 4 (DPP-4) inhibitor, SGLT2 in- glycemic goals; there is also very little course of treatment (Fig. 9.2). As glu- hibitor, GLP-1 receptor agonist, or basal trial-based evidence to guide this choice. cose toxicity resolves, simplifying the insulin; the choice of which agent to add In all cases, treatment regimens need regimen and/or changing to oral agents is based on drug-specific effects and to be continuously reviewed for effi- is often possible. patient factors (Fig. 9.1 and Table cacy, side effects, and patient burden 9.1). For patients in whom ASCVD, HF, (Table 9.1). In some instances, patients Combination Therapy or CKD predominates, the best choice will require medication reduction or dis- Although there are numerous trials for a second agent is a GLP-1 receptor continuation. Common reasons for this comparing dual therapy with metformin agonist or SGLT2 inhibitor with demon- include ineffectiveness, intolerable side alone, few directly compare drugs as strated cardiovascular risk reduction, af- effects, expense, or a change in glycemic add-on therapy. A comparative effective- ter consideration of drug-specific and goals (e.g., in response to development ness meta-analysis suggests that each patient factors (Table 9.1). For patients of comorbidities or changes in treatment new class of noninsulin agents added to without established ASCVD or CKD, the goals). See Section 12 “Older Adults” for a initial therapy generally lowers A1C ap- choice of a second agent to add to full discussion of treatment considera- proximately 0.7–1.0% (46). If the A1C metformin is not yet guided by empiric tions in older adults. target is not achieved after approxi- evidence. Rather, drug choice is based on Even though most patients prefer oral mately 3 months and the patient does avoidance of side effects, particularly medications to drugs that need to be not have ASCVD or CKD, consider a com- hypoglycemia and weight gain, cost, injected, the eventual need for the bination of metformin and any one of the and patient preferences (47). Similar greater potency of injectable medications S98 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 42, Supplement 1, January 2019

is common, particularly in people with a of MACE in a group of subjects with, or should avoid using insulin as a threat or longer duration of diabetes. The addition at high risk for, ASCVD (55). In both of describing it as a sign of personal failure of basal insulin, either human NPH or one these trials, SGLT2 inhibitors reduced or punishment. Rather, the utility and of the long-acting insulin analogs, to oral hospitalization for HF (54,55); this was a importance of insulin to maintain gly- agent regimens is a well-established ap- secondary outcome of these studies and cemic control once progression of the proach that is effective for many patients. will require confirmationinmoredefined disease overcomes the effect of oral In addition, recent evidence supports the populations. In people with type 2 di- agents should be emphasized. Educat- utility of GLP-1 receptor agonists in pa- abetes with ASCVD or increased risk for ing and involving patients in insulin tients not reaching glycemic targets with ASCVD, the addition of liraglutide de- management is beneficial. Instruction oral agent regimens. In trials comparing creased MACE and mortality (56), and of patients in self-titration of insulin the addition of GLP-1 receptor agonists the closely related GLP-1 receptor agonist doses based on self-monitoring of blood or insulin in patients needing further semaglutide also had favorable effects glucose improves glycemic control in glucose lowering, the efficacy of the on cardiovascular end points in high- patients with type 2 diabetes initiating two treatments was similar (48–50). How- risk subjects (57). In these cardiovascular insulin(58). Comprehensive education re- ever, GLP-1 receptor agonists had a lower outcomes trials, empagliflozin, canagliflo- garding self-monitoring of blood glucose, risk ofhypoglycemiaandbeneficialeffects zin, liraglutide, and semaglutide all had diet, and the avoidance and appropriate on body weight compared with insulin, beneficial effects on composite indices treatment of hypoglycemia are critically albeit with greater gastrointestinal side of CKD (54–57). See ANTIHYPERGLYCEMIC important in any patient using insulin. effects. Thus, trial results support a GLP-1 THERAPIES AND CARDIOVASCULAR OUTCOMES in Sec- receptor agonist as the preferred option tion 10 “Cardiovascular Disease and Basal Insulin for patients requiring the potency of an Risk Management” and Table 10.4 for Basal insulin alone is the most convenient injectable therapy for glucose control a detailed description of these cardiovas- initial insulin regimen and can be added (Fig. 9.2). However, high costs and tol- cular outcomes trials, as well as a discus- to metformin and other oral agents. erability issues are important barriers to sion of how HF may impact treatment Starting doses can be estimated based the use of GLP-1 receptor agonists. choices. See Section 11 “Microvascular on body weight (e.g., 10 units a day or Cost-effectiveness models of the Complications and Foot Care” for a de- 0.1–0.2 units/kg/day) and the degree newer agents based on clinical utility tailed discussion on how CKD may impact of hyperglycemia, with individualized and glycemic effect have been reported treatment choices. Additional large ran- titration over days to weeks as needed. (51). Table 9.2 provides cost information domized trials of other agents in these The principal action of basal insulin is for currently approved noninsulin ther- classes are ongoing. to restrain hepatic glucose production, apies. Of note, prices listed are average The subjects enrolled in the cardio- with a goal of maintaining euglycemia wholesale prices (AWP) (52) and National vascular outcomes trials using empa- overnight and between meals (59,60). Average Drug Acquisition Costs (NADAC) gliflozin, canagliflozin, liraglutide, and Control of fasting glucose can be (53) and do not account for discounts, semaglutide had A1C $7%, and more achieved with human NPH insulin or rebates, or other price adjustments often than 70% were taking metformin at with the use of a long-acting insulin involved in prescription sales that affect baseline. Moreover, the benefitof analog. In clinical trials, long-acting basal the actual cost incurred by the patient. treatment was less evident in subjects analogs (U-100 glargine or detemir) have While there are alternative means to with lower risk for ASCVD. Thus, ex- been demonstrated to reduce the risk estimate medication prices, AWP and tension of these results to practice is of symptomatic and nocturnal hypo- NADAC were utilized to provide two most appropriate for people with type 2 glycemia compared with NPH insulin separate measures to allow for a com- diabetes and established ASCVD who (61–66), although these advantages are parison of drug prices with the primary require additional glucose-lowering generally modest and may not persist goal of highlighting the importance of treatment beyond metformin and life- (67). Longer-acting basal analogs (U-300 cost considerations when prescribing style management. For these patients, glargine or degludec) may convey a lower antihyperglycemic treatments. incorporating one of the SGLT2 inhib- hypoglycemia risk compared with U-100 itors or GLP-1 receptor agonists that glargine when used in combination with Cardiovascular Outcomes Trials have been demonstrated to reduce oral agents (68–74). Despite evidence There are now multiple large randomized cardiovascular events is recommended for reduced hypoglycemia with newer, controlled trials reporting statistically (Table 9.1). longer-acting basal insulin analogs in significant reductions in cardiovascular clinical trial settings, in practice they may events in patients with type 2 diabetes Insulin Therapy not affect the development of hypogly- treated with an SGLT2 inhibitor (empa- Many patients with type 2 diabetes cemia compared with NPH insulin (75). gliflozin, canagliflozin) or GLP-1 recep- eventually require and benefitfrom The cost of insulin has been rising tor agonist (liraglutide, semaglutide). In insulin therapy (Fig. 9.2). See the section steadily, and at a pace several fold that people with diabetes with established above, INSULIN INJECTION TECHNIQUE,forim- of other medical expenditures, over ASCVD, empagliflozin decreased a com- portant guidance on how to administer the past decade (76). This expense con- posite three-point major cardiovascular insulin safely and effectively. The pro- tributes significant burden to the pa- event (MACE) outcome and mortality gressive nature of type 2 diabetes tient as insulin has become a growing compared with placebo (54). Similarly, should be regularly and objectively “out-of-pocket” cost for people with canagliflozin reduced the occurrence explainedtopatients,andproviders diabetes, and direct patient costs care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S99

contribute to treatment nonadherence pharmacokinetics with delayed onset lowering actions and less weight gain (76). Therefore, consideration of cost is and longer duration of action, character- and hypoglycemia compared with in- an important component of effective istics more like an intermediate-acting tensified insulin regimens (83–85). management. For many patients with insulin. U-300 glargine and U-200 deglu- Two different once-daily fixed-dual type 2 diabetes (e.g., individuals with dec are three and two times as concen- combination products containing basal in- relaxed A1C goals, low rates of hypogly- trated, respectively, as their U-100 sulin plus a GLP-1 receptor agonist are cemia, and prominent insulin resistance, formulations and allow higher doses of available: insulin glargine plus lixisenatide as well as those with cost concerns), basal insulin administration per volume and insulin degludec plus liraglutide. human insulin (NPH and Regular) may be used. U-300 glargine has a longer dura- Intensification ofinsulintreatment can the appropriate choice of therapy, and tion of action than U-100 glargine but be done by adding doses of prandial to clinicians should be familiar with its use modestly lower efficacy per unit admin- basal insulin. Starting with a single pran- (77). Table 9.3 provides AWP (52) and istered (80,81). The FDA has also approved a dial dose with the largest meal of the day is NADAC (53) information (cost per 1,000 concentrated formulation of rapid-acting simple and effective, and it can be ad- units) for currently available insulin and insulinlispro,U-200 (200units/mL). These vanced to a regimen with multiple pran- insulin combination products in the concentrated preparations may be more dial doses if necessary (86). Alternatively, U.S. As stated for Table 9.2, AWP and convenient and comfortable for patients in a patient on basal insulin in whom NADAC prices listed do not account for to inject and may improve adherence in additional prandial coverage is desired, discounts, rebates, or other price adjust- those with insulin resistance who require the regimen can be converted to two or ments that may affect the actual cost to large doses of insulin. While U-500 reg- three doses of a premixed insulin. Each the patient. For example, human regular ular insulin is available in both prefilled approach has advantages and disadvan- insulin, NPH, and 70/30 NPH/Regular pens and vials (a dedicated syringe was tages. For example, basal/prandial regi- products can be purchased for consid- FDA approved in July 2016), other con- mens offer greater flexibility for patients erably less than the AWP and NADAC centrated insulins are available only in who eat on irregular schedules. On the prices listed in Table 9.3 at select phar- prefilled pens to minimize the risk of other hand, two doses of premixed insulin macies. dosing errors. is a simple, convenient means of spreading insulin across the day. Moreover, hu- Prandial Insulin Inhaled Insulin man insulins, separately or as premixed Individuals with type 2 diabetes may Inhaled insulin is available for prandial NPH/Regular (70/30) formulations, are less require doses of insulin before meals use with a limited dosing range; studies in costly alternatives to insulin analogs. Fig- in addition to basal insulin. The recom- people with type 1 diabetes suggest rapid ure 9.2 outlines these options, as well as mended starting dose of mealtime insulin pharmacokinetics (20). A pilot study found recommendations for further intensifica- is either 4 units or 10% of the basal dose at evidence that compared with injectable tion, if needed, to achieve glycemic goals. each meal. Titration is done based on rapid-acting insulin, supplemental doses When initiating combination inject- home glucose monitoring or A1C. With of inhaled insulin taken based on post- able therapy, metformin therapy should significant additions to the prandial insulin prandial glucose levels may improve blood be maintained while sulfonylureas and dose, particularly with the evening meal, glucose management without additional DPP-4 inhibitors are typically discontin- consideration should be given to decreas- hypoglycemia or weight gain, although ued. In patients with suboptimal blood ing the basal insulin dose. Meta-analyses results from a larger study are needed for glucose control, especially those requir- fi of trials comparing rapid-acting insulin con rmation (82). ing large insulin doses, adjunctive use of analogs with human regular insulin in Inhaled insulin is contraindicated in a thiazolidinedione or an SGLT2 inhibitor patients with type 2 diabetes have not patients with chronic lung disease, such may help to improve control and reduce reported important differences in A1C as asthma and chronic obstructive pul- the amount of insulin needed, though or hypoglycemia (78,79). monary disease, and is not recom- potential side effects should be consid- mended in patients who smoke or who ered. Once a basal/bolus insulin regimen is Premixed Insulin recently stopped smoking. All patients initiated, dose titration is important, with Premixed insulin products contain both requirespirometry(FEV1) testing to iden- adjustments made in both mealtime and a basal and prandial component, allowing tify potential lung disease prior to and basal insulins based on the blood glucose coverage of both basal and prandial needs after starting inhaled insulin therapy. levels and an understanding of the phar- with a single injection. The NPH/Regular macodynamic profile of each formulation premix is composed of 70% NPH insulin Combination Injectable Therapy (pattern control). As people with type 2 and 30% regular insulin. The use of pre- If basal insulin has been titrated to an diabetes get older, it may become neces- mixed insulin products has its advantages acceptable fasting blood glucose level sary to simplify complex insulin regimens and disadvantages, as discussed below in (or if the dose is .0.5 units/kg/day) because of a decline in self-management COMBINATION INJECTABLE THERAPY. and A1C remains above target, consider ability (see Section 12 “Older Adults”). Concentrated Insulin Products advancing to combination injectable ther- Several concentrated insulin prepara- apy (Fig.9.2).Thisapproach canuse a GLP- References tions are currently available. U-500 reg- 1 receptor agonist added to basal insulin 1. Peters A, Laffel L (Eds.). American Diabetes ular insulin is, by definition, five times or multiple doses of insulin. The com- Association/JDRF Type 1 Diabetes Sourcebook. more concentrated than U-100 regu- bination of basal insulin and GLP-1 Alexandria, VA, American Diabetes Association, lar insulin. Regular U-500 has distinct receptor agonist has potent glucose- 2013 S100 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 42, Supplement 1, January 2019

2. Chiang JL, Kirkman MS, Laffel LMB, Peters AL; versus the general population. Diabetes Care 29. Ratner RE, Dickey R, Fineman M, et al. Amylin Type 1 Diabetes Sourcebook Authors. Type 1 di- 2016;39:1378–1383 replacement with pramlintide as an adjunct to abetes through the life span: a position state- 15. Tricco AC, Ashoor HM, Antony J, et al. Safety, insulin therapy improves long-term glycaemic ment of the American Diabetes Association. effectiveness, and cost effectiveness of long and weight control in type 1 diabetes mellitus: Diabetes Care 2014;37:2034–2054 acting versus intermediate acting insulin for a 1-year, randomized controlled trial. Diabet 3. Wolpert HA, Atakov-Castillo A, Smith SA, patients with type 1 diabetes: systematic re- Med 2004;21:1204–1212 Steil GM. Dietary fat acutely increases glucose view and network meta-analysis. BMJ 2014;349: 30. Edelman S, Garg S, Frias J, et al. A double- concentrations and insulin requirements in pa- g5459 blind, placebo-controlled trial assessing pramlin- tients with type 1 diabetes: implications for 16. Bartley PC, Bogoev M, Larsen J, Philotheou A. tide treatment in the setting of intensive insulin carbohydrate-based bolus dose calculation and Long-term efficacy and safety of insulin detemir therapy in type 1 diabetes. Diabetes Care 2006; intensive diabetes management. Diabetes Care compared to Neutral Protamine Hagedorn in- 29:2189–2195 2013;36:810–816 sulin in patients with type 1 diabetes using a 31. Meng H,ZhangA, LiangY,Hao J,Zhang X,Lu J. 4. Bell KJ, Toschi E, Steil GM, Wolpert HA. treat-to-target basal-bolus regimen with insulin Effect of metformin on glycaemic control in Optimized mealtime insulin dosing for fat and aspart at meals: a 2-year, randomized, controlled patients with type 1 diabetes: a meta-analysis protein in type 1 diabetes: application of a model- trial. Diabet Med 2008;25:442–449 of randomized controlled trials. Diabetes Metab based approach to derive insulin doses for open- 17. DeWitt DE, Hirsch IB. Outpatient insulin Res Rev 2018;34:e2983 loop diabetes management. Diabetes Care 2016; therapy in type 1 and type 2 diabetes mellitus: 32. Petrie JR, Chaturvedi N, Ford I, et al.; 39:1631–1634 scientific review. JAMA 2003;289:2254–2264 REMOVAL Study Group. Cardiovascular and 5. Bell KJ, Smart CE, Steil GM, Brand-Miller JC, 18. Lane W, Bailey TS, Gerety G, et al.; Group metabolic effects of metformin in patients King B, Wolpert HA. Impact of fat, protein, and Information; SWITCH 1. Effect of insulin degludec with type 1 diabetes (REMOVAL): a double-blind, glycemic index on postprandial glucose control vs insulin glargine U100 on hypoglycemia in randomised, placebo-controlled trial. Lancet Di- in type 1 diabetes: implications for intensive diabetes patients with type 1 diabetes: the SWITCH 1 ran- abetes Endocrinol 2017;5:597–609 management in the continuous glucose monitoring domized clinical trial. JAMA 2017;318:33–44 33. Wang W, Liu H, Xiao S, Liu S, Li X, Yu P. Effects era. Diabetes Care 2015;38:1008–1015 19. Home PD, Bergenstal RM, Bolli GB, et al. New of insulin plus glucagon-like peptide-1 receptor 6. Yeh H-C, Brown TT, Maruthur N, et al. Com- insulin glargine 300 units/mL versus glargine agonists (GLP-1RAs) in treating type 1 diabetes parative effectiveness and safety of methods of 100 units/mL in people with type 1 diabetes: mellitus: a systematic review and meta-analysis. insulin delivery and glucose monitoring for di- a randomized, phase 3a, open-label clinical trial Diabetes Ther 2017;8:727–738 abetes mellitus: a systematic review and meta- (EDITION 4). Diabetes Care 2015;38:2217–2225 34. Henry RR, Thakkar P, Tong C, Polidori D, Alba analysis. Ann Intern Med 2012;157:336–347 20. Bode BW, McGill JB, Lorber DL, Gross JL, M. Efficacy and safety of canagliflozin, a sodium– 7. Pickup JC. The evidence base for diabetes Chang PC, Bregman DB; Affinity 1 Study Group. glucose cotransporter 2 inhibitor, as add-on to technology: appropriate and inappropriate meta- Inhaled technosphere insulin compared with insulin in patients with type 1 diabetes. Diabetes analysis. J Diabetes Sci Technol 2013;7:1567– injected prandial insulin in type 1 diabetes: Care 2015;38:2258–2265 1574 a randomized 24-week trial. Diabetes Care 35. Dandona P, Mathieu C, Phillip M, et al.; 8. Bergenstal RM, Klonoff DC, Garg SK, et al.; 2015;38:2266–2273 DEPICT-1 Investigators. Efficacy and safety of ASPIRE In-Home Study Group. Threshold-based 21. Frid AH, Kreugel G, Grassi G, et al. New dapagliflozin in patients with inadequately insulin-pump interruption for reduction of hy- insulin delivery recommendations. Mayo Clin controlled type 1 diabetes (DEPICT-1): 24 poglycemia. N Engl J Med 2013;369:224–232 Proc 2016;91:1231–1255 week results from a multicentre, double-blind, 9. Buckingham BA, Raghinaru D, Cameron F, 22. Karges B, Boehm BO, Karges W. Early hypo- phase 3, randomised controlled trial. Lancet et al.; In Home Closed Loop Study Group. Pre- glycaemia after accidental intramuscular injec- Diabetes Endocrinol 2017;5:864–876 dictive low-glucose insulin suspension reduces tion of insulin glargine. Diabet Med 2005;22: 36. Patoulias D, Imprialos K, Stavropoulos K, duration of nocturnal hypoglycemia in children 1444–1445 Athyros V, Doumas M. SGLT-2 inhibitors in without increasing ketosis. Diabetes Care 2015; 23. Frid A, Gunnarsson R, Guntner¨ P, Linde B. type 1 diabetes mellitus: a comprehensive review 38:1197–1204 Effects of accidental intramuscular injection on of the literature. Curr Clin Pharmacol. 7 August 10. Bergenstal RM, Garg S, Weinzimer SA, et al. insulin absorption in IDDM. Diabetes Care 1988; 2018 [Epub ahead of print]. DOI: 10.2174/ Safety of a hybrid closed-loop insulin delivery 11:41–45 1574884713666180807150509 system in patients with type 1 diabetes. JAMA 24. Gibney MA, Arce CH, Byron KJ, Hirsch LJ. Skin 37. Lexicon Pharmaceuticals. FDA to review 2016;316:1407–1408 and subcutaneous adipose layer thickness in adults ZynquistaTM (sotagliflozin) as potential treatment 11. Garg SK, Weinzimer SA, Tamborlane WV, with diabetes at sites usedforinsulininjections: for type 1 diabetes [Internet], 2018. Available et al. Glucose outcomes with the in-home use implications for needle length recommendations. from http://www.lexpharma.com/media-center/ of a hybrid closed-loop insulin delivery system Curr Med Res Opin 2010;26:1519–1530 news/673-fda-to-review-zynquista-sotagliflozin- in adolescents and adults with type 1 diabetes. 25. Hirsch LJ, Gibney MA, Albanese J, et al. as-potential-treatment-for-type-1-diabetes. Ac- Diabetes Technol Ther 2017;19:155–163 Comparative glycemic control, safety and pa- cessed 30 September 2018 12. Cleary PA, Orchard TJ, Genuth S, et al.; DCCT/ tient ratings for a new 4 mm 3 32G insulin pen 38. Robertson RP, Davis C, Larsen J, Stratta R, EDIC Research Group. The effect of intensive needle in adults with diabetes. Curr Med Res Sutherland DER; American Diabetes Association. glycemic treatment on coronary artery calcifi- Opin 2010;26:1531–1541 Pancreas and islet transplantation in type 1 di- cation in type 1 diabetic participants of the 26. Miwa T, Itoh R, Kobayashi T, et al. Compar- abetes. Diabetes Care 2006;29:935 Diabetes Control and Complications Trial/ isonofthe effectsofanew32-gauge34-mmpen 39. Davies MJ, D’Alessio DA, Fradkin J, et al. Epidemiology of Diabetes Interventions and needle and a 32-gauge 3 6-mm pen needle on Management of hyperglycemia in type 2 diabe- Complications (DCCT/EDIC) Study. Diabetes glycemic control, safety, and patient ratings in tes, 2018. A consensus report by the American 2006;55:3556–3565 Japanese adults with diabetes. Diabetes Technol Diabetes Association (ADA) and the European 13. Nathan DM, Cleary PA, Backlund J-YC, et al.; Ther 2012;14:1084–1090 Association for the Study of Diabetes (EASD). Diabetes Control and Complications Trial/ 27. Bergenstal RM, Strock ES, Peremislov D, Diabetes Care 2018;41:2669–2701 Epidemiology of Diabetes Interventions and Gibney MA, Parvu V, Hirsch LJ. Safety and efficacy 40. Holman RR, Paul SK, Bethel MA, Matthews Complications (DCCT/EDIC) Study Research of insulin therapy delivered via a 4mm pen needle DR, Neil HAW. 10-year follow-up of intensive Group. Intensive diabetes treatment and cardio- in obese patients with diabetes. Mayo Clin Proc glucose control in type 2 diabetes. N Engl J Med vascular disease in patients with type 1 diabetes. 2015;90:329–338 2008;359:1577–1589 N Engl J Med 2005;353:2643–2653 28. Famulla S, Hovelmann¨ U, Fischer A, et al. 41. Maruthur NM, Tseng E, Hutfless S, et al. 14. Diabetes Control and Complications Trial Insulin injection into lipohypertrophic tissue: Diabetes medications as monotherapy or (DCCT)/Epidemiology of Diabetes Interventions blunted and more variable insulin absorption metformin-based combination therapy for and Complications (EDIC) Study Research Group. and action and impaired postprandial glucose type 2 diabetes: a systematic review and meta- Mortality in type 1 diabetes in the DCCT/EDIC control. Diabetes Care 2016;39:1486–1492 analysis. Ann Intern Med 2016;164:740–751 care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S101

42. U.S. Food and Drug Administration. FDA cardiovascular outcomes, and mortality in controlled trial (EDITION 3). Diabetes Obes Drug Safety Communication: FDA revises warn- type 2 diabetes. N Engl J Med 2015;373: Metab 2015;17:386–394 ings regarding use of the diabetes medicine 2117–2128 69. Terauchi Y, Koyama M, Cheng X, et al. New metformin in certain patients with reduced kidney 55. Neal B, Perkovic V, Mahaffey KW, et al.; insulin glargine 300 U/ml versus glargine 100 function [Internet]. Available from http://www.fda CANVAS Program Collaborative Group. Cana- U/ml in Japanese people with type 2 diabetes .gov/Drugs/DrugSafety/ucm493244.htm. Accessed gliflozin and cardiovascular and renal events in using basal insulin and oral antihyperglycaemic 14 October 2016 type 2 diabetes. N Engl J Med 2017;377:644–657 drugs: glucose control and hypoglycaemia in a 43. Out M, Kooy A, Lehert P, Schalkwijk CA, 56. Marso SP, Daniels GH, Brown-Frandsen K, randomized controlled trial (EDITION JP 2). Dia- Stehouwer CDA. Long-term treatment with met- et al.; LEADER Steering Committee; LEADER Trial betes Obes Metab 2016;18:366–374 formin in type 2 diabetes and methylmalonic Investigators. Liraglutide and cardiovascular 70. Yki-Jarvinen¨ H, Bergenstal RM, Bolli GB, et al. acid: post hoc analysis of a randomized con- outcomes in type 2 diabetes. N Engl J Med Glycaemic control and hypoglycaemia with new trolled 4.3 year trial. J Diabetes Complications 2016;375:311–322 insulin glargine 300 U/ml versus insulin glargine 2018;32:171–178 57. Marso SP, Bain SC, Consoli A, et al.; SUSTAIN- 100 U/ml in people with type 2 diabetes using 44. Aroda VR, Edelstein SL, Goldberg RB, et al.; 6 Investigators. Semaglutide and cardiovascular basal insulin and oral antihyperglycaemic drugs: Diabetes Prevention Program Research Group. outcomes in patients with type 2 diabetes. N Engl the EDITION 2 randomized 12-month trial in- Long-term metformin use and vitamin B12 de- J Med 2016;375:1834–1844 cluding 6-month extension. Diabetes Obes fi ciency in the Diabetes Prevention Program 58. Blonde L, Merilainen M, Karwe V, Raskin P; Metab 2015;17:1142–1149 Outcomes Study. J Clin Endocrinol Metab 2016; TITRATE Study Group. Patient-directed titration for 71. Marso SP, McGuire DK, Zinman B, et al.; – 101:1754 1761 achieving glycaemic goals using a once-daily basal DEVOTE Study Group. Efficacy and safety of 45. Henry RR, Murray AV, Marmolejo MH, insulin analogue: an assessment of two different degludec versus glargine in type 2 diabetes. N fl – Hennicken D, Ptaszynska A, List JF. Dapagli ozin, fasting plasma glucose targets the TITRATE study. Engl J Med 2017;377:723–732 – metformin XR, or both: initial pharmacotherapy Diabetes Obes Metab 2009;11:623 631 72. Rodbard HW, Cariou B, Zinman B, et al.; for type 2 diabetes, a randomised controlled 59. Porcellati F, Lucidi P, Cioli P, et al. Pharma- BEGIN Once Long trial investigators. Comparison – trial. Int J Clin Pract 2012;66:446 456 cokinetics and pharmacodynamics of insulin of insulin degludec with insulin glargine 46. Bennett WL, Maruthur NM, Singh S, et al. glargine given in the evening as compared in insulin-naive subjects with type 2 diabetes: Comparative effectiveness and safety of medi- with in the morning in type 2 diabetes. Diabetes a 2-year randomized, treat-to-target trial. Diabet cations for type 2 diabetes: an update including Care 2015;38:503–512 Med 2013;30:1298–1304 new drugs and 2-drug combinations. Ann Intern 60. Wang Z, Hedrington MS, Gogitidze Joy N, 73. Wysham C, Bhargava A, Chaykin L, et al. Med 2011;154:602–613 et al. Dose-response effects of insulin glargine in Effect of insulin degludec vs insulin glargine U100 47. Vijan S, Sussman JB, Yudkin JS, Hayward type 2 diabetes. Diabetes Care 2010;33:1555– on hypoglycemia in patients with type 2 diabetes: RA. Effect of patients’ risks and preferences 1560 the SWITCH 2 randomized clinical trial. JAMA on health gains with plasma glucose level lowering 61. Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett 2017;318:45–56 in type 2 diabetes mellitus. JAMA Intern Med H. Efficacy and safety of insulin analogues for 74. Zinman B, Philis-Tsimikas A, Cariou B, et al.; 2014;174:1227–1234 the management of diabetes mellitus: a meta- NN1250-3579 (BEGIN Once Long) Trial Investi- 48. Singh S, Wright EE Jr, Kwan AYM, et al. analysis. CMAJ 2009;180:385–397 gators. Insulin degludec versus insulin glargine Glucagon-like peptide-1 receptor agonists 62. Horvath K, Jeitler K, Berghold A, et al. Long- in insulin-naive patients with type 2 diabetes: compared with basal insulins for the treatment acting insulin analogues versus NPH insulin of type 2 diabetes mellitus: a systematic review (human isophane insulin) for type 2 diabetes a 1-year, randomized, treat-to-target trial (BEGIN – and meta-analysis. Diabetes Obes Metab 2017; mellitus. Cochrane Database Syst Rev 2007;2: Once Long). Diabetes Care 2012;35:2464 19:228–238 CD005613 2471 49. Levin PA, Nguyen H, Wittbrodt ET, Kim SC. 63. Monami M, Marchionni N, Mannucci E. 75. Lipska KJ, Parker MM, Moffet HH, Huang ES, Glucagon-like peptide-1 receptor agonists: a sys- Long-acting insulin analogues versus NPH human Karter AJ. Association of initiation of basal insulin tematic review of comparative effectiveness insulin in type 2 diabetes: a meta-analysis. Di- analogs vs neutral protamine Hagedorn insulin research. Diabetes Metab Syndr Obes 2017; abetes Res Clin Pract 2008;81:184–189 with hypoglycemia-related emergency department 10:123–139 64. Owens DR, Traylor L, Mullins P, Landgraf W. visits or hospital admissions and with glycemic 50. Abd El Aziz MS, Kahle M, Meier JJ, Nauck Patient-level meta-analysis of efficacy and hypo- control in patients with type 2 diabetes. JAMA MA. A meta-analysis comparing clinical effects glycaemia in people with type 2 diabetes initi- 2018;320:53–62 of short- or long-acting GLP-1 receptor agonists ating insulin glargine 100 U/mL or neutral 76. Cefalu WT, Dawes DE, Gavlak G, et al.; Insulin versus insulin treatment from head-to-head protamine Hagedorn insulin analysed according Access and Affordability Working Group. Insu- studies in type 2 diabetic patients. Diabetes to concomitant oral antidiabetes therapy. Di- lin Access and Affordability Working Group: Obes Metab 2017;19:216–227 abetes Res Clin Pract 2017;124(Suppl. C):57–65 conclusions and recommendations. Diabetes 51. Institute for Clinical and Economic Review. 65. Riddle MC, Rosenstock J, Gerich J; Insulin Care 2018;41:1299–1311 Controversies in the management of patients Glargine 4002 Study Investigators. The treat-to- 77. Lipska KJ, Hirsch IB, Riddle MC. Human with type 2 diabetes [Internet], December 2014. target trial: randomized addition of glargine or insulin for type 2 diabetes: an effective, less- Available from https://icer-review.org/wp-content/ human NPH insulin to oral therapy of type 2 diabetic expensive option. JAMA 2017;318:23–24 uploads/2015/03/CEPAC-T2D-Final-Report- patients. Diabetes Care 2003;26:3080–3086 78. Mannucci E, Monami M, Marchionni N. December-22.pdf. Accessed 9 November 2018 66. Hermansen K, Davies M, Derezinski T, Martinez Short-acting insulin analogues vs. regular human 52. Truven Health Analytics. Micromedex 2.0 Ravn G, Clauson P, Home P. A 26-week, randomized, insulin in type 2 diabetes: a meta-analysis. Di- Introduction to RED BOOK Online [Internet], 2018. parallel, treat-to-target trial comparing insulin abetes Obes Metab 2009;11:53–59 Available from http://www.micromedexsolutions detemir with NPH insulin as add-on therapy 79. Heller S, Bode B, Kozlovski P, Svendsen AL. .com/micromedex2/4.34.0/WebHelp/RED_BOOK/ to oral glucose-lowering drugs in insulin-naive Meta-analysis of insulin aspart versus regular Introduction_to_REDB_BOOK_Online.htm. Ac- people with type 2 diabetes. Diabetes Care human insulin used in a basal-bolus regimen for cessed 5 September 2018 2006;29:1269–1274 the treatment of diabetes mellitus. J Diabetes 53. Centers for Medicare & Medicaid Services. 67. Yki-Jarvinen¨ H, Kauppinen-Makelin¨ R, 2013;5:482–491 NADAC (national average drug acquisition cost), Tiikkainen M, et al. Insulin glargine or NPH 80. Riddle MC, Yki-Jarvinen¨ H, Bolli GB, et al. drug pricing and payment [Internet], 2018. Avail- combined with metformin in type 2 diabetes: the One-year sustained glycaemic control and less able from https://data.medicaid.gov/Drug-Pricing- LANMET study. Diabetologia 2006;49:442–451 hypoglycaemia with new insulin glargine 300 and-Payment/NADAC-National-Average-Drug- 68. Bolli GB, Riddle MC, Bergenstal RM, et al.; U/ml compared with 100 U/ml in people with Acquisition-Cost-/a4y5-998d. Accessed 5 September EDITION 3 study investigators. New insulin glar- type 2 diabetes using basal plus meal-time 2018 gine 300 U/ml compared with glargine 100 U/ml insulin: the EDITION 1 12-month randomized 54. ZinmanB, WannerC,LachinJM, et al.; EMPA- in insulin-na¨ıve people with type 2 diabetes on trial, including 6-month extension. Diabetes REG OUTCOME Investigators. Empagliflozin, oral glucose-lowering drugs: a randomized Obes Metab 2015;17:835–842 S102 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 42, Supplement 1, January 2019

81. Yki-Jarvinen¨ H, Bergenstal R, Ziemen M, dailyinjections:the STATstudy.DiabetesTechnol 85. Maiorino MI, Chiodini P, Bellastella G, et al.; EDITION 2 Study Investigators. New insulin Ther 2018;20:639–647 Capuano A, Esposito K, Giugliano D. Insulin and glargine 300 units/mL versus glargine 100 units/ 83. Diamant M, Nauck MA, Shaginian R, et al.; 4B glucagon-like peptide 1 receptor agonist combi- mL in people with type 2 diabetes using oral Study Group. Glucagon-like peptide 1 receptor nation therapy in type 2 diabetes: a systematic agents and basal insulin: glucose control and agonist or bolus insulin with optimized basal review and meta-analysis of randomized con- hypoglycemia in a 6-month randomized con- insulin in type 2 diabetes. Diabetes Care 2014;37: trolled trials. Diabetes Care 2017;40:614–624 trolled trial (EDITION 2). Diabetes Care 2014; 2763–2773 86. Rodbard HW, Visco VE, Andersen H, Hiort LC, 37:3235–3243 84. Eng C, Kramer CK, Zinman B, Retnakaran R. Shu DHW. Treatment intensiﬁcation with step- 82. Akturk HK, Snell-Bergeon JK, Rewers A, et al. Glucagon-like peptide-1 receptor agonist and wise addition of prandial insulin aspart boluses Improved postprandial glucose with inhaled basal insulin combination treatment for the man- compared with full basal-bolus therapy (FullSTEP technosphere insulin compared with insulin as- agement of type 2 diabetes: a systematic review Study): a randomised, treat-to-target clinical part in patients with type 1 diabetes on multiple and meta-analysis. Lancet 2014;384:2228–2234 trial. Lancet Diabetes Endocrinol 2014;2:30–37 Diabetes Care Volume 42, Supplement 1, January 2019 S103

10. Cardiovascular Disease and American Diabetes Association Risk Management: Standards of Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S103–S123 | https://doi.org/10.2337/dc19S010 0 ADOACLRDSAEADRS MANAGEMENT RISK AND DISEASE CARDIOVASCULAR 10. The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

For prevention and management of diabetes complications in children and adolescents, please refer to Section 13 “Children and Adolescents.” Atherosclerotic cardiovascular disease (ASCVD)ddefined as coronary heart disease, cerebrovascular disease, or peripheral arterial disease presumed to be of atherosclerotic origindis the leading cause of morbidity and mortality for individuals with diabetes and results in an estimated $37.3 billion in cardiovascular-related spending per year associated with diabetes (1). Common conditions coexisting with type 2 diabetes (e.g., hypertension and dyslipidemia) are clear risk factors for ASCVD, and diabetes itself confers independent risk. Numerous studies have shown the efficacy of controlling individual cardiovascular risk factors in preventing or slowing ASCVD in people with diabetes. Furthermore, large benefits are seen when multiple cardiovascular risk factors are addressed simultaneously. Under the current paradigm of aggressive risk factor modification in patients with diabetes, there is evidence that measures of 10-year coronary heart disease (CHD) risk among U.S. adults with diabetes have improved significantly over the past decade (2) and that ASCVD morbidity and mortality have decreased (3,4). Heart failure is another major cause of morbidity and mortality from cardiovascular disease. Recent studies have found that rates of incident heart failure hospitalization (adjusted for age and sex) were twofold higher in patients with diabetes compared This section has received endorsement from the American College of Cardiology. with those without (5,6). People with diabetes may have heart failure with preserved Suggested citation: American Diabetes Asso- ejection fraction (HFpEF) or with reduced ejection fraction (HFrEF). Hypertension ciation. 10. Cardiovascular disease and risk is often a precursor of heart failure of either type, and ASCVD can coexist with either management: Standards of Medical Care in type (7), whereas prior myocardial infarction (MI) is often a major factor in HFrEF. Diabetesd2019. Diabetes Care 2019;42(Suppl. 1): Rates of heart failure hospitalization have been improved in recent trials including S103–S123 patients with type 2 diabetes, most of whom also had ASCVD, with sodium– © 2018 by the American Diabetes Association. glucose cotransporter 2 (SGLT2) inhibitors (8–10). Readers may use this article as long as the work is properly cited, the use is educational and not For prevention and management of both ASCVD and heart failure, cardiovascular risk for profit, and the work is not altered. More infor- factors should be systematically assessed at least annually in all patients with diabetes. mation is available at http://www.diabetesjournals These risk factors include obesity/overweight, hypertension, dyslipidemia, smoking, a .org/content/license. S104 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

family history of premature coronary Screening and Diagnosis adverse effects of antihyper- disease, chronic kidney disease, and Recommendations tensive medications, and patient the presence of albuminuria. Modifiable 10.1 Blood pressure should be mea- preferences. C abnormal risk factors should be treated sured at every routine clinical 10.4 For individuals with diabetes as described in these guidelines. visit. Patients found to have el- and hypertension at higher car- $ The Risk Calculator evated blood pressure ( 140/ diovascular risk (existing athero- The American College of Cardiology/ 90 mmHg) should have blood sclerotic cardiovascular disease American Heart Association ASCVD risk pressure confirmed using multi- or 10-year atherosclerotic car- calculator (Risk Estimator Plus) is gen- ple readings, including measure- diovascular disease risk .15%), erally a useful tool to estimate 10-year ments on a separate day, to abloodpressuretargetof,130/ ASCVD risk (http://tools.acc.org/ASCVD- diagnose hypertension. B 80 mmHg may be appropriate, Risk-Estimator-Plus).Thesecalculatorshave 10.2 All hypertensive patients with if it can be safely attained. C diabetes as a risk factor, since diabetes diabetes should monitor their 10.5 For individuals with diabetes itself confers increased risk for ASCVD, blood pressure at home. B and hypertension at lower although it should be acknowledged that risk for cardiovascular disease these risk calculators do not account for Blood pressure should be measured by a (10-year atherosclerotic cardio- the duration of diabetes or the presence trained individual and should follow the vasculardiseaserisk,15%),treat of diabetes complications, such as albumin- guidelines established for the general to a blood pressure target of uria. Although some variability in calibra- population: measurement in the seated ,140/90 mmHg. A fl tion exists in various subgroups, including position, with feet on the oor and arm 10.6 In pregnant patients with dia- by sex, race, and diabetes, the overall risk supported at heart level, after 5 min of betes and preexisting hyper- prediction does not differ in those with rest. Cuff size should be appropriate for tension who are treated with or without diabetes (11–14), validating the upper-arm circumference. Elevated antihypertensive therapy, blood fi the use of risk calculators in people with values should be con rmed on a separate pressure targetsof 120–160/80– diabetes. The 10-year risk of a first ASCVD day. Postural changes in blood pressure 105 mmHg are suggested in the event should be assessed to better stratify and pulse may be evidence of autonomic interest of optimizing long-term ASCVD risk and help guide therapy, as neuropathy and therefore require ad- maternal health and minimiz- described below. justment of blood pressure targets. Or- ing impaired fetal growth. E Recently, risk scores and other cardio- thostatic blood pressure measurements vascular biomarkers have been devel- should be checked on initial visit and as Randomized clinical trials have demon- oped for risk stratification of secondary indicated. strated unequivocally that treatment prevention patients (i.e., those who are Home blood pressure self-monitoring of hypertension to blood pressure already high risk because they have and 24-h ambulatory blood pressure ,140/90 mmHg reduces cardiovascular ASCVD) but are not yet in widespread monitoring may provide evidence of events as well as microvascular compli- use (15,16). With newer, more expensive white coat hypertension, masked hyper- cations (21–27). Therefore, patients with lipid-lowering therapies now available, tension, or other discrepancies between type 1 or type 2 diabetes who have fi “ ” use of these risk assessments may help of ce and true blood pressure (17). In hypertension should, at a minimum, fi target these new therapies to “higher addition to con rming or refuting a di- be treated to blood pressure targets risk” ASCVD patients in the future. agnosis of hypertension, home blood of ,140/90 mmHg. The benefits and pressure assessment may be useful to risks of intensifying antihypertensive monitor antihypertensive treatment. therapy to target blood pressures lower HYPERTENSION/BLOOD PRESSURE Studies of individuals without diabetes , , CONTROL than 140/90 mmHg (e.g., 130/80 or found that home measurements may ,120/80 mmHg) have been evaluated in Hypertension, defined as a sustained better correlate with ASCVD risk than large randomized clinical trials and meta- blood pressure $140/90 mmHg, is com- office measurements (18,19). Moreover, analyses of clinical trials. Notably, there mon among patients with either type 1 home blood pressure monitoring may is an absence of high-quality data avail- or type 2 diabetes. Hypertension is a improve patient medication adherence able to guide blood pressure targets in major risk factor for both ASCVD and and thus help reduce cardiovascular type 1 diabetes. microvascular complications. Moreover, risk (20). numerous studies have shown that an- Randomized Controlled Trials of Intensive tihypertensive therapy reduces ASCVD Versus Standard Blood Pressure Control events, heart failure, and microvascular Treatment Goals The Action to Control Cardiovascular Risk complications. Please refer to the Amer- in Diabetes blood pressure (ACCORD BP) Recommendations ican Diabetes Association (ADA) position trial provides the strongest direct assess- 10.3 For patients with diabetes and statement “Diabetes and Hypertension” ment of the benefits and risks of intensive hypertension, blood pressure for a detailed review of the epidemiol- blood pressure control among people targets should be individual- ogy, diagnosis, and treatment of hyper- with type 2 diabetes (28). In ACCORD ized through a shared decision- tension (17). The recommendations BP, compared with standard blood pres- making process that addresses presented here reflect ADA’s updated sure control (target systolic blood pres- cardiovascular risk, potential stance on blood pressure. sure ,140 mmHg), intensive blood care.diabetesjournals.org Cardiovascular Disease and Risk Management S105

Table 10.1—Randomized controlled trials of intensive versus standard hypertension treatment strategies Clinical trial Population Intensive Standard Outcomes ACCORD BP 4,733 participants with T2D Systolic blood pressure Systolic blood pressure target: c No benefit in primary end (28) aged 40–79 years with target: ,120 mmHg 130–140 mmHg point: composite of nonfatal prior evidence of CVD or Achieved (mean) systolic/ Achieved (mean) systolic/ MI, nonfatal stroke, and CVD multiple cardiovascular diastolic: 119.3/64.4 mmHg diastolic: 133.5/70.5 mmHg death risk factors c Stroke risk reduced 41% with intensive control, not sustained through follow-up beyond the period of active treatment c Adverse events more common in intensive group, particularly elevated serum creatinine and electrolyte abnormalities ADVANCE BP 11,140 participants with T2D Intervention: a single-pill, fixed- Control: placebo c Intervention reduced risk (29) aged 55 years and older dose combination of Achieved (mean) systolic/ of primary composite withpriorevidenceofCVD perindopril and indapamide diastolic: 141.6/75.2 mmHg end point of major or multiple cardiovascular Achieved (mean) systolic/ macrovascular and risk factors diastolic: 136/73 mmHg microvascular events (9%), death from any cause (14%), and death from CVD (18%) c 6-year observational follow-up found reduction in risk of death in intervention group attenuated but still significant (174) HOT (173) 18,790 participants, Diastolic blood pressure Diastolic blood pressure c In the overall trial, there was including 1,501 with target: #80 mmHg target: #90 mmHg no cardiovascular benefit diabetes with more intensive targets c In the subpopulation with diabetes, an intensive diastolic target was associated with a significantly reduced risk (51%) of CVD events SPRINT (39) 9,361 participants without Systolic blood pressure Systolic blood pressure c Intensive systolic blood diabetes target: ,120 mmHg target: ,140 mmHg pressure target lowered risk Achieved (mean): 121.4 mmHg Achieved (mean): 136.2 mmHg of the primary composite outcome 25% (MI, ACS, stroke, HF, and death due to CVD) c Intensive target reduced risk of death 27% c Intensive therapy increased risks of electrolyte abnormalities and AKI ACS, acute coronary syndrome; AKI, acute kidney injury; CVD, cardiovascular disease; HF, heart failure; MI, myocardial infarction; T2D, type 2 diabetes. Data from this table can also be found in the ADA position statement “Diabetes and Hypertension” (17).

pressure control (target systolic blood beneﬁt and have been educated about Diamicron MR Controlled Evaluation– pressure ,120 mmHg) did not reduce added treatment burden, side effects, Blood Pressure (ADVANCE BP) trial did total major atherosclerotic cardiovascu- and costs, as discussed below. not explicitly test blood pressure targets lar events but did reduce the risk of Additional studies, such as the Sys- (29); the achieved blood pressure in the stroke, at the expense of increased ad- tolic Blood Pressure Intervention Trial intervention group was higher than verse events (Table 10.1). The ACCORD BP (SPRINT) and the Hypertension Optimal that achieved in the ACCORD BP in- results suggest that blood pressure tar- Treatment (HOT) trial, also examined tensive arm and would be consistent gets more intensive than ,140/90 mmHg effects of intensive versus standard con- with a target blood pressure of ,140/ are not likely to improve cardiovascular trol (Table 10.1), though the relevance 90 mmHg. Notably, ACCORD BP and outcomes among most people with of their results to people with diabetes SPRINT measured blood pressure using type 2 diabetes but may be reasonable is less clear. The Action in Diabetes automated ofﬁce blood pressure measure- for patients who may derive the most and Vascular Disease: Preterax and ment,whichyieldsvaluesthataregenerally S106 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

lower than typical office blood pressure provider judgment (35). Secondary ana- all pregnant women. The American Col- readings by approximately 5–10 mmHg lyses of ACCORD BP and SPRINT suggest lege of Obstetricians and Gynecologists (30), suggesting that implementing the that clinical factors can help determine (ACOG) has recommended that women ACCORD BP or SPRINT protocols in an individuals more likely to benefit and less with mild to moderate gestational hyper- outpatient clinic might require a sys- likely to be harmed by intensive blood tension (systolic blood pressure ,160 tolic blood pressure target higher than pressure control (36). mmHg or diastolic blood pressure ,110 ,120 mmHg, such as ,130 mmHg. Absolute benefit from blood pressure mmHg) do not need to be treated with A number of post hoc analyses have reduction correlated with absolute base- antihypertensive medications as there is attempted to explain the apparently di- line cardiovascular risk in SPRINT and in no benefitidentified that clearly outweighs vergent results of ACCORD BP and SPRINT. earlier clinical trials conducted at higher potential risks of therapy (42). A 2014 Co- Some investigators have argued that the baseline blood pressure levels (11,37). chrane systematic review of antihyperten- divergent results are not due to differ- Extrapolation of these studies suggests sive therapy for mild to moderate chronic ences between people with and without that patients with diabetes may also be hypertension that included 49 trials and diabetes but rather are due to differ- more likely to benefitfromintensive over 4,700 women did not find any con- ences in study design or to characteristics blood pressure control when they have clusive evidence for or against blood pres- other than diabetes (31–33). Others have high absolute cardiovascular risk. There- sure treatment to reduce the risk of opined that the divergent results are most fore, it may be reasonable to target blood preeclampsia for the mother or effects readily explained by the lack of benefitof pressure ,130/80 mmHg among patients on perinatal outcomes such as preterm intensive blood pressure control on cardio- with diabetes and either clinically diag- birth, small-for-gestational-age infants, vascular mortality in ACCORD BP, which nosed cardiovascular disease (particularly or fetal death (43). For pregnant women may be due to differential mechanisms stroke, which was significantly reduced in who require antihypertensive therapy, underlying cardiovascular disease in type ACCORD BP) or10-year ASCVD risk $15%, systolic blood pressure levels of 120– 2 diabetes, to chance, or both (34). if it can be attained safely. This approach 160 mmHg and diastolic blood pressure is consistent with guidelines from the levels of 80–105 mmHg are suggested to Meta-analyses of Trials American College of Cardiology/American optimize maternal health without risking To clarify optimal blood pressure targets Heart Association, which advocate a fetal harm. Lower targets (systolic blood in patients with diabetes, meta-analyses blood pressure target ,130/80 mmHg pressure 110–119 mmHg and diastolic have stratified clinical trials by mean for all patients, with or without diabe- blood pressure 65–79 mmHg) may con- baseline blood pressure or mean blood tes (38). tribute to improved long-term mater- pressure attained in the intervention Potential adverse effects of antihyper- nal health; however, they may be (or intensive treatment) arm. Based on tensive therapy (e.g., hypotension, syn- associated with impaired fetal growth. these analyses, antihypertensive treatment cope, falls, acute kidney injury, and Pregnant women with hypertension and appears to be beneficial when mean electrolyte abnormalities) should also be evidence of end-organ damage from car- baseline blood pressure is $140/90 taken into account (28,39–41). Patients diovascular and/or renal disease may be mmHg or mean attained intensive with older age, chronic kidney disease, considered for lower blood pressure tar- blood pressure is $130/80 mmHg and frailty have been shown to be at gets to avoid progression of these con- (17,21,22,24–26). Among trials with higher risk of adverse effects of intensive ditions during pregnancy. lower baseline or attained blood pres- blood pressure control (41). In addition, During pregnancy, treatment with sure, antihypertensive treatment re- patients with orthostatic hypotension, ACE inhibitors, angiotensin receptor duced the risk of stroke, retinopathy, substantial comorbidity, functional limi- blockers (ARBs), and spironolactone and albuminuria, but effects on other tations, or polypharmacy may be at high are contraindicated as they may cause ASCVD outcomes and heart failure risk of adverse effects, and some patients fetal damage. Antihypertensive drugs were not evident. Taken together, these may prefer higher blood pressure targets known to be effective and safe in preg- meta-analyses consistently show that to enhance quality of life. Patients with nancy include methyldopa, labetalol, and treating patients with baseline blood low absolute cardiovascular risk (10-year long-acting nifedipine, while hydralzine pressure $140 mmHg to targets ,140 ASCVD risk ,15%) or with a history of may be considered in the acute manage- mmHg is beneficial, while more inten- adverse effects of intensive blood pres- ment of hypertension in pregnancy or sive targets may offer additional (though sure control or at high risk of such adverse severe preeclampsia (42). Diuretics are probably less robust) benefits. effects should have a higher blood pres- not recommended for blood pressure sure target. In such patients, a blood control in pregnancy but may be used Individualization of Treatment Targets pressure target of ,140/90 mmHg is during late-stage pregnancy if needed for Patients and clinicians should engage in recommended, if it can be safely attained. volume control (42,44). ACOG also recom- a shared decision-making process to mends that postpartum patients with ges- determine individual blood pressure tar- Pregnancy and Antihypertensive Medications tational hypertension, preeclampsia, and gets (17). This approach acknowledges Since there is a lack of randomized con- superimposed preeclampsia have their that the benefits and risks of intensive trolled trials of antihypertensive therapy blood pressures observed for 72 h in blood pressure targets are uncertain and in pregnant women with diabetes, rec- the hospital and for 7–10 days postpartum. may vary across patients and is consis- ommendations for the management of Long-term follow-up is recommended for tent with a patient-focused approach to hypertension in pregnant women with these women as they have increased life- care that values patient priorities and diabetes should be similar to those for time cardiovascular risk (45). See Section care.diabetesjournals.org Cardiovascular Disease and Risk Management S107

14 “ManagementofDiabetesinPregnancy” (48–50). Single-pill antihypertensive com- to lifestyle therapy, have for additional information. binations may improve medication adher- prompt initiation and timely ence in some patients (51). titration of two drugs or a Treatment Strategies single-pill combination of drugs Classes of Antihypertensive Medications. Ini- Lifestyle Intervention demonstrated to reduce car- tial treatment for hypertension should Recommendations diovascular events in patients include any of the drug classes demon- 10.7 For patients with blood pres- with diabetes. A stratedtoreducecardiovasculareventsin sure .120/80 mmHg, lifestyle 10.10 Treatment for hypertension patients with diabetes: ACE inhibitors intervention consists of weight should include drug classes (52,53), ARBs (52,53), thiazide-like di- loss if overweight or obese, a demonstrated to reduce car- uretics (54), or dihydropyridine calcium Dietary Approaches to Stop Hy- diovascular events in patients channel blockers (55). For patients with pertension (DASH)-style dietary with diabetes (ACE inhibitors, albuminuria (urine albumin-to-creatinine pattern including reducing so- angiotensin receptor blockers, ratio $30 mg/g), initial treatment should dium and increasing potassium thiazide-like diuretics, or dihy- include an ACE inhibitor or ARB in order to intake, moderation of alcohol in- dropyridine calcium channel reduce the risk of progressive kidney take, and increased physical ac- blockers). A disease (17) (Fig. 10.1). In the absence of tivity. B 10.11 Multiple-drug therapy is gen- albuminuria, risk of progressive kidney erally required to achieve disease is low, and ACE inhibitors and Lifestyle management is an important blood pressure targets. How- ARBs have not been found to afford su- component of hypertension treatment ever, combinations of ACE perior cardioprotection when compared because it lowers blood pressure, en- inhibitors and angiotensin re- with thiazide-like diuretics or dihydro- hances the effectiveness of some anti- ceptor blockers and combina- pyridine calcium channel blockers (56). hypertensive medications, promotes tions of ACE inhibitors or b-Blockers may be used for the treat- other aspects of metabolic and vascular angiotensin receptor blockers ment of prior MI, active angina, or heart health, and generally leads to few adverse with direct renin inhibitors failure but have not been shown to re- effects. Lifestyle therapy consists of re- should not be used. A duce mortality as blood pressure-lowering ducing excess body weight through calo- 10.12 An ACE inhibitor or angioten- agents in the absence of these conditions ric restriction, restricting sodium intake sin receptor blocker, at the (23,57). (,2,300 mg/day), increasing consump- maximum tolerated dose in- tion of fruits and vegetables (8–10 serv- dicated for blood pressure Multiple-Drug Therapy. Multiple-drug ther- ings per day) and low-fat dairy products treatment, is the recommen- apy is often required to achieve blood (2–3 servings per day), avoiding excessive ded first-line treatment for hy- pressure targets (Fig. 10.1), particularly alcohol consumption (no more than pertension in patients with in the setting of diabetic kidney disease. 2 servings per day in men and no more diabetes and urinary albumin- However, the use of both ACE inhibitors than 1 serving per day in women) (46), to-creatinine ratio $300 mg/g and ARBs in combination, or the combi- and increasing activity levels (47). creatinine A or 30–299 mg/g nation of an ACE inhibitor or ARB and a These lifestyle interventions are reason- creatinine. B If one class is not directrenininhibitor,isnotrecommended able for individuals with diabetes and tolerated, the other should be given the lack of added ASCVD benefitand mildly elevated blood pressure (systolic substituted. B increased rate of adverse eventsdnamely, .120 mmHg or diastolic .80 mmHg) 10.13 For patients treated with an hyperkalemia, syncope, and acute kidney and should be initiated along with phar- ACE inhibitor, angiotensin injury (AKI) (58–60). Titration of and/or macologic therapy when hypertension is receptor blocker, or diuretic, addition of further blood pressure medi- diagnosed (Fig. 10.1) (47). A lifestyle ther- serum creatinine/estimated cations should be made in a timely fashion apy plan should be developed in collabo- glomerular filtration rate and to overcome clinical inertia in achieving ration with the patient and discussed as serum potassium levels should blood pressure targets. part of diabetes management. be monitored at least annu- Bedtime Dosing. Growing evidence sug- ally. B Pharmacologic Interventions gests that there is an association between the absence of nocturnal blood Recommendations Initial Number of Antihypertensive Medications. pressure dipping and the incidence of 10.8 fi fi Patients with con rmed of ce- Initial treatment for people with diabe- ASCVD. A meta-analysis of randomized $ based blood pressure 140/90 tes depends on the severity of hypertension clinical trials found a small benefitof mmHg should, in addition to (Fig. 10.1). Those with blood pressure be- evening versus morning dosing of antihy- lifestyle therapy, have prompt tween 140/90 mmHg and 159/99 mmHg pertensivemedicationswithregardtoblood initiation and timely titration may begin with a single drug. For patients pressure control but had no data on clinical of pharmacologic therapy to with blood pressure $160/100 mmHg, effects (61). In two subgroup analyses of a A achieve blood pressure goals. initial pharmacologic treatment with single subsequent randomized controlled 10.9 fi fi Patients with con rmed of ce- two antihypertensive medications is rec- trial, moving at least one antihypertensive $ based blood pressure 160/ ommended in order to more effectively medication to bedtime significantly re- 100 mmHg should, in addition achieve adequate blood pressure control duced cardiovascular events, but results S108 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

Figure 10.1—Recommendations for the treatment of conﬁrmed hypertension in people with diabetes. *An ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) is suggested to treat hypertension for patients with urine albumin-to-creatinine ratio 30–299 mg/g creatinine and strongly recommended for patients with urine albumin-to-creatinine ratio $300 mg/g creatinine. **Thiazide-like diuretic; long-acting agents shown to reduce cardiovascular events, such as chlorthalidone and indapamide, are preferred. ***Dihydropyridine calcium channel blocker (CCB). BP, blood pressure. Adapted from de Boer et al. (17).

were based on a small number of events diuretics can cause AKI and either hypo- cardiovascular events and death (65). (62). kalemia or hyperkalemia (depending on Therefore, serum creatinine and potas- mechanism of action) (63,64). Detection sium should be monitored during treat- Hyperkalemia and Acute Kidney Injury. Treat- and management of these abnormali- ment with an ACE inhibitor, ARB, or ment with ACE inhibitors or ARBs can ties is important because AKI and hyper- diuretic, particularly among patients cause AKI and hyperkalemia, while kalemia each increase the risks of with reduced glomerular ﬁltration who care.diabetesjournals.org Cardiovascular Disease and Risk Management S109

are at increased risk of hyperkalemia and saturated fat and trans fat; after initiation or a change in AKI (63,64,66). increaseofdietaryn-3fattyacids, dose, and annually thereafter viscous fiber, and plant stanols/ as it may help to monitor the Resistant Hypertension sterols intake; and increased response to therapy and in- Recommendation physical activity should be form medication adherence. E 10.14 Patients with hypertension recommended to improve the who are not meeting blood lipid profile and reduce the risk In adults with diabetes, it is reason- pressure targets on three clas- of developing atherosclerotic able to obtain a lipid profile (total choles- ses of antihypertensive medi- cardiovascular disease in pa- terol, LDL cholesterol, HDL cholesterol, cations (including a diuretic) tients with diabetes. A and triglycerides) at the time of diagnosis, should be considered for min- 10.16 Intensify lifestyle therapy and at the initial medical evaluation, and at eralocorticoid receptor antag- optimize glycemic control for least every 5 years thereafter in patients onist therapy. B patients with elevated triglyc- under the age of 40 years. In younger eride levels ($150 mg/dL [1.7 patients with longer duration of disease Resistant hypertension is defined as mmol/L]) and/or low HDL cho- (such as those with youth-onset type 1 , fi blood pressure $140/90 mmHg de- lesterol ( 40 mg/dL [1.0 diabetes), more frequent lipid pro les , spite a therapeutic strategy that includes mmol/L] for men, 50 mg/dL may be reasonable. A lipid panel should C appropriate lifestyle management plus [1.3 mmol/L] for women). also be obtained immediately before initiat- a diuretic and two other antihypertensive ing statin therapy. Once a patient is taking drugs belonging to different classes at Lifestyle intervention, including weight a statin, LDL cholesterol levels should be – adequate doses. Prior to diagnosing re- loss (72), increased physical activity, assessed 4 12 weeks after initiation of sistant hypertension, a number of other and medical nutrition therapy, allows statin therapy, after any change in dose, conditions should be excluded, including some patients to reduce ASCVD risk andonanindividualbasis(e.g.,to medication nonadherence, white coat factors. Nutrition intervention should monitor for medication adherence and ’ fi hypertension, and secondary hyperten- be tailored according to each patient s ef cacy). If LDL cholesterol levels are not sion. In general, barriers to medication age, diabetes type, pharmacologic responding in spite of medication adher- adherence (such as cost and side ef- treatment, lipid levels, and medical ence, clinical judgment is recommended fects) should be identified and addressed conditions. to determine the need for and timing of (Fig. 10.1). Mineralocorticoid receptor Recommendations should focus on lipid panels. In individual patients, the – antagonists are effective for manage- application of a Mediterranean diet highly variable LDL cholesterol lowering ment of resistant hypertension in pa- (73) or Dietary Approaches to Stop Hy- response seen with statins is poorly tients with type 2 diabetes when added pertension (DASH) dietary pattern, re- understood (75). Clinicians should at- fi to existing treatment with an ACE inhib- ducing saturated and trans fat intake tempt to nd a dose or alternative statin itor or ARB, thiazide-like diuretic, and and increasing plant stanols/sterols, that is tolerable if side effects occur. fi fi dihydropyridine calcium channel blocker n-3 fatty acids, and viscous ber There is evidence for bene tfromeven (67). Mineralocorticoid receptor antag- (such as in oats, legumes, and citrus) extremely low, less than daily statin onists also reduce albuminuria and intake (74). Glycemic control may also doses (76). fi have additional cardiovascular benefits bene cially modify plasma lipid levels, – particularly in patients with very high (68 71). However, adding a mineralo- Statin Treatment corticoidreceptorantagonisttoa regimen triglycerides and poor glycemic control. “ ” including an ACE inhibitor or ARB may See Section 5 Lifestyle Management Recommendations 10.19 increase the risk for hyperkalemia, em- for additional nutrition information. For patients of all ages with phasizing the importance of regular mon- diabetes and atherosclerotic cardiovascular disease or 10- itoring for serum creatinine and potassium Ongoing Therapy and Monitoring in these patients, and long-term outcome year atherosclerotic cardio- With Lipid Panel . studies are needed to better evaluate the vascular disease risk 20%, role of mineralocorticoid receptor antag- Recommendations high-intensity statin therapy 10.17 onists in blood pressure management. In adults not taking statins or should be added to lifestyle other lipid-lowering therapy, therapy. A LIPID MANAGEMENT it is reasonable to obtain a lipid 10.20 For patients with diabetes aged profile at the time of diabetes ,40 years with additional Lifestyle Intervention diagnosis, at an initial medical atherosclerotic cardiovascu- Recommendations evaluation, and every 5 years lar disease risk factors, the 10.15 Lifestyle modification focusing thereafter if under the age of patient and provider should on weight loss (if indicated); 40 years, or more frequently if consider using moderate- application of a Mediterranean indicated. E intensity statin in addition to diet or Dietary Approaches to 10.18 Obtain a lipid profile at initia- lifestyle therapy. C Stop Hypertension (DASH) dition of statins or other lipid- 10.21 For patients with diabetes etary pattern; reduction of lowering therapy, 4–12 weeks aged 40–75 years A and S110 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

demonstrated the beneficial effects of As in those without diabetes, absolute .75 years B without athero- statin therapy on ASCVD outcomes in reductions in ASCVD outcomes (CHD sclerotic cardiovascular dis- subjects with and without CHD (77,78). death and nonfatal MI) are greatest in ease, use moderate-intensity Subgroup analyses of patients with di- people with high baseline ASCVD risk statin in addition to lifestyle abetes in larger trials (79–83) and trials in (known ASCVD and/or very high LDL therapy. patients with diabetes (84,85) showed cholesterol levels), but the overall bene- 10.22 In patients with diabetes who significant primary and secondary pre- fits of statin therapy in people with di- have multiple atherosclerotic vention of ASCVD events and CHD death abetes at moderate or even low risk for cardiovascular disease risk fac- in patients with diabetes. Meta-analyses, ASCVDareconvincing(87,88).Therelative tors, it is reasonable to con- including data from over 18,000 patients benefit of lipid-lowering therapy has been sider high-intensity statin withdiabetesfrom14randomizedtrialsof uniform across most subgroups tested therapy. C statin therapy (mean follow-up 4.3 years), (78,86), including subgroups that varied 10.23 For patients who do not tol- demonstrate a 9% proportional reduction with respect to age and other risk factors. erate the intended intensity, in all-cause mortality and 13% reduction in the maximally tolerated sta- vascular mortality for each mmol/L (39 Primary Prevention (Patients Without tin dose should be used. E mg/dL) reduction in LDL cholesterol (86). ASCVD) 10.24 For patients with diabetes and For primary prevention, moderate-dose Accordingly, statins are the drugs of atherosclerotic cardiovascular statin therapy is recommended for those choice for LDL cholesterol lowering and disease, if LDL cholesterol is 40 years and older (80,87,88), though cardioprotection. Table 10.2 shows rec- $70 mg/dL on maximally tol- high-intensity therapy may be consid- ommended lipid-lowering strategies, erated statin dose, consider add- ered on an individual basis in the context and Table 10.3 shows the two statin ing additional LDL-lowering of additional ASCVD risk factors. The dosing intensities that are recommended therapy (such as ezetimibe or evidence is strong for patients with di- for use in clinical practice: high-intensity PCSK9 inhibitor). A Ezetimibe abetes aged 40–75 years, an age-group statin therapy will achieve approximately may be preferred due to lower well represented in statin trials showing a 50% reduction in LDL cholesterol, and cost. benefit. Since risk is enhanced in patients moderate-intensity statin regimens 10.25 Statin therapy is contraindi- with diabetes, as noted above, patients achieve 30–50% reductions in LDL cho- cated in pregnancy. B who also have multiple other coronary lesterol. Low-dose statin therapy is gen- risk factors have increased risk, equiva- erally not recommended in patients with lent to that of those with ASCVD. As such, Initiating Statin Therapy Based on Risk diabetes but is sometimes the only dose recent guidelines recommend that in pa- Patients with type 2 diabetes have an of statin that a patient can tolerate. For tients with diabetes who have multiple increased prevalence of lipid abnormal- patients who do not tolerate the intended ASCVD risk factors, it is reasonable to ities, contributing to their high risk of intensityofstatin,themaximallytolerated prescribe high-intensity statin therapy ASCVD. Multiple clinical trials have statin dose should be used. (12,89). Furthermore, for patients with diabetes whose ASCVD risk is .20%, i.e., Table 10.2—Recommendations for statin and combination treatment in adults an ASCVD risk equivalent, the same high- with diabetes intensity statin therapy is recommended ASCVD or asforthosewithdocumentedASCVD(12). 10-year ASCVD Recommended statin intensity^ and combination The evidence is lower for patients . Age risk 20% treatment* aged .75 years; relatively few older ,40 years No None† patients with diabetes have been en- Yes High rolled in primary prevention trials. How- $ c In patients with ASCVD, if LDL cholesterol 70 ever, heterogeneity by age has not been mg/dL despite maximally tolerated statin dose, fi consider adding additional LDL-lowering therapy seen in the relative bene t of lipid- (such as ezetimibe or PCSK9 inhibitor)# lowering therapy in trials that included $40 years No Moderate‡ older participants (78,85,86), and be- Yes High cause older age confers higher risk, the c In patients with ASCVD, if LDL cholesterol $70 absolute benefits are actually greater mg/dL despite maximally tolerated statin dose, (78,90).Moderate-intensitystatintherapy consider adding additional LDL-lowering therapy is recommended in patients with diabetes (such as ezetimibe or PCSK9 inhibitor) that are 75 years or older. However, the ASCVD, atherosclerotic cardiovascular disease; PCSK9, proprotein convertase subtilisin/kexin type risk-benefitprofile should be routinely 9. *In addition to lifestyle therapy. ^For patients who do not tolerate the intended intensity of evaluated in this population, with down- statin, the maximally tolerated statin dose should be used. †Moderate-intensity statin may be considered based on risk-benefit profile and presence of ASCVD risk factors. ASCVD risk factors ward titration of dose performed as include LDL cholesterol $100 mg/dL (2.6 mmol/L), high blood pressure, smoking, chronic kidney needed. See Section 12 “Older Adults” for disease, albuminuria, and family history of premature ASCVD. ‡High-intensity statin may be more details on clinical considerations fi fi , considered based on risk-bene t pro le and presence of ASCVD risk factors. #Adults aged 40 for this population. years with prevalent ASCVD were not well represented in clinical trials of non-statin–based LDL reduction. Before initiating combination lipid-lowering therapy, consider the potential for Age < 40 Years and/or Type 1 Diabetes. Very further ASCVD risk reduction, drug-specific adverse effects, and patient preferences. little clinical trial evidence exists for care.diabetesjournals.org Cardiovascular Disease and Risk Management S111

Table 10.3—High-intensity and moderate-intensity statin therapy* diabetes (27% of participants), the com- High-intensity statin therapy Moderate-intensity statin therapy bination of moderate-intensity simvas- (lowers LDL cholesterol by $50%) (lowers LDL cholesterol by 30–50%) tatin (40 mg) and ezetimibe (10 mg) showed a signiﬁcant reduction of major Atorvastatin 40–80 mg Atorvastatin 10–20 mg Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg adverse cardiovascular events with an Simvastatin 20–40 mg absolute risk reduction of 5% (40% vs. Pravastatin 40–80 mg 45% cumulative incidence at 7 years) Lovastatin 40 mg and relative risk reduction of 14% (hazard Fluvastatin XL 80 mg ratio [HR] 0.86 [95% CI 0.78–0.94]) over Pitavastatin 2–4mg moderate-intensity simvastatin (40 mg) *Once-daily dosing. XL, extended release. alone (94).

Statins and PCSK9 Inhibitors patients with type 2 diabetes under the events with more intensive therapy, in Placebo-controlled trials evaluating the ageof40yearsorforpatientswithtype patients with and without diabetes addition of the PCSK9 inhibitors evolo- 1 diabetes of any age. For pediatric rec- (78,82,92). cumab and alirocumab to maximally “ ommendations, see Section 13 Children Over the past few years, there have tolerated doses of statin therapy in par- ” and Adolescents. In the Heart Protection been multiple large randomized trials ticipants who were at high risk for ASCVD fi Study (lower age limit 40 years), the sub- investigating the bene ts of adding non- demonstrated an average reduction in ; group of 600 patients with type 1 diabetes statin agents to statin therapy, including LDL cholesterol ranging from 36% to had a proportionately similar, although not those that evaluated further lowering 59%. These agents have been approved fi statistically signi cant, reduction in risk as of LDL cholesterol with ezetimibe (90,94) as adjunctive therapy for patients with patients with type 2 diabetes (80). Even and proprotein convertase subtilisin/ ASCVD or familial hypercholesterolemia fi though the data are not de nitive, similar kexin type 9 (PCSK9) inhibitors (93). who are receiving maximally tolerated fi fi statin treatment approaches should be Each trial found a signi cant bene tin statin therapy but require additional considered for patients with type 1 or the reduction of ASCVD events that was lowering of LDL cholesterol (95,96). type 2 diabetes, particularly in the presence directly related to the degree of further The effects of PCSK9 inhibition on of other cardiovascular risk factors. Patients LDL cholesterol lowering. These large ASCVD outcomes was investigated in fi below the age of 40 have lower risk of trials included a signi cant number of the Further Cardiovascular Outcomes developing a cardiovascular event over a participants with diabetes. For patients Research With PCSK9 Inhibition in Sub- 10-year horizon; however, their lifetime risk with ASCVD who are on high-intensity jects With Elevated Risk (FOURIER) trial, of developing cardiovascular disease and (and maximally tolerated) statin therapy which enrolled 27,564 patients with prior $ suffering an MI, stroke, or cardiovascular and have an LDL cholesterol 70 mg/dL, ASCVD and an additional high-risk feature death is high. For patients under the age of the addition of nonstatin LDL-lowering who were receiving their maximally tol- 40 years and/or who have type 1 diabetes therapy is recommended following a erated statin therapy (two-thirds were on with other ASCVD risk factors, we recom- clinician-patient discussion about the high-intensity statin) but who still had an fi Table mend that the patient and health care net bene t, safety, and cost ( LDL cholesterol $70 mg/dL or a non-HDL fi 10.2 provider discuss the relative bene ts and ). cholesterol $100 mg/dL (93). Patients risks and consider the use of moderate- were randomized to receive subcutane- intensity statin therapy. Please refer to Combination Therapy for LDL ous injections of evolocumab (either “ Type 1 Diabetes Mellitus and Cardiovas- Cholesterol Lowering 140 mg every 2 weeks or 420 mg every cular Disease: A ScientificStatementFrom Statins and Ezetimibe month based on patient preference) ver- the American Heart Association and Amer- The IMProved Reduction of Outcomes: sus placebo. Evolocumab reduced LDL ” ican Diabetes Association (91) for addi- Vytorin Efficacy International Trial cholesterol by 59% from a median of tional discussion. (IMPROVE-IT) was a randomized con- 92 to 30 mg/dL in the treatment arm. Secondary Prevention (Patients With trolled trial in 18,144 patients comparing During the median follow-up of 2.2 ASCVD) the addition of ezetimibe to simvastatin years, the composite outcome of car- Because risk is high in patients with therapy versus simvastatin alone. Indi- diovascular death, MI, stroke, hospitali- ASCVD, intensive therapy is indicated viduals were $50 years of age, had zation for angina, or revascularization and has been shown to be of benefitin experienced a recent acute coronary syn- occurred in 11.3% vs. 9.8% of the pla- multiple large randomized cardiovascu- drome (ACS), and were treated for an cebo and evolocumab groups, respec- lar outcomes trials (86,90,92,93). High- averageof6years.Overall,theaddition of tively, representing a 15% relative risk intensity statin therapy is recommended ezetimibe led to a 6.4% relative benefit reduction (P , 0.001). The combined for all patients with diabetes and ASCVD. and a 2% absolute reduction in major endpointofcardiovasculardeath,MI,or This recommendation is based on the adverse cardiovascular events, with the stroke was reduced by 20%, from 7.4% Cholesterol Treatment Trialists’ Collab- degree of benefit being directly propor- to 5.9% (P , 0.001). Importantly, similar oration involving 26 statin trials, of tional to the change in LDL choles- benefits were seen in prespecified sub- which 5 compared high-intensity versus terol, which was 70 mg/dL in the statin group of patients with diabetes, com- moderate-intensity statins. Together, they group on average and 54 mg/dL in the prising 11,031 patients (40% of the found reductions in nonfatal cardiovascular combination group (90). In those with trial) (97). S112 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

Treatment of Other Lipoprotein increase in ischemic stroke in those on vascular disease outcomes and Fractions or Targets combination therapy (104). isgenerallynotrecommended.A The much larger Heart Protection Recommendations 10.29 Combination therapy (statin/ Study 2–Treatment of HDL to Reduce 10.26 For patients with fasting tri- niacin) has not been shown to the Incidence of Vascular Events (HPS2- glyceride levels $500 mg/dL provide additional cardiovas- THRIVE) trial also failed to show a benefit (5.7 mmol/L), evaluate for sec- cular benefit above statin ther- of adding niacin to background statin ondary causes of hypertri- apy alone, may increase the therapy (105). A total of 25,673 patients glyceridemia and consider risk of stroke with additional with prior vascular disease were random- medical therapy to reduce sideeffects,andisgenerallynot ized to receive 2 g of extended-release theriskofpancreatitis.C recommended. A niacin and 40 mg of laropiprant (an 10.27 In adults with moderate hy- antagonist of the prostaglandin D2 re- pertriglyceridemia (fasting or Statin and Fibrate ceptor DP that has been shown to nonfasting triglycerides 175– 1 Combination therapy (statin and fibrate) improve adherence to niacin therapy) 499 mg/dL), clinicians should is associated with an increased risk for versus a matching placebo daily and address and treat lifestyle fac- abnormal transaminase levels, myositis, followed for a median follow-up period tors (obesity and meta- and rhabdomyolysis. The risk of rhabdo- of 3.9 years. There was no significant bolic syndrome), secondary myolysis is more common with higher difference in the rate of coronary death, factors (diabetes, chronic liver doses of statins and renal insufficiency MI, stroke, or coronary revascularization or kidney disease and/or ne- andappearstobehigherwhenstatinsare with the addition of niacin–laropiprant phrotic syndrome, hypothy- combined with gemfibrozil (compared versus placebo (13.2% vs. 13.7%; rate roidism), and medications that with fenofibrate) (101). ratio 0.96; P 5 0.29). Niacin–laropiprant raise triglycerides. C In the ACCORD study, in patients was associated with an increased inci- with type 2 diabetes who were at Hypertriglyceridemia should be addressed dence of new-onset diabetes (absolute high risk for ASCVD, the combination , with dietary and lifestyle changes includ- excess, 1.3 percentage points; P 0.001) of fenofibrate and simvastatin did not ing weight loss and abstinence from and disturbances in diabetes control reduce the rate of fatal cardiovascular alcohol (98). Severe hypertriglyceride- among those with diabetes. In addition, events, nonfatal MI, or nonfatal stroke mia (fasting triglycerides $500 mg/dL there was an increase in serious adverse as compared with simvastatin alone. and especially .1,000 mg/dL) may events associated with the gastrointes- Prespecified subgroup analyses sug- warrant pharmacologic therapy (fibric tinal system, musculoskeletal system, gested heterogeneity in treatment ef- acid derivatives and/or fish oil) to reduce skin, and, unexpectedly, infection and fects with possible benefitformenwith the risk of acute pancreatitis. In addition, bleeding. both a triglyceride level $204 mg/dL if 10-year ASCVD risk is $7.5%, it is Therefore, combination therapy with a (2.3mmol/L)andanHDLcholesterol reasonable to initiate moderate-intensity statin and niacin is not recommended level #34 mg/dL (0.9 mmol/L) (102). A fi statin therapy or increase statin inten- given the lack of ef cacy on major ASCVD prospective trial of a newer fibrate in sity from moderate to high. In patients outcomes and increased side effects. this specific population of patients is with moderate hypertriglyceridemia, ongoing (103). lifestyle interventions, treatment of sec- Diabetes With Statin Use ondary factors, and avoidance of medi- Several studies have reported a modestly cations that might raise triglycerides are Statin and Niacin increased risk of incident diabetes with recommended. The Atherothrombosis Intervention in statin use (106,107), which may be lim- Low levels of HDL cholesterol, often Metabolic Syndrome With Low HDL/ ited to those with diabetes risk factors. associated with elevated triglyceride lev- High Triglycerides: Impact on Global An analysis of one of the initial studies els, are the most prevalent pattern of Health Outcomes (AIM-HIGH) trial ran- suggested that although statin use was dyslipidemia in individuals with type 2 domized over 3,000 patients (about one- associated with diabetes risk, the car- diabetes. However, the evidence for the third with diabetes) with established diovascular event rate reduction with use of drugs that target these lipid frac- ASCVD, low LDL cholesterol levels statins far outweighed the risk of in- , tions is substantially less robust than ( 180 mg/dL [4.7 mmol/L]), low HDL cident diabetes even for patients at high- , that for statin therapy (99). In a large cholesterol levels (men 40 mg/dL est risk for diabetes (108). The absolute , trial in patients with diabetes, fenofibrate [1.0 mmol/L] and women 50 mg/dL risk increase was small (over 5 years of failed to reduce overall cardiovascular [1.3 mmol/L]), and triglyceride levels of follow-up, 1.2% of participants on pla- – – outcomes (100). 150 400 mg/dL (1.7 4.5 mmol/L) to cebo developed diabetes and 1.5% on statin therapy plus extended-release ni- rosuvastatin developed diabetes) (108). acin or placebo. The trial was halted early A meta-analysis of 13 randomized statin Other Combination Therapy due to lack of efficacy on the primary trials with 91,140 participants showed an ASCVD outcome (first event of the com- odds ratio of 1.09 for a new diagnosis of Recommendations posite of death from CHD, nonfatal MI, diabetes, so that (on average) treatment 10.28 Combination therapy (statin/ ischemic stroke, hospitalization for an of 255 patients with statins for 4 years fibrate) has not been shown to ACS, or symptom-driven coronary or resulted in one additional case of diabe- improve atherosclerotic cardio- cerebral revascularization) and a possible tes while simultaneously preventing 5.4 care.diabetesjournals.org Cardiovascular Disease and Risk Management S113

vascular events among those 255 patients gastrointestinal bleeding and other extra- primary prevention strategy (107). cranial bleeding. There were no significant in those with diabetes who differences by sex, weight, or duration of are at increased cardiovascu- Lipid-Lowering Agents and Cognitive diabetes or other baseline factors includ- lar risk, after a discussion with Function ing ASCVD risk score. thepatientonthebenefits Although this issue has been raised, Two other large randomized trials of versus increased risk of several lines of evidence point against aspirin for primary prevention, in pa- bleeding. C this association, as detailed in a 2018 tients without diabetes (ARRIVE [Aspirin European Atherosclerosis Society Con- to Reduce Risk of Initial Vascular Events]) sensus Panel statement (109). First, there Risk Reduction (122) and in the elderly (ASPREE [Aspirin are three large randomized trials of statin Aspirin has been shown to be effective in Reducing Events in the Elderly]) (123), versus placebo where specific cognitive in reducing cardiovascular morbidity including 11% with diabetes, found no tests were performed, and no differences and mortality in high-risk patients with benefit of aspirin on the primary efficacy were seen between statin and placebo previous MI or stroke (secondary preven- end point and an increased risk of bleed- (110–113). In addition, no change in tion) and is strongly recommended. In ing. In ARRIVE, with 12,546 patients over cognitive function has been reported primary prevention, however, among a period of 60 months follow-up, the in studies with the addition of ezetimibe patients with no previous cardiovascular primary end point occurred in 4.29% vs. (90) or PCSK9 inhibitors (93,114) to statin events, its net benefit is more contro- 4.48% of patients in the aspirin versus therapy, including among patients versial (116,117). placebo groups (HR 0.96; 95% CI 0.81– treatedtoverylowLDLcholesterol Previous randomized controlled trials 1.13; P 5 0.60). Gastrointestinal bleeding levels. In addition, the most recent sys- of aspirin specifically in patients with events (characterized as mild) occurred tematic review of the U.S. Food and diabetes failed to consistently show a in 0.97% of patients in the aspirin group Drug Administration’s (FDA’s) postmar- significant reduction in overall ASCVD vs. 0.46% in the placebo group (HR 2.11; keting surveillance databases, random- end points, raising questions about the ef- 95% CI 1.36–3.28; P 5 0.0007). In ized controlled trials, and cohort, case- ficacy of aspirin for primary prevention in ASPREE, including 19,114 persons, for control, and cross-sectional studies eval- people with diabetes, although some sex the rate of cardiovascular disease (fatal uating cognition in patients receiving sta- differences were suggested (118–120). CHD, MI, stroke, or hospitalization for tins found that published data do not The Antithrombotic Trialists’ Collabo- heart failure) after a median of 4.7 years reveal an adverse effect of statins on ration published an individual patient– of follow-up, the rates per 1,000 person- cognition (115). Therefore, a concern level meta-analysis (116) of the six large years were 10.7 vs. 11.3 events in aspi- thatstatinsorotherlipid-lowering agents trials of aspirin for primary prevention in rin vs. placebo groups (HR 0.95; 95% might cause cognitive dysfunction or the general population. These trials col- CI 0.83–1.08). The rate of major hem- dementia is not currently supported by lectively enrolled over 95,000 partic- orrhage per 1,000 person-years was evidence and should not deter their use ipants, including almost 4,000 with 8.6 events vs. 6.2 events, respec- in individuals with diabetes at high risk diabetes. Overall, they found that aspirin tively (HR 1.38; 95% CI 1.18–1.62; for ASCVD (115). reduced the risk of serious vascular P , 0.001). events by 12% (RR 0.88 [95% CI 0.82– Thus, aspirin appears to have a modest 0.94]). The largest reduction was for effect on ischemic vascular events, with ANTIPLATELET AGENTS nonfatal MI, with little effect on CHD the absolute decrease in events depend- death (RR 0.95 [95% CI 0.78–1.15]) or ing on the underlying ASCVD risk. The Recommendations total stroke. main adverse effect is an increased risk 10.30 Use aspirin therapy (75–162 Most recently, the ASCEND (A Study of of gastrointestinal bleeding. The excess mg/day) as a secondary pre- Cardiovascular Events iN Diabetes) trial risk may be as high as 5 per 1,000 per vention strategy in those with randomized 15,480 patients with diabe- year in real-world settings. However, for diabetes and a history of tes but no evident cardiovascular dis- adults with ASCVD risk .1% per year, atherosclerotic cardiovascular ease to aspirin 100 mg daily or placebo the number of ASCVD events prevented disease. A (121). The primary efficacy end point will be similar to the number of episodes 10.31 For patients with atheroscle- was vascular death, MI, or stroke or of bleeding induced, although these com- rotic cardiovascular disease transient ischemic attack. The primary plications do not have equal effects on and documented aspirin al- safety outcome was major bleeding (i.e., long-term health (124). lergy, clopidogrel (75 mg/day) intracranial hemorrhage, sight-threatening should be used. B bleeding in the eye, gastrointestinal bleed- 10.32 Dual antiplatelet therapy (with Treatment Considerations ing, or other serious bleeding). During In 2010, a position statement of the ADA, low-dose aspirin and a P2Y12 a mean follow-up of 7.4 years, there the American Heart Association, and the inhibitor) is reasonable for a was a significant 12% reduction in the American College of Cardiology Founda- year after an acute coronary primary efficacy end point (8.5% vs. 9.6%; tion recommended that low-dose (75–162 syndrome A and may have P 5 0.01). In contrast, major bleeding mg/day) aspirin for primary prevention benefits beyond this period. B was significantly increased from 3.2% to is reasonable for adults with diabetes 10.33 Aspirintherapy(75–162mg/day) 4.1% in the aspirin group (rate ratio 1.29; and no previous history of vascular dis- may be considered as a P 5 0.003), with most of the excess being ease who are at increased ASCVD risk S114 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

and who are not at increased risk for have altered function, it is unclear cardiovascular disease risk fac- bleeding (125). These recommendations what, if any, effect that finding has on tors are treated. A for using aspirin as primary prevention the required dose of aspirin for cardio- 10.35 Consider investigations for coro- include both men and women aged $50 protective effects in the patient with nary artery disease in the pres- years with diabetes and at least one diabetes. Many alternate pathways for ence of any of the following: additional major risk factor (family his- platelet activation exist that are inde- atypical cardiac symptoms (e.g., tory of premature ASCVD, hypertension, pendent of thromboxane A and thus are 2 unexplained dyspnea, chest dis- dyslipidemia, smoking, or chronic kidney not sensitive to the effects of aspirin comfort); signs or symptoms disease/albuminuria) who are not at in- (133). “Aspirin resistance” has been de- of associated vascular disease creased risk of bleeding (e.g., older age, scribed in patients with diabetes when including carotid bruits, tran- anemia, renal disease) (126–129). Non- measured by a variety of ex vivo and sient ischemic attack, stroke, invasive imaging techniques such as in vitro methods (platelet aggregometry, claudication, or peripheral ar- coronary computed tomography angiog- measurement of thromboxane B ) (134), 2 terial disease; or electrocar- raphy may potentially help further tailor but other studies suggest no impairment diogram abnormalities (e.g., aspirin therapy, particularly in those at in aspirin response among patients with Qwaves).E low risk (130), but are not generally diabetes (135). A recent trial suggested recommended. For patients over the that more frequent dosing regimens of Treatment age of 70 years (with or without diabe- aspirin may reduce platelet reactivity in 10.36 In patients with known athero- tes), the balance appears to have greater individuals with diabetes (136); how- sclerotic cardiovascular dis- fi risk than bene t (121,123). Thus, for ever, these observations alone are in- ease, consider ACE inhibitor or fi primary prevention, the use of aspirin suf cient to empirically recommend that angiotensin receptor blocker needs to be carefully considered and may higher doses of aspirin be used in this therapy to reduce the risk of generally not be recommended. Aspirin group at this time. Another recent meta- cardiovascular events. B may be considered in the context of high analysis raised the hypothesis that low- 10.37 In patients with prior myocar- fi cardiovascular risk with low bleeding risk, dose aspirin ef cacy is reduced in those dial infarction, b-blockers should but generally not in older adults. For weighing more than 70kg (137); however, be continued for at least 2 fi patients with documented ASCVD, use of the ASCEND trial found bene toflow years after the event. B aspirin for secondary prevention has far dose aspirin in those in this weight range, 10.38 In patients with type 2 dia- fi greater bene t than risk; for this indica- which would thus not validate this sug- betes with stable congestive tion, aspirin is still recommended (116). gested hypothesis (121). It appears that heart failure, metformin may – 75 162 mg/day is optimal. be used if estimated glomer- < Aspirin Use in People 50 Years of Age ular filtration rate remains Aspirin is not recommended for those Indications for P2Y12 Receptor .30 mL/min but should be at low risk of ASCVD (such as men and Antagonist Use avoided in unstable or hospi- women aged ,50 years with diabetes A P2Y12 receptor antagonist in combi- talized patients with conges- with no other major ASCVD risk factors) nation with aspirin should be used for at tive heart failure. B as the low benefit is likely to be out- least 1 year in patients following an ACS 10.39 Among patients with type 2 weighed by the risks of bleeding. Clinical and may have benefits beyond this pe- diabetes who have established judgment should be used for those at riod. Evidence supports use of either atherosclerotic cardiovascular intermediate risk (younger patients with ticagrelor or clopidogrel if no percuta- disease, sodium–glucose co- one or more risk factors or older patients neous coronary intervention was per- transporter 2 inhibitors or withnoriskfactors) untilfurther research formed and clopidogrel, ticagrelor, or glucagon-like peptide 1 recep- is available. Patients’ willingness to un- prasugrel if a percutaneous coronary tor agonists with demon- dergo long-term aspirin therapy should intervention was performed (138). In strated cardiovascular disease also be considered (131). Aspirin use in patients with diabetes and prior MI benefit(Table 9.1) are recom- patients aged ,21 years is generally (1–3 years before), adding ticagrelor mended as part of the antihy- contraindicated due to the associated to aspirin significantly reduces the risk perglycemic regimen. A risk of Reye syndrome. of recurrent ischemic events including 10.40 Among patients with athero- cardiovascular and CHD death (139). sclerotic cardiovascular dis- Aspirin Dosing ease at high risk of heart Average daily dosages used in most CARDIOVASCULAR DISEASE failure or in whom heart failure clinical trials involving patients with di- coexists, sodium–glucose co- Recommendations abetes ranged from 50 mg to 650 mg transporter 2 inhibitors are but were mostly in the range of 100–325 Screening preferred. C mg/day. There islittle evidencetosupport 10.34 In asymptomatic patients, rou- any specific dose, but using the lowest tine screening for coronary possible dose may help to reduce side artery disease is not recommen- Cardiac Testing effects (132). In the U.S., the most com- Candidates for advanced or invasive car- ded as it does not improve out- mon low-dose tablet is 81 mg. Although diac testing include those with 1) typi- comesaslongasatherosclerotic platelets from patients with diabetes cal or atypical cardiac symptoms and care.diabetesjournals.org Cardiovascular Disease and Risk Management S115

2) an abnormal resting electrocardiogram for different treatment strategies remains cardiovascular disease (see Table 10.4). (ECG). Exercise ECG testing without or unproven in asymptomatic patients with Cardiovascular outcomes trials of dipep- with echocardiography may be used diabetes, though research is ongoing. tidyl peptidase 4 (DPP-4) inhibitors have as the initial test. In adults with diabetes Although asymptomatic patients with all, so far, not shown cardiovascular $40 years of age, measurement of cor- diabetes with higher coronary disease bur- benefits relative to placebo. However, onary artery calcium is also reasonable den have more future cardiac events results from other new agents have for cardiovascular risk assessment. Phar- (144,150,151), the role of these tests provided a mix of results. macologic stress echocardiography or beyond risk stratification is not clear. The BI 10773 (Empagliflozin) Cardio- nuclear imaging should be considered While coronary artery screening meth- vascular Outcome Event Trial in Type 2 in individuals with diabetes in whom ods, such as calcium scoring, may im- Diabetes Mellitus Patients (EMPA-REG resting ECG abnormalities preclude ex- prove cardiovascular risk assessment in OUTCOME) trial was a randomized, ercise stress testing (e.g., left bundle people with type 2 diabetes (152), their double-blind trial that assessed the effect branch block or ST-T abnormalities). In routine use leads to radiation exposure of empagliflozin, an SGLT2 inhibitor, ver- addition, individuals who require stress and may result in unnecessary invasive sus placebo on cardiovascular outcomes testing and are unable to exercise should testing such as coronary angiography in 7,020 patients with type 2 diabetes undergo pharmacologic stress echocar- and revascularization procedures. The and existing cardiovascular disease. Study diography or nuclear imaging. ultimate balance of benefit, cost, and risks participants had a mean age of 63 years, of such an approach in asymptomatic 57% had diabetes for more than 10 years, Screening Asymptomatic Patients patients remains controversial, particu- and 99% had established cardiovascular The screening of asymptomatic patients larly in the modern setting of aggressive disease. EMPA-REG OUTCOME showed with high ASCVD risk is not recommended ASCVD risk factor control. that over a median follow-up of 3.1 (140), in part because these high-risk years, treatment reduced the composite patients should already be receiving in- Lifestyle and Pharmacologic outcome of MI, stroke, and cardiovascu- tensive medical therapydan approach Interventions lar death by 14% (absolute rate 10.5% vs. that provides similar benefit as invasive Intensive lifestyle intervention focusing 12.1% in the placebo group, HR in the revascularization (141,142). There is also on weight loss through decreased calo- empagliflozin group 0.86; 95% CI 0.74– some evidence that silent ischemia may ric intake and increased physical activ- 0.99; P 5 0.04 for superiority) and car- reverse over time, adding to the contro- ity as performed in the Action for Health diovascular death by 38% (absolute rate versy concerning aggressive screening in Diabetes (Look AHEAD) trial may be 3.7% vs. 5.9%, HR 0.62; 95% CI 0.49– strategies (143). In prospective studies, considered for improving glucose control, 0.77; P , 0.001) (8). The FDA added an coronary artery calcium has been estab- fitness, and some ASCVD risk factors indication for empagliflozin to reduce lished as an independent predictor of (153). Patients at increased ASCVD risk the risk of major adverse cardiovascu- future ASCVD events in patients with should receive aspirin and a statin and lar death in adults with type 2 diabetes diabetes and is consistently superior ACE inhibitor or ARB therapy if the and cardiovascular disease. to both the UK Prospective Diabetes patient has hypertension, unless there A second large cardiovascular out- Study (UKPDS) risk engine and the Fra- are contraindications to a particular drug comes trial program of an SGLT2 inhib- mingham Risk Score in predicting risk in class. While clear benefit exists for ACE itor, canagliflozin, has been reported (9). this population (144–146). However, a inhibitor or ARB therapy in patients with The Canagliflozin Cardiovascular Assess- randomized observational trial demon- diabetic kidney disease or hypertension, ment Study (CANVAS) integrated data strated no clinical benefit to routine the benefits in patients with ASCVD in from two trials, including the CANVAS screening of asymptomatic patients the absence of these conditions are less trial that started in 2009 before with type 2 diabetes and normal ECGs clear, especially when LDL cholesterol the approval of canagliflozin and the (147). Despite abnormal myocardial per- is concomitantly controlled (154,155). CANVAS-Renal (CANVAS-R) trial that fusion imaging in more than one in five In patients with prior MI, active angina, started in 2014 after the approval of cana- patients, cardiac outcomes were essen- or HFrEF, b-blockers should be used (156). gliflozin. Combining both these trials, tially equal (and very low) in screened 10,142 participants with type 2 diabetes versus unscreened patients. Accord- Antihyperglycemic Therapies and (two-thirds with established CVD) were ingly, indiscriminate screening is not Cardiovascular Outcomes randomized to canagliflozin or placebo considered cost-effective. Studies have In 2008, the FDA issued a guidance for and were followed for an average 3.6 found that a risk factor–based approach industry to perform cardiovascular out- years. The mean age of patients was to the initial diagnostic evaluation and comes trials for all new medications for 63 years and 66% had a history of car- subsequentfollow-upforcoronary artery the treatment for type 2 diabetes amid diovascular disease. The combined anal- disease fails to identify which patients concerns of increased cardiovascular ysis of the two trials found that with type 2 diabetes will have silent risk (157). Previously approved diabetes canagliflozin significantly reduced the ischemia on screening tests (148,149). medications were not subject to the composite outcome of cardiovascular Any benefit of newer noninvasive cor- guidance. Recently published cardiovas- death, MI, or stroke versus placebo (oc- onary artery disease screening methods, cular outcomes trials have provided ad- curring in 26.9 vs. 31.5 participants per such as computed tomography cal- ditional data on cardiovascular outcomes 1,000 patient-years; HR 0.86 [95% CI cium scoring and computed tomography in patients with type 2 diabetes with 0.75–0.97]; P , 0.001 for noninferiority; angiography, to identify patient subgroups cardiovascular disease or at high risk for P 5 0.02 for superiority). The specific S116 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

estimates for canagliflozin versus placebo Semaglutide in Subjects With Type 2 events per 100 person-years) in the on the primary composite cardiovascular Diabetes (SUSTAIN-6) was the initial ran- placebo group (HR 0.91 [95% CI 0.83– outcome were HR 0.88 (0.75–1.03) for domized trial powered to test noninfer- 1.00]; P , 0.001 for noninferiority) but the CANVAS trial and 0.82 (0.66–1.01) for iority of semaglutide for the purpose of was notsuperior to placebowithrespect CANVAS-R, with no heterogeneity found initial regulatory approval. In this study, to the primary end point (P 5 0.06 for between trials. In the combined analysis, 3,297 patients with type 2 diabetes were superiority). However, all-cause mortal- there was not a statistically significant randomized to receive once-weekly sem- ity was lower in the exenatide group (HR difference in cardiovascular death (HR aglutide (0.5 mg or 1.0 mg) or placebo for 0.86 [95% CI 0.77–0.97]. The incidence 0.87 [95% CI 0.72–1.06]). The initial 2 years. The primary outcome (the first of acute pancreatitis, pancreatic cancer, CANVAS trial was partially unblinded occurrence of cardiovascular death, non- medullary thyroid carcinoma, and seri- prior to completion because of the fatal MI, or nonfatal stroke) occurred in ous adverse events did not differ sig- need to file interim cardiovascular out- 108 patients (6.6%) in the semaglutide nificantly between the two groups. comes data for regulatory approval of group vs. 146 patients (8.9%) in the The Harmony Outcomes trial random- the drug (158). Of note, there was an placebo group (HR 0.74 [95% CI 0.58– ized 9,463 patients with type 2 diabetes increased risk of lower-limb amputation 0.95]; P , 0.001). More patients dis- and cardiovascular disease to once- with canaglifozin (6.3 vs. 3.4 participants continued treatment in the semaglutide weekly subcutaneous albiglutide or per 1,000 patient-years; HR 1.97 [95% CI group because of adverse events, mainly matching placebo, in addition to their 1.41–2.75]) (9). gastrointestinal. standard care. Over a median duration The Liraglutide Effect and Action in The Evaluation of Lixisenatide in Acute of 1.6 years, the GLP-1 receptor agonist Diabetes: Evaluation of Cardiovascular Coronary Syndrome (ELIXA) trial studied reduced the risk of cardiovascular death, Outcome Results (LEADER) trial was a the once-daily GLP-1 receptor agonist MI, or stroke to an incidence rate of 4.6 randomized, double-blind trial that as- lixisenatide on cardiovascular outcomes events per 100 person-years in the albi- sessedtheeffectofliraglutide, aglucagon- in patients with type 2 diabetes who had glutide group vs. 5.9 events in the pla- like peptide 1 (GLP-1) receptor agonist, had a recent acute coronary event (161). cebo group (HR ratio 0.78, P 5 0.0006 for versus placebo on cardiovascular out- A total of 6,068 patients with type 2 superiority) (163). This agent is not cur- comes in 9,340 patients with type 2 di- diabetes with a recent hospitalization rently available for clinical use. abetes at high risk for cardiovascular for MI or unstable angina within the In summary, there are now several disease or with cardiovascular disease. previous 180 days were randomized to large randomized controlled trials report- Study participants had a mean age of receive lixisenatide or placebo in addi- ing statistically significant reductions in 64 years and a mean duration of diabetes tion to standard care and were followed cardiovascular events for two of the FDA- of nearly 13 years. Over 80% of study for a median of approximately 2.1 years. approved SGLT2 inhibitors (empagliflozin participants had established cardiovas- The primary outcome of cardiovascular and canagliflozin) and three FDA-approved cular disease. After a median follow-up death, MI, stroke, or hospitalization for GLP-1 receptor agonists (liraglutide, albiglu- of 3.8 years, LEADER showed that the unstable angina occurred in 406 patients tide [although that agent was removed primarycompositeoutcome (MI, stroke, (13.4%) in the lixisenatide group vs. from the market for business reasons], or cardiovascular death) occurred in 399 (13.2%) in the placebo group (HR and semaglutide [lower risk of cardiovas- fewer participants in the treatment 1.2 [95% CI 0.89–1.17]), which demon- cular events in a moderate-sized clinical group (13.0%) when compared with strated the noninferiority of lixisenatide trial but one not powered as a cardiovas- the placebo group (14.9%) (HR 0.87; to placebo (P , 0.001) but did not show cular outcomes trial]). In these trials, the 95% CI 0.78–0.97; P , 0.001 for non- superiority (P 5 0.81). majority, if not all, patients in the trial had inferiority; P 5 0.01 for superiority). The Exenatide Study of Cardiovascular ASCVD. The empagliflozin and liraglutide Deaths from cardiovascular causes Event Lowering (EXSCEL) trial also re- trials further demonstrated significant were significantly reduced in the liraglu- ported results with the once-weekly reductions in cardiovascular death. Once- tide group (4.7%) compared with the GLP-1 receptor agonist extended-release weekly exenatide did not have statistically placebo group (6.0%) (HR 0.78; 95% CI exenatide and found that major adverse significant reductions in major adverse 0.66–0.93; P 5 0.007) (159). The FDA cardiovascular events were numerically cardiovascular events or cardiovascular approved the use of liraglutide to re- lower with use of extended-release mortality but did have a significant reduce the risk of major adverse cardiovas- exenatide compared with placebo, duction in all-cause mortality. In con- cular events, including heart attack, stroke, although this difference was not sta- trast, other GLP-1 receptor agonists have and cardiovascular death, in adults tistically significant(162).A total of14,752 not shown similar reductions in cardio- with type 2 diabetes and established patients with type 2 diabetes (of whom vascular events (Table 10.4). Additional cardiovascular disease. 10,782 [73.1%] had previous cardiovas- large randomized trials of other agents Results from a moderate-sized trial of cular disease) were randomized to re- in these classes are ongoing. another GLP-1 receptor agonist, sema- ceive extended-release exenatide 2 mg Of note, these studies examined the glutide, were consistent with the LEADER or placebo and followed for a median of drugs in combination with metformin trial (160). Semaglutide is a once-weekly 3.2 years. The primary end point of (Table 10.4) in the great majority of GLP-1 receptor agonist approved by cardiovascular death, MI, or stroke oc- patients for whom metformin was not the FDA for the treatment of type 2 diabe- curredin839patients(11.4%;3.7events contraindicated or was tolerated. For tes. The Trial to Evaluate Cardiovascular per 100 person-years) in the exenatide patients with type 2 diabetes who have and Other Long-term Outcomes With group and in 905 patients (12.2%; 4.0 ASCVD, on lifestyle and metformin care.diabetesjournals.org Table 10.4—Cardiovascular outcomes trials of available antihyperglycemic medications completed after the issuance of the FDA 2008 guidelines DPP-4 inhibitors GLP-1 receptor agonists SGLT2 inhibitors SAVOR-TIMI EMPA-REG 53 (168) EXAMINE (175) TECOS (171) ELIXA (161) LEADER (159) SUSTAIN-6 (160)* EXSCEL (162) OUTCOME (8) CANVAS (9) CANVAS-R (9) (n 5 16,492) (n 5 5,380) (n 5 14,671) (n 5 6,068) (n 5 9,340) (n 5 3,297) (n 5 14,752) (n 5 7,020) (n 5 4,330) (n 5 5,812) Intervention Saxagliptin/ Alogliptin/ Sitagliptin/ Lixisenatide/ Liraglutide/placebo Semaglutide/placebo Exenatide QW/ Empagliflozin/ Canagliflozin/placebo placebo placebo placebo placebo placebo placebo Main inclusion Type 2 diabetes Type 2 diabetes Type 2 diabetes Type 2 Type 2 diabetes Type 2 diabetes and Type 2 diabetes Type 2 diabetes Type 2 diabetes and preexisting CVD criteria and history of or and ACS within and preexisting diabetes and and preexisting CVD, preexisting CVD, HF, or with or without and preexisting at $30 years of age or .2 cardiovascular multiple risk 15–90 days CVD history of ACS kidney disease, or HF at CKD at $50 years of age or preexisting CVD CVD risk factors at $50 years of age factors for CVD before (,180 days) $50 years of age or cardiovascular risk at $60 randomization cardiovascular risk at years of age $60 years of age A1C inclusion criteria (%) $6.5 6.5–11.0 6.5–8.0 5.5–11.0 $7.0 $7.0 6.5–10.0 7.0–10.0 7.0–10.5 Age (years)†† 65.1 61.0 65.4 60.3 64.3 64.6 62 63.1 63.3 Diabetes duration (years)†† 10.3 7.1 11.6 9.3 12.8 13.9 12 57% .10 13.5 Median follow-up (years) 2.1 1.5 3.0 2.1 3.8 2.1 3.2 3.1 5.7 2.1 Statin use (%) 78 91 80 93 72 73 74 77 75 Metformin use (%) 70 66 82 66 76 73 77 74 77 Prior CVD/CHF (%) 78/13 100/28 74/18 100/22 81/18 60/24 73.1/16.2 99/10 65.6/14.4 Mean baseline A1C (%) 8.0 8.0 7.2 7.7 8.7 8.7 8.0 8.1 8.2 Mean difference in A1C between groups at end of treatment (%) 20.3^ 20.3^ 20.3^ 20.3^ 20.4^ 20.7 or – 1.0^† 20.53^ 20.3^‡ 20.58^ Year started/ reported 2010/2013 2009/2013 2008/2015 2010/2015 2010/2016 2013/2016 2010/2017 2010/2015 2009/2017 Primary outcome§ 3-point MACE 3-point MACE 4-point MACE 4-point MACE 3-point MACE 3-point MACE 3-point MACE 3-point MACE 3-point MACE Progression to

albuminuria** S117 Management Risk and Disease Cardiovascular 1.00 (0.89–1.12) 0.96 (95% 0.98 (0.89–1.08) 1.02 (0.89–1.17) 0.87 (0.78–0.97) 0.74 (0.58–0.95) 0.91 (0.83–1.00) 0.86 (0.74–0.99) 0.86 (0.75–0.97)§ 0.73 (0.47–0.77) UL #1.16) Key secondary Expanded MACE 4-point MACE 3-point MACE Expanded MACE Expanded MACE Expanded MACE Individual 4-point MACE All-cause and 40% reduction in outcome§ components of cardiovascular composite eGFR, MACE (see mortality (see renal replacement, below) below) renal death 1.02 (0.94–1.11) 0.95 (95% UL 0.99 (0.89–1.10) 1.00 (0.90–1.11) 0.88 (0.81–0.96) 0.74 (0.62–0.89) 0.89 (0.78–1.01) 0.60 (0.47–0.77) #1.14) Cardiovascular 0.96 (0.77–1.18)¶ death§ 1.03 (0.87–1.22) 0.85 (0.66–1.10) 1.03 (0.89–1.19) 0.98 (0.78–1.22) 0.78 (0.66–0.93) 0.98 (0.65–1.48) 0.88 (0.76–1.02) 0.62 (0.49–0.77) 0.87 (0.72–1.06)# MI§ 0.95 (0.80–1.12) 1.08 (0.88–1.33) 0.95 (0.81–1.11) 1.03 (0.87–1.22) 0.86 (0.73–1.00) 0.74 (0.51–1.08) 0.97 (0.85–1.10) 0.87 (0.70–1.09) 0.85 (0.65–1.11) 0.85 (0.61–1.19) Stroke§ 1.11 (0.88–1.39) 0.91 (0.55–1.50) 0.97 (0.79–1.19) 1.12 (0.79–1.58) 0.86 (0.71–1.06) 0.61 (0.38–0.99) 0.85 (0.70–1.03) 1.18 (0.89–1.56) 0.97 (0.70 –1.35) 0.82 (0.57–1.18) HF hospitalization§ 1.27 (1.07–1.51) 1.19 (0.90–1.58) 1.00 (0.83–1.20) 0.96 (0.75–1.23) 0.87 (0.73–1.05) 1.11 (0.77–1.61) 0.94 (0.78–1.13) 0.65 (0.50–0.85) 0.77 (0.55–1.08) 0.56 (0.38–0.83) Continued on p. S118 S118 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

therapy, it is recommended to incorporate an agent with strong evidence for cardiovascular risk reduction, espe-

5,812) cially those with proven reduction of car- 5 ‡‡ diovascular death, after consideration of n ( ed. **On the cant difference CANVAS-R (9) 0.77) fi fi fi Table 9.1 1.07)## 1.01) – drug-speci c patient factors ( ). – –

d See Fig. 9.1 for additional recommenda- 6.0 mg/dL .

). ^Signi tions on antihyperglycemic treatment in ed in treating hierarchy as 0.60 (0.47 ﬁ 0.90 (0.76 0.87 (0.74 adults with type 2 diabetes. 4,330) 5 n SGLT2 inhibitors CANVAS (9) ( Antihyperglycemic Therapies and Heart Failure As many as 50% of patients with type 2 0.82) 1.34) 0.70) – – – ation, or creatinine glucose cotransporter 2; UL, upper limit. diabetes may develop heart failure (164). 7,020) – centage of population with diabetes duration 5 Data on the effects of glucose-lowering n EMPA-REG (

OUTCOME (8) agents on heart failure outcomes have 0.61 (0.53 EXAMINE, which reported medians; diabetes demonstrated that thiazolidinediones 0.97) 0.68 (0.57 1.18) 0.99 (0.74 have a strong and consistent relation- – – ted data (refers to pooled data from CANVAS, including before , the need for continuous renal-replacement therapy, 14,752)

2 ship with increased risk of heart failure d

5 (165–167). Therefore, thiazolidinedione n EXSCEL (162) ( use should be avoided in patients with ned as the new onset of urine albumin-to-creatinine ratio

ﬁ symptomatic heart failure. Recent studies have also examined the 1.50) 0.86 (0.77 1.44) 1.05 (0.94 0.88) – – – relationship between DPP-4 inhibitors 3,297) 45 mL/min/1.73 m and heart failure and have had mixed , 5 n m CANVAS after 20 November 2012 plus CANVAS-R; prespeci

( results. The Saxagliptin Assessment of

SUSTAIN-6 (160)* Vascular Outcomes Recorded in Patients gram). ##Nontruncated integra with Diabetes Mellitus2Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI *Powered to rule out a hazard ratio of 1.8; superiority hypothesis not prespeci

ltration rate of 53) study showed that patients treated ﬁ Age was reported as means in all trials except 0.97) 1.05 (0.74 1.26) 0.82 (0.47 0.92) 0.64 (0.46 – – – GLP-1 receptor agonists with saxagliptin (a DPP-4 inhibitor) were †† 9,340) AlC change of 0.30 in EMPA-REG OUTCOME is based on pooled results for both doses (i.e., 0.24% for

(0.67 more likely to be hospitalized for heart 5 ‡ n ( cant.

LEADER (159) failure than those given placebo (3.5% ﬁ 0.78 Diabetes Care. vs. 2.8%, respectively) (168). Two other (95% CI). ||Worsening nephropathy is de recent multicenter, randomized, double- blind, noninferiority trials, Examination 1.13) 0.85 (0.74 2.62) 0.98 (0.76 – –

ovascular death in the CANVAS Pro of Cardiovascular Outcomes with Aloglip- 6,068) ed exploratory adjudicated outcome in SAVOR-TIMI 53, LEADER, and SUSTAIN-6 but not in EMPA-REG OUTCOME. ﬁ

5 tin versus Standard of Care (EXAMINE) n ELIXA (161) ( and Trial Evaluating Cardiovascular Out- comes with Sitagliptin (TECOS), did not show associations between DPP-4 inhib- 1.14) 0.94 (0.78 1.16) 1.11 (0.47 – – Truncated integrated data set (refers to pooled data fro

DER, and SUSTAIN-6 and as doubling of creatinine level, initiation of dialysis, renal transplant itor use and heart failure. The FDA re- ‡‡ 14,671) not viewed as statistically signi

5 ported that the hospital admission rate for n TECOS (171) ( heart failure in EXAMINE was 3.9% for patients randomly assigned to alogliptin

of all-cause mortality and cardi compared with 3.3% for those randomly 1.09) 1.01 (0.90 1.37) 0.90 (0.70 – –

5,380) assigned to placebo (169). Alogliptin had dd d ozin). §Outcomes reported as hazard ratio ﬂ 5 no effect on the composite end point of n ( DPP-4 inhibitors EXAMINE (175) cardiovascular death and hospital admis-

ed in treating hierarchy as the principal data set for analysis for superiority of all-cause mortality and cardiovascular death in the CANVAS Program sion for heart failure in the post hoc ﬁ 1.32) 1.27) 0.88 (0.71 1.60) 0.90 (0.60 –

0.05). #Nontruncated data set. analysis (HR 1.0 [95% CI 0.82 1.21]) – – – 16,492) , (170). TECOS showed no difference in P 5 53 (168) n

SAVOR-TIMI the rate of heart failure hospitalization ( 1.08 (0.88 for the sitagliptin group (3.1%; 1.07 per ed outcomes, the renal outcomes are ﬁ 100 person-years) compared with the | ltration rate; GLP-1, glucagon-like peptide 1; HF, heart failure; MACE, major adverse cardiac event; MI, myocardial infarction; SGLT2, sodium A1C change of 0.66% with 0.5 mg and 1.05% with 1 mg dose of semaglutide. — Continued ﬁ placebo group (3.1%; 1.09 per 100 person- † years) (171). mol/L) in SAVOR-TIMI 53. Worsening nephropathy was a prespeci

m In four cardiovascular outcome trials , not assessed/reported; ACS, acute coronary syndrome; CHF, congestive heart failure; CKD, chronic kidney disease; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase 4; eGFR, estimated nephropathy§ hospitalization§ 1.19 (0.89 300 mg/g creatinine or a doubling of the serum creatinine level and an estimated glomerular 10 years. of GLP-1 receptor agonists, no evidence Worsening the principal data set20 for November analysis 2012 for plus superiority CANVAS-R). All-cause mortality§ 1.11 (0.96 in A1C between groups ( Unstable angina (530 ¶Truncated data set (prespeci 10 mg and 0.36%. for 25 mg of empagli Table 10.4 d glomerular or death from renal disease in EMPA-REG OUTCOME, LEA Data from this table was adapted from Cefalu et al. (176) in the January 2018 issue of duration was reported. as means in all but four trials, with SAVOR-TIMI 58, EXAMINE, and EXSCEL reporting medians and EMPA-REG OUTCOME reporting as per basis of prespeci for an increased risk of heart failure was care.diabetesjournals.org Cardiovascular Disease and Risk Management S119

found and the agents had a neutral effect ejection fraction: from mechanisms to therapies. analysis of randomized controlled studies. J Hy- on hospitalization for heart failure (159– Eur Heart J 2018;39:2780–2792 pertens 2013;31:455–467; discussion 467–468 162). 8. Zinman B, Wanner C, Lachin JM, et al.; EMPA- 21. Emdin CA, Rahimi K, Neal B, Callender T, REG OUTCOME Investigators. Empagliflozin, Perkovic V, Patel A. Blood pressure lowering in A benefit on the incidence of heart cardiovascular outcomes, and mortality in type 2 diabetes: a systematic review and meta- failure has been observed with the use type 2 diabetes. N Engl J Med 2015;373:2117– analysis. JAMA 2015;313:603–615 of some SGLT2 inhibitors. In EMPA- 2128 22. Arguedas JA, Leiva V, Wright JM. Blood REG OUTCOME, the addition of empa- 9. Neal B, Perkovic V, Mahaffey KW, et al.; pressure targets for hypertension in people fl fi CANVAS Program Collaborative Group. Cana- with diabetes mellitus. Cochrane Database gli ozin to standard care led to a signi cant gliflozin and cardiovascular and renal events in Syst Rev 2013;10:CD008277 35% reduction in hospitalization for type 2 diabetes. N Engl J Med 2017;377:644–657 23. Ettehad D, Emdin CA, Kiran A, et al. Blood heart failure compared with placebo 10. Fitchett D, Butler J, van de Borne P, et al.; pressure lowering for prevention of cardiovas- (8). Although the majority of patients EMPA-REG OUTCOMEÒ trial investigators. Ef- cular disease and death: a systematic review and fl – in the study did not have heart failure fects of empagli ozin on risk for cardiovascular meta-analysis. Lancet 2016;387:957 967 fi death and heart failure hospitalization across 24. Brunstrom¨ M, Carlberg B. Effect of antihy- at baseline, this bene t was consistent the spectrum of heart failure risk in the EMPA- pertensive treatment at different blood pressure in patients with and without a prior REG OUTCOMEÒ trial. Eur Heart J 2018;39:363– levels in patients with diabetes mellitus: system- history of heart failure (172). Similarly, 370 atic review and meta-analyses. BMJ 2016;352: in CANVAS, there was a 33% reduction in 11. Blood Pressure Lowering Treatment Tria- i717 ’ hospitalization for heart failure with lists Collaboration. Blood pressure-lowering 25. Bangalore S, Kumar S, Lobach I, Messerli FH. fl treatment based on cardiovascular risk: a meta- Blood pressure targets in subjects with type 2 canagli ozin versus placebo (9). Al- analysis of individual patient data. Lancet 2014;384: diabetes mellitus/impaired fasting glucose: though heart failure hospitalizations 591–598 observations from traditional and Bayesian were prospectively adjudicated in both 12. Grundy SM, Stone NJ, Bailey AL, et al. 2018 random-effects meta-analyses of randomized trials, the type(s) of heart failure events AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ trials. Circulation 2011;123:2799–2810 prevented were not characterized. These APhA/ASPC/NLA/PCNA guideline on the manage- 26. Thomopoulos C, Parati G, Zanchetti A. Ef- ment of blood cholesterol: a report of the fects of blood-pressure-lowering treatment on preliminary findings, which strongly sug- American College of Cardiology/American Heart outcome incidence in hypertension: 10 - should gest heart failure–related benefits of Association Task Force on Clinical Practice blood pressure management differ in hyperten- SGLT2 inhibitors (particularly the preven- Guidelines. J Am Coll Cardiol. November sive patients with and without diabetes mellitus? tion of heart failure), are being followed 2018 [Epub ahead of print]. DOI: 10.1016/j. Overview and meta-analyses of randomized jacc.2018.11.003 trials. J Hypertens 2017;35:922–944 up with new outcomes trials in patients 13. MuntnerP, ColantonioLD, CushmanM, et al. 27. Xie X, Atkins E, Lv J, et al. Effects of intensive with established heart failure, both Validation of the atherosclerotic cardiovascular blood pressure lowering on cardiovascular and with and without diabetes, to deter- disease Pooled Cohort risk equations. JAMA 2014; renal outcomes: updated systematic review and mine their efficacy in treatment of heart 311:1406–1415 meta-analysis. Lancet 2016;387:435–443 failure. 14. DeFilippisAP, YoungR, McEvoy JW,et al.Risk 28. Cushman WC, Evans GW, Byington RP, et al.; score overestimation: the impact of individual ACCORD Study Group. Effects of intensive blood- References cardiovascular risk factors and preventive ther- pressure control in type 2 diabetes mellitus. 1. American Diabetes Association. Economic apies on the performance of the American Heart N Engl J Med 2010;362:1575–1585 costs of diabetes in the U.S. in 2017. Diabetes Association-American College of Cardiology- 29. Patel A, MacMahon S, Chalmers J, et al.; Care 2018;41:917–928 Atherosclerotic Cardiovascular Disease risk score ADVANCE Collaborative Group. Effects of a fixed 2. Ali MK, Bullard KM, Saaddine JB, Cowie CC, in a modern multi-ethnic cohort. Eur Heart J 2017; combination of perindopril and indapamide on Imperatore G, Gregg EW. Achievement of goals 38:598–608 macrovascular and microvascular outcomes in in U.S. diabetes care, 1999–2010. N Engl J Med 15. Bohula EA, Morrow DA, Giugliano RP, et al. patients with type 2 diabetes mellitus (the 2013;368:1613–1624 Atherothrombotic risk stratification and ezetimibe ADVANCE trial): a randomised controlled trial. 3. Buse JB, Ginsberg HN, Bakris GL, et al.; Amer- for secondary prevention. J Am Coll Cardiol 2017; Lancet 2007;370:829–840 ican Heart Association; American Diabetes As- 69:911–921 30. Bakris GL. The implications of blood pressure sociation. Primary prevention of cardiovascular 16. Bohula EA, Bonaca MP, Braunwald E, et al. measurement methods on treatment targets for diseases in people with diabetes mellitus: a sci- atherothrombotic risk stratification and the ef- blood pressure. Circulation 2016;134:904–905 entific statement from the American Heart As- ficacy and safety of vorapaxar in patients with 31. Margolis KL, O’Connor PJ, Morgan TM, et al. sociationandtheAmericanDiabetesAssociation. stable ischemic heart disease and previous Outcomes of combined cardiovascular risk factor Diabetes Care 2007;30:162–172 myocardial infarction. Circulation 2016;134: management strategies in type 2 diabetes: the 4. Gaede P, Lund-Andersen H, Parving H-H, 304–313 ACCORD randomized trial. Diabetes Care 2014; Pedersen O. Effect of a multifactorial interven- 17. de Boer IH, Bangalore S, Benetos A, et al. 37:1721–1728 tion on mortality in type 2 diabetes. N Engl J Med Diabetes and hypertension: a position statement 32. Buckley LF, Dixon DL, Wohlford GF IV, 2008;358:580–591 by the American Diabetes Association. Diabetes Wijesinghe DS, Baker WL, Van Tassell BW. Intensive 5. Cavender MA, Steg PG, Smith SC Jr, et al.; Care 2017;40:1273–1284 versus standard blood pressure control in SPRINT- REACH Registry Investigators. Impact of diabetes 18. Bobrie G, Genes` N, Vaur L, et al. Is “isolated eligible participants of ACCORD-BP [published cor- mellitus on hospitalization for heart failure, home” hypertension as opposed to “isolated rection appears in Diabetes Care 2018;41:2048]. cardiovascular events, and death: outcomes at office” hypertension a sign of greater cardiovas- Diabetes Care 2017;40:1733–1738 4 years from the Reduction of Atherothrombosis cular risk? Arch Intern Med 2001;161:2205–2211 33. Brouwer TF, Vehmeijer JT, Kalkman DN, et al. for Continued Health (REACH) registry. Circula- 19. Sega R, Facchetti R, Bombelli M, et al. Intensive blood pressure lowering in patients tion 2015;132:923–931 Prognostic value of ambulatory and home blood with and patients without type 2 diabetes: 6. McAllister DA, Read S, Kerssens J, et al. In- pressures compared with office blood pressure a pooled analysis from two randomized trials. cidence of hospitalisation for heart failure and in the general population: follow-up results Diabetes Care 2018;41:1142–1148 case-fatality among 3.25 million people with from the Pressioni Arteriose Monitorate e Loro 34. Lamprea-Montealegre JA, de Boer IH. Re- and without diabetes. Circulation. 27 June Associazioni (PAMELA) study. Circulation 2005; evaluating the evidence for blood pressure tar- 2018 [Epub ahead of print]. DOI: 10.1161/ 111:1777–1783 gets in type 2 Diabetes. Diabetes Care 2018;41: CIRCULATIONAHA.118.034986 20. Omboni S, Gazzola T, Carabelli G, Parati G. 1132–1133 7. Lam CSP, Voors AA, de Boer RA, Solomon SD, Clinical usefulness and cost effectiveness of 35. de Boer IH, Bakris G, Cannon CP. individu- van Veldhuisen DJ. Heart failure with preserved home blood pressure telemonitoring: meta- alizing blood pressure targets for people with S120 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

diabetes and hypertension: comparing the ADA 49. FeldmanRD,ZouGY,VandervoortMK,Wong 64. Bandak G, Sang Y, Gasparini A, et al. Hyper- and the ACC/AHA recommendations. JAMA 2018; CJ, Nelson SAE, Feagan BG. A simplified approach kalemia after initiating renin-angiotensin system 319:1319–1320 to the treatment of uncomplicated hypertension: blockade: the Stockholm Creatinine Measure- 36. Basu S, Sussman JB, Rigdon J, Steimle L, a cluster randomized, controlled trial. Hyperten- ments (SCREAM) project. J Am Heart Assoc 2017; Denton BT, Hayward RA. Benefit and harm of sion 2009;53:646–653 6:e005428 intensive blood pressure treatment: derivation 50. Webster R, Salam A, de Silva HA, Selak V, 65. Hughes-Austin JM, Rifkin DE, Beben T, et al. and validation of risk models using data from Stepien S, Rajapakse S, et al. Fixed low-dose triple The relation of serum potassium concentration the SPRINT and ACCORD trials. PLoS Med 2017; combination antihypertensive medication vs with cardiovascular events and mortality in 14:e1002410 usual care for blood pressure control in patients community-living individuals. Clin J Am Soc 37. Phillips RA, Xu J, Peterson LE, Arnold RM, with mild to moderate hypertension in Sri Lanka: Nephrol 2017;12:245–252 Diamond JA, Schussheim AE. Impact of cardio- a randomized clinical trial. JAMA 2018;320: 66. James MT, Grams ME, Woodward M, et al.; vascular risk on the relative benefit and harm of 566–579 CKD Prognosis Consortium. A meta-analysis of intensive treatment of hypertension. J Am Coll 51. Bangalore S, Kamalakkannan G, Parkar S, the association of estimated GFR, albumin- Cardiol 2018;71:1601–1610 Messerli FH. Fixed-dose combinations improve uria, diabetes mellitus, and hypertension with 38. Whelton PK, Carey RM, Aronow WS, et al. medication compliance: a meta-analysis. Am J acute kidney injury. Am J Kidney Dis 2015;66: 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ Med 2007;120:713–719 602–612 ASH/ASPC/NMA/PCNA guideline for the preven- 52. Catala-L´ opez´ F, Mac´ıas Saint-Gerons D, 67. Iliescu R, Lohmeier TE, Tudorancea I, LaffinL, tion, detection, evaluation, and management of Gonzalez-Bermejo´ D, et al. Cardiovascular and Bakris GL. Renal denervation for the treatment of high blood pressure in adults: a report of the renal outcomes of renin-angiotensin system resistant hypertension: review and clinical per- American College of Cardiology/American Heart blockade in adult patients with diabetes mellitus: spective. Am J Physiol Renal Physiol 2015;309: Association Task Force on Clinical Practice Guide- a systematic review with network meta-analyses. F583–F594 lines. J Am Coll Cardiol 2018;71:e127–e248 PLoS Med 2016;13:e1001971 68. Bakris GL, Agarwal R, Chan JC, et al.; 39. Wright JT Jr, Williamson JD, Whelton PK, 53. Palmer SC, Mavridis D, Navarese E, et al. Mineralocorticoid Receptor Antagonist Tolera- et al.; SPRINT Research Group. A randomized trial Comparative efficacy and safety of blood pressure- bility Study–Diabetic Nephropathy (ARTS-DN) of intensive versus standard blood-pressure con- loweringagents in adults with diabetesand kidney Study Group. Effect of finerenone on albumin- trol. N Engl J Med 2015;373:2103–2116 disease: a network meta-analysis. Lancet 2015; uria in patients with diabetic nephropathy: 40. Beddhu S, Greene T, Boucher R, et al. In- 385:2047–2056 a randomized clinical trial. JAMA 2015;314: tensive systolic blood pressure control and in- 54. Barzilay JI, Davis BR, Bettencourt J, et al.; 884–894 cident chronic kidney disease in people with and ALLHAT Collaborative Research Group. Cardio- 69. Williams B, MacDonald TM, Morant S, without diabetes mellitus: secondary analyses of vascular outcomes using doxazosin vs. chlor- et al.; British Hypertension Society’s PATHWAY two randomised controlled trials. Lancet Diabetes thalidone for the treatment of hypertension in Studies Group. Spironolactone versus placebo, Endocrinol 2018;6:555–563 older adults with and without glucose disorders: bisoprolol, and doxazosin to determine the 41. Sink KM, Evans GW, Shorr RI, et al. Syncope, a report from the ALLHAT study. J Clin Hypertens optimal treatment for drug-resistant hyper- hypotension, and falls in the treatment of hy- (Greenwich) 2004;6:116–125 tension (PATHWAY-2): a randomised, double- pertension: results from the randomized clinical 55. Weber MA, Bakris GL, Jamerson K, et al.; blind, crossover trial. Lancet 2015;386:2059– Systolic Blood Pressure Intervention Trial. J Am ACCOMPLISH Investigators. Cardiovascularevents 2068 Geriatr Soc 2018;66:679–686 during differing hypertension therapies in pa- 70. Filippatos G, Anker SD, Bohm¨ M, et al. 42. American College of Obstetricians and Gy- tients with diabetes. J Am Coll Cardiol 2010;56: A randomized controlled study of finerenone necologists’ TaskForceonHypertensioninPreg- 77–85 vs. eplerenone in patients with worsening nancy. Hypertension in pregnancy. Report of the 56. Bangalore S, Fakheri R, Toklu B, Messerli FH. chronic heart failure and diabetes mellitus American College of Obstetricians and Gynecolo- Diabetes mellitus as a compelling indication for and/or chronic kidney disease. Eur Heart J 2016; gists’ TaskForceonHypertensioninPregnancy. use of renin angiotensin system blockers: sys- 37:2105–2114 Obstet Gynecol 2013;122:1122–1131 tematic review and meta-analysis of randomized 71. Bomback AS, Klemmer PJ. Mineralocorticoid 43. Abalos E, Duley L, Steyn DW. Antihyperten- trials. BMJ 2016;352:i438 receptor blockade in chronic kidney disease. sive drug therapy for mild to moderate hyper- 57. Carlberg B, Samuelsson O, Lindholm LH. Blood Purif 2012;33:119–124 tension during pregnancy. Cochrane Database Atenolol in hypertension: is it a wise choice? 72. Jensen MD, Ryan DH, Apovian CM, et al.; Syst Rev 2014;2:CD002252 Lancet 2004;364:1684–1689 American College of Cardiology/American Heart 44. Al-Balas M, Bozzo P, Einarson A. Use of 58. Yusuf S, Teo KK, Pogue J, et al.; ONTARGET Association Task Force on Practice Guidelines; diuretics during pregnancy. Can Fam Physician Investigators. Telmisartan, ramipril, or both in Obesity Society. 2013 AHA/ACC/TOS guideline 2009;55:44–45 patients at high risk for vascular events. N Engl J for the management of overweight and obesity 45. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Med 2008;358:1547–1559 in adults: a report of the American College Long term mortality of mothers and fathers 59. Fried LF, Emanuele N, Zhang JH, et al.; VA of Cardiology/American Heart Association Task after pre-eclampsia: population based cohort NEPHRON-D Investigators. Combined angio- Force on Practice Guidelines and The Obesity study. BMJ 2001;323:1213–1217 tensin inhibition for the treatment of diabetic Society. J Am Coll Cardiol 2014;129(25 Suppl. 2): 46. Sacks FM, Svetkey LP, Vollmer WM, et al.; nephropathy. N Engl J Med 2013;369:1892–1903 S102–S138 DASH-Sodium Collaborative Research Group. 60. Makani H, Bangalore S, Desouza KA, Shah A, 73. Estruch R, Ros E, Salas-Salvado´ J, et al.; Effects on blood pressure of reduced dietary Messerli FH. Efficacy and safety of dual blockade PREDIMED Study Investigators. Primary preven- sodium and the Dietary Approaches to Stop of the renin-angiotensin system: meta-analysis tion of cardiovascular disease with a Mediter- Hypertension (DASH) diet. N Engl J Med 2001; of randomised trials. BMJ 2013;346:f360 ranean diet supplemented with extra-virgin olive 344:3–10 61. Zhao P, Xu P, Wan C, Wang Z. Evening versus oil or nuts. N Engl J Med 2018;378:e34 47. James PA, Oparil S, Carter BL, et al. 2014 morning dosing regimen drug therapy for hy- 74. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ evidence-basedguidelineforthemanagementof pertension. Cochrane Database Syst Rev 2011; ACC guideline on lifestyle management to reduce high blood pressure in adults: report from the 10:CD004184 cardiovascular risk: a report of the American panel members appointed to the Eighth Joint 62. Hermida RC, Ayala DE, Mojon´ A, Fernandez´ College of Cardiology/American Heart Association National Committee (JNC 8). JAMA 2014;311: JR. Influence of time of day of blood pressure- Task Force on Practice Guidelines. Circulation 507–520 lowering treatment on cardiovascular risk in 2013;129:S76–S99 48. Bakris GL, Weir MR; Study of Hypertension hypertensive patients with type 2 diabetes. Di- 75. ChasmanDI,PosadaD,SubrahmanyanL,Cook and the Efficacy of Lotrel in Diabetes (SHIELD) abetes Care 2011;34:1270–1276 NR, Stanton VP Jr, Ridker PM. Pharmacogenetic Investigators. Achieving goal blood pressure in 63. Nilsson E, Gasparini A, Arnl¨ ov¨ J, et al. In- study of statin therapy and cholesterol reduction. patients with type 2 diabetes: conventional versus cidence and determinants of hyperkalemia and JAMA 2004;291:2821–2827 fixed-dose combination approaches. J Clin Hyper- hypokalemia in a large healthcare system. Int J 76. Meek C, Wierzbicki AS, Jewkes C, et al. Daily tens (Greenwich) 2003;5:202–209 Cardiol 2017;245:277–284 and intermittent rosuvastatin 5 mg therapy in care.diabetesjournals.org Cardiovascular Disease and Risk Management S121

statin intolerant patients: an observational 88. Carter AA, Gomes T, Camacho X, Juurlink DN, (the FIELD study): randomised controlled trial. study. Curr Med Res Opin 2012;28:371–378 Shah BR, Mamdani MM. Risk of incident diabetes Lancet 2005;366:1849–1861 77. Mihaylova B, Emberson J, Blackwell L, et al.; among patients treated with statins: population 101. Jones PH, Davidson MH. Reporting rate of Cholesterol Treatment Trialists’ (CTT) Collabo- based study [published correction appears in BMJ rhabdomyolysis with fenofibrate 1 statin versus rators. The effects of lowering LDL cholesterol 2013;347:f4356]. BMJ 2013;346:f2610 gemfibrozil 1 any statin. Am J Cardiol 2005;95: with statin therapy in people at low risk of 89. Baigent C, Blackwell L, Emberson J, et al.; 120–122 vascular disease: meta-analysis of individual Cholesterol Treatment Trialists’ (CTT) Collabora- 102. Ginsberg HN, Elam MB, Lovato LC, et al.; data from 27 randomised trials. Lancet 2012; tion. Efficacy and safety of more intensive low- ACCORD Study Group. Effects of combination 380:581–590 ering of LDL cholesterol: a meta-analysis of data lipid therapy in type 2 diabetes mellitus. N Engl J 78. Baigent C, Keech A, Kearney PM, et al.; from 170,000 participants in 26 randomised Med 2010;362:1563–1574 Cholesterol Treatment Trialists’ (CTT) Collabo- trials. Lancet 2010;376:1670–1681 103. Kowa Research Institute, Inc. Pemafibrate rators. Efficacy and safety of cholesterol-lowering 90. Cannon CP, Blazing MA, Giugliano RP, et al.; to Reduce Cardiovascular OutcoMes by Reduc- treatment:prospectivemeta-analysisofdatafrom IMPROVE-IT Investigators. Ezetimibe added to ing Triglycerides IN patiENts With diabeTes 90,056 participants in 14 randomised trials of statin therapy after acute coronary syndromes. (PROMINENT) In: ClinicalTrials.gov [Internet]. statins. Lancet 2005;366:1267–1278 N Engl J Med 2015;372:2387–2397 Bethesda, MD, National Library of Medicine. 79. Pyor˘ al¨ a¨ K, Pedersen TR, Kjekshus J, 91. de Ferranti SD, de Boer IH, Fonseca V, et al. Available from https://clinicaltrials.gov/ct2/show/ Faergeman O, Olsson AG, Thorgeirsson G. Cho- Type 1 diabetes mellitus and cardiovascular NCT03071692. NLM Identifier: NCT03071692. lesterol lowering with simvastatin improves disease:ascientificstatementfromthe American Accessed 8 October 2018 prognosis of diabetic patients with coronary Heart Association and American Diabetes Asso- 104. Boden WE, Probstfield JL, Anderson T, et al.; heart disease. A subgroup analysis of the Scan- ciation. Circulation 2014;130:1110–1130 AIM-HIGH Investigators. Niacin in patients with dinavian Simvastatin Survival Study (4S). Diabe- 92. Cannon CP, Braunwald E, McCabe CH, et al.; low HDL cholesterol levels receiving intensive tes Care 1997;20:614–620 Pravastatin or Atorvastatin Evaluation and In- statin therapy. N Engl J Med 2011;365:2255– 80. Collins R, Armitage J, Parish S, Sleigh P, Peto fection Therapy-Thrombolysis in Myocardial In- 2267 R; Heart Protection Study Collaborative Group. farction 22 Investigators. Intensive versus 105. Landray MJ, Haynes R, Hopewell JC, et al.; MRC/BHF Heart Protection Study of cholesterol- moderate lipid lowering with statins after acute HPS2-THRIVE Collaborative Group. Effects of lowering with simvastatin in 5963 people with coronary syndromes. N Engl J Med 2004;350: extended-release niacin with laropiprant in diabetes: a randomised placebo-controlled trial. 1495–1504 high-risk patients. N Engl J Med 2014;371: Lancet 2003;361:2005–2016 93. Sabatine MS, Giugliano RP, Keech AC, et al.; 203–212 81. Goldberg RB, Mellies MJ, Sacks FM, et al.; FOURIER Steering Committee and Investigators. 106. Rajpathak SN, Kumbhani DJ, Crandall J, The Care Investigators. Cardiovascular events Evolocumab and clinical outcomes in patients Barzilai N, Alderman M, Ridker PM. Statin ther- and their reduction with pravastatin in diabetic with cardiovascular disease. N Engl J Med 2017; apy and risk of developing type 2 diabetes: a and glucose-intolerant myocardial infarction 376:1713–1722 meta-analysis. Diabetes Care 2009;32:1924– survivors with average cholesterol levels: sub- 94. Giugliano RP, Cannon CP, Blazing MA, et al.; 1929 group analyses in the Cholesterol and Recurrent IMPROVE-IT (Improved Reduction of Outcomes: 107. Sattar N, Preiss D, Murray HM, et al. Statins Events (CARE) trial. Circulation 1998;98:2513– Vytorin Efficacy International Trial) Investigators. and risk of incident diabetes: a collaborative 2519 Benefit of adding ezetimibe to statin therapy meta-analysis of randomised statin trials. Lancet 82. Shepherd J, Barter P, Carmena R, et al. Effect on cardiovascular outcomes and safety in patients 2010;375:735–742 of lowering LDL cholesterol substantially below with versus without diabetes mellitus: results 108. RidkerPM,PradhanA,MacFadyenJG,Libby currently recommended levels in patients with from IMPROVE-IT (Improved Reduction of Out- P, Glynn RJ. Cardiovascular benefits and diabetes coronary heart disease and diabetes: the Treat- comes: Vytorin Efficacy InternationalTrial).Circu- risks of statin therapy in primary prevention: an ing to New Targets (TNT) study. Diabetes Care lation 2018;137:1571–1582 analysis from the JUPITER trial. Lancet 2012;380: 2006;29:1220–1226 95. Moriarty PM, Jacobson TA, Bruckert E, et al. 565–571 83. Sever PS, Poulter NR, Dahlof¨ B, et al. Re- Efficacy and safety of alirocumab, a monoclonal 109. Mach F, Ray KK, Wiklund O, et al.; European duction in cardiovascular events with atorvas- antibody to PCSK9, in statin-intolerant patients: Atherosclerosis Society Consensus Panel. Ad- tatin in 2,532 patients with type 2 diabetes: design and rationale of ODYSSEY ALTERNATIVE, a verse effects of statin therapy: perception vs. Anglo-Scandinavian Cardiac Outcomes Trial– randomized phase 3 trial. J Clin Lipidol 2014;8: the evidence – focus on glucose homeostasis, lipid-lowering arm (ASCOT-LLA). Diabetes Care 554–561 cognitive, renal and hepatic function, haemo- 2005;28:1151–1157 96. Zhang X-L, Zhu Q-Q, Zhu L, et al. Safety and rrhagic stroke and cataract. Eur Heart J 2018;39: 84. Knopp RH, d’Emden M, Smilde JG, Pocock SJ. efficacy of anti-PCSK9 antibodies: a meta-analysis 2526–2539 Efficacy and safety of atorvastatin in the pre- of 25 randomized, controlled trials. BMC Med 110. Heart Protection Study Collaborative Group. vention of cardiovascular end points in subjects 2015;13:123 MRC/BHF Heart Protection Study of cholesterol with type 2 diabetes: the Atorvastatin Study for 97. Sabatine MS, Leiter LA, Wiviott SD, et al. lowering with simvastatin in 20,536 high-risk Prevention of Coronary Heart Disease Endpoints Cardiovascular safety and efficacy of the PCSK9 individuals: a randomisedplacebo-controlledtrial. in Non-Insulin-Dependent Diabetes Mellitus inhibitor evolocumab in patients with and with- Lancet 2002;360:7–22 (ASPEN). Diabetes Care 2006;29:1478–1485 out diabetes and the effect of evolocumab on 111. Shepherd J, Blauw GJ, Murphy MB, et al.; 85. Colhoun HM, Betteridge DJ, Durrington PN, glycaemia and risk of new-onset diabetes: a pre- PROSPER study group. PROspective Study of et al.; CARDS investigators. Primary prevention specified analysis of the FOURIER randomised con- Pravastatin in the Elderly at Risk. Pravastatin of cardiovascular disease with atorvastatin in trolled trial. Lancet Diabetes Endocrinol 2017;5: in elderly individuals at risk of vascular disease type 2 diabetes in the Collaborative Atorvastatin 941–950 (PROSPER): a randomised controlled trial. Lancet Diabetes Study (CARDS): multicentre rando- 98. Berglund L, Brunzell JD, Goldberg AC, et al.; 2002;360:1623–1630 mised placebo-controlled trial. Lancet 2004; Endocrine Society. Evaluation and treatment of 112. Trompet S, van Vliet P, de Craen AJM, et al. 364:685–696 hypertriglyceridemia: an Endocrine Society clin- Pravastatin and cognitive function in the elderly. 86. Kearney PM, Blackwell L, Collins R, et al.; ical practice guideline. J Clin Endocrinol Metab Results of the PROSPER study. J Neurol 2010;257: Cholesterol Treatment Trialists’ (CTT) Collabo- 2012;97:2969–2989 85–90 rators. Efficacy of cholesterol-lowering therapy 99. Singh IM, Shishehbor MH, Ansell BJ. High- 113. Yusuf S, Bosch J, Dagenais G, et al.; HOPE-3 in 18,686 people with diabetes in 14 randomised density lipoprotein as a therapeutic target: Investigators. Cholesterol lowering in interme- trials of statins: a meta-analysis. Lancet 2008; a systematic review. JAMA 2007;298:786– diate-risk persons without cardiovascular dis- 371:117–125 798 ease. N Engl J Med 2016;374:2021–2031 87. Taylor F, Huffman MD, Macedo AF, et al. 100. Keech A, Simes RJ, Barter P, et al.; FIELD 114. Giugliano RP, Mach F, Zavitz K, et al.; Statins for the primary prevention of cardiovas- study investigators. Effects of long-term feno- EBBINGHAUS Investigators. Cognitive function cular disease. Cochrane Database Syst Rev 2013; fibrate therapy on cardiovascular events in in a randomized trial of evolocumab. N Engl J 1:CD004816 9795 people with type 2 diabetes mellitus Med 2017;377:633–643 S122 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

115. Richardson K, Schoen M, French B, et al. 127. Peters SAE, Huxley RR, Woodward M. Di- therapy with or without PCI for stable coronary Statins and cognitive function: a systematic re- abetes as risk factor for incident coronary heart disease. N Engl J Med 2007;356:1503–1516 view. Ann Intern Med 2013;159:688–697 disease in women compared with men: a sys- 142. BARI 2D Study Group, Frye RL, August P, 116. Baigent C, Blackwell L, Collins R, et al.; tematic review and meta-analysis of 64 cohorts et al. A randomized trial of therapies for type 2 Antithrombotic Trialists’ (ATT) Collaboration. including 858,507 individuals and 28,203 diabetes and coronary artery disease. N Engl J Aspirin in the primary and secondary prevention coronary events. Diabetologia 2014;57:1542– Med 2009;360:2503–2015 of vascular disease: collaborative meta-analysis 1551 143. Wackers FJT, Chyun DA, Young LH, et al.; of individual participant data from randomised 128. Kalyani RR, Lazo M, Ouyang P, et al. Sex Detection of Ischemia in Asymptomatic Diabetics trials. Lancet 2009;373:1849–1860 differences in diabetes and risk of incident (DIAD) Investigators. Resolution of asymptom- 117. Perk J, De Backer G, Gohlke H, et al.; coronary artery disease in healthy young and atic myocardial ischemia in patients with type 2 European Association for Cardiovascular Preven- middle-aged adults. Diabetes Care 2014;37:830– diabetes in the Detection of Ischemia in Asymp- tion & Rehabilitation (EACPR); ESC Committee for 838 tomatic Diabetics (DIAD) study. Diabetes Care Practice Guidelines(CPG). EuropeanGuidelineson 129. Peters SAE, Huxley RR, Woodward M. Di- 2007;30:2892–2898 cardiovascular disease prevention in clinical prac- abetes as a risk factor for stroke in women 144. Elkeles RS, Godsland IF, Feher MD, et al.; tice (version 2012): The Fifth Joint Task Force of compared with men: a systematic review and PREDICT Study Group. Coronary calcium mea- the European Society of Cardiology and Other meta-analysis of 64 cohorts, including 775,385 surement improves prediction of cardiovascular Societies on Cardiovascular Disease Prevention in individuals and 12,539 strokes. Lancet 2014;383: events in asymptomatic patients with type 2 Clinical Practice (constituted by representatives of 1973–1980 diabetes: the PREDICT study. Eur Heart J 2008; nine societies and by invited experts). Eur Heart 130. Dimitriu-Leen AC, Scholte AJHA, van 29:2244–2251 J 2012;33:1635–1701 Rosendael AR, et al. Value of coronary computed 145. Raggi P, Shaw LJ, Berman DS, Callister TQ. 118. Belch J, MacCuish A, Campbell I, et al. The tomography angiography in tailoring aspirin Prognostic value of coronary artery calcium prevention of progression of arterial disease and therapy for primary prevention of atheroscle- screening in subjects with and without diabetes. diabetes (POPADAD) trial: factorial randomised rotic events in patients at high risk with diabetes J Am Coll Cardiol 2004;43:1663–1669 placebo controlled trial of aspirin and antiox- mellitus. Am J Cardiol 2016;117:887–893 146. Anand DV, Lim E, Hopkins D, et al. Risk idants in patients with diabetes and asymptom- 131. Mora S, Ames JM, Manson JE. Low-dose stratification in uncomplicated type 2 diabetes: atic peripheral arterial disease. BMJ 2008;337: aspirin in the primary prevention of cardiovas- prospective evaluation of the combined use of a1840 cular disease: shared decision making in clinical coronary artery calcium imaging and selective 119. Zhang C, Sun A, Zhang P, et al. Aspirin for practice. JAMA 2016;316:709–710 myocardial perfusion scintigraphy. Eur Heart J primary prevention of cardiovascular events in 132. Campbell CL, Smyth S, Montalescot G, 2006;27:713–721 patients with diabetes: a meta-analysis. Diabetes Steinhubl SR. Aspirin dose for the prevention 147. Young LH, Wackers FJT, Chyun DA, et al.; Res Clin Pract 2010;87:211–218 of cardiovascular disease: a systematic review. DIAD Investigators. Cardiac outcomes after 120. De Berardis G, Sacco M, Strippoli GFM, JAMA 2007;297:2018–2024 screening for asymptomatic coronary artery et al. Aspirin for primary prevention of cardio- 133. Dav`ı G, Patrono C. Platelet activation and disease in patients with type 2 diabetes: the vascular events in people with diabetes: meta- atherothrombosis. N Engl J Med 2007;357:2482– DIAD study: a randomized controlled trial. JAMA analysis of randomised controlled trials. BMJ 2494 2009;301:1547–1555 2009;339:b4531 134. Larsen SB, Grove EL, Neergaard-Petersen S, 148. Wackers FJT, Young LH, Inzucchi SE, et al.; 121. ASCEND Study Collaborative Group. Effects Wurtz¨ M, HvasA-M, KristensenSD.Determinants Detection of Ischemia in Asymptomatic Diabetics of aspirin for primary prevention in persons with of reduced antiplatelet effect of aspirin in pa- Investigators. Detection of silent myocardial is- diabetes mellitus. N Engl J Med 2018;379:1529– tients with stable coronary artery disease. PLoS chemia in asymptomatic diabetic subjects: the 1539 One 2015;10:e0126767 DIAD study. Diabetes Care 2004;27:1954–1961 122. Gaziano JM, Brotons C, Coppolecchia R, 135. Zaccardi F, Rizzi A, Petrucci G, et al. In vivo 149. Scognamiglio R, Negut C, Ramondo A, et al.; ARRIVE Executive Committee. Use of platelet activation and aspirin responsiveness in Tiengo A, Avogaro A. Detection of coronary aspirin to reduce risk of initial vascular events type 1 diabetes. Diabetes 2016;65:503–509 artery disease in asymptomatic patients with in patients at moderate risk of cardiovascular 136. Bethel MA, Harrison P, Sourij H, et al. type 2 diabetes mellitus. J Am Coll Cardiol 2006; disease (ARRIVE): a randomised, double-blind, Randomized controlled trial comparing im- 47:65–71 placebo-controlled trial. Lancet 2018;392:1036– pact on platelet reactivity of twice-daily with 150. Hadamitzky M, Hein F, Meyer T, et al. 1046 once-daily aspirin in people with type 2 diabetes. Prognostic value of coronary computed tomo- 123. McNeilJJ,WolfeR, WoodsRL,etal.;ASPREE Diabet Med 2016;33:224–230 graphic angiography in diabetic patients with- Investigator Group. Effect of aspirin on cardio- 137. Rothwell PM, Cook NR, Gaziano JM, et al. out known coronary artery disease. Diabetes vascular events and bleeding in the healthy Effects of aspirin on risks of vascular events and Care 2010;33:1358–1363 elderly. N Engl J Med 2018;379:1509–1518 cancer according to bodyweight and dose: anal- 151. ChoiE-K,ChunEJ,ChoiS-I,et al.Assessment 124. Pignone M, Earnshaw S, Tice JA, Pletcher ysis of individual patient data from randomised of subclinical coronary atherosclerosis in asymp- MJ. Aspirin, statins, or both drugs for the primary trials. Lancet 2018;392:387–399 tomatic patients with type 2 diabetes mellitus prevention of coronary heart disease events in 138. Vandvik PO, Lincoff AM, Gore JM, et al. with single photon emission computed tomog- men: a cost-utility analysis. Ann Intern Med Primary and secondary prevention of cardiovas- raphy and coronary computed tomography an- 2006;144:326–336 cular disease: Antithrombotic Therapy and Pre- giography. Am J Cardiol 2009;104:890–896 125. Pignone M, Alberts MJ, Colwell JA, et al.; vention of Thrombosis, 9th ed: American College 152. Malik S, Zhao Y, Budoff M, et al. Coronary American Diabetes Association; American Heart of Chest Physicians Evidence-Based Clinical Prac- artery calcium score for long-term risk classification Association; American College of Cardiology tice Guidelines [published correction appears in individuals with type 2 diabetes and metabolic Foundation. Aspirin for primary prevention of inChest 2012;141:1129]. Chest 2012;141(Suppl.): syndrome from the Multi-Ethnic Study of Athero- cardiovascular events in people with diabetes: e637S–e668S sclerosis. JAMA Cardiol 2017;2:1332–1340 a position statement of the American Diabetes 139. Bhatt DL, Bonaca MP, Bansilal S, et al. 153. Wing RR, Bolin P, Brancati FL, et al.; Look Association, a scientific statement of the Amer- Reduction in ischemic events with ticagrelor AHEAD Research Group. Cardiovascular effects ican Heart Association, and an expert consensus in diabetic patients with prior myocardial in- of intensive lifestyle intervention in type 2 di- document of the American College of Cardiol- farction in PEGASUS-TIMI 54. J Am Coll Cardiol abetes. N Engl J Med 2013;369:145–154 ogy Foundation. Diabetes Care 2010;33:1395– 2016;67:2732–2740 154. Braunwald E, Domanski MJ, Fowler SE, 1402 140. Bax JJ, Young LH, Frye RL, Bonow RO, et al.; PEACE Trial Investigators. Angiotensin- 126. Huxley RR, Peters SAE, Mishra GD, Steinberg HO, Barrett EJ. Screening for coronary converting-enzyme inhibition in stable coronary Woodward M. Risk of all-cause mortality and artery disease in patients with diabetes. Diabetes artery disease. N Engl J Med 2004;351:2058– vascular events in women versus men with type 1 Care 2007;30:2729–2736 2068 diabetes: a systematic review and meta-analysis. 141. Boden WE, O’Rourke RA, Teo KK, et al.; 155. Telmisartan Randomised AssessmeNt Study Lancet Diabetes Endocrinol 2015;3:198–206 COURAGETrial Research Group. Optimal medical in ACE iNtolerant subjects with cardiovascular care.diabetesjournals.org Cardiovascular Disease and Risk Management S123

Disease (TRANSCEND) Investigators, Yusuf S, Teo 162. Holman RR, Bethel MA, Mentz RJ, et al.; diabetes medicines containing saxagliptin and K, etal. Effectsof the angiotensin-receptor blocker EXSCEL Study Group. Effects of once-weekly alogliptin [Internet], 2016. Available from http:// telmisartan on cardiovascular events in high-risk exenatide on cardiovascular outcomes in type www.fda.gov/Drugs/DrugSafety/ucm486096 patients intolerant to angiotensin-converting 2 diabetes. N Engl J Med 2017;377:1228–1239 .htm. Accessed 24 September 2018 enzyme inhibitors: a randomised controlled 163. Hernandez AF, Green JB, Janmohamed S, 170. Zannad F, Cannon CP, Cushman WC, et al.; trial. Lancet 2008;372:1174–1183 et al.; Harmony Outcomes committees and in- EXAMINE Investigators. Heart failure and mor- 156. Kezerashvili A, Marzo K, De Leon J. Beta vestigators. Albiglutide and cardiovascular out- tality outcomes in patients with type 2 diabetes blocker use after acute myocardial infarction in comes in patients with type 2 diabetes and taking alogliptin versus placebo in EXAMINE: the patient with normal systolic function: when is it cardiovascular disease (Harmony Outcomes): a multicentre, randomised, double-blind trial. “ok” to discontinue? Curr Cardiol Rev 2012;8:77–84 a double-blind, randomised placebo-controlled Lancet 2015;385:2067–2076 157. U.S. Food and Drug Administration. Guidance trial. Lancet 2018;392:1519–1529 171. Green JB, Bethel MA, Armstrong PW, et al.; for industry. Diabetes mellitusdevaluating cardio- 164. Kannel WB, Hjortland M, Castelli WP. TECOS Study Group. Effect of sitagliptin on car- vascular risk in new antidiabetic therapies to treat Role of diabetes in congestive heart failure: diovascular outcomes in type 2 diabetes. N Engl J type 2 diabetes[Internet]. Silver Spring,MD, 2008. the Framingham study. Am J Cardiol 1974;34: Med 2015;373:232–242 Available from http://www.fda.gov/downloads/ 29–34 172. Fitchett D, Butler J, van de Borne P, et al. Drugs/GuidanceComplianceRegulatoryInformation/ 165. Dormandy JA, Charbonnel B, Eckland DJA, Effects of empagliflozin on risk for cardiovascular Guidances/ucm071627.pdf). Accessed 3 November et al.; PROactive Investigators. Secondary pre- death and heart failure hospitalization across the 2017 vention of macrovascular events in patients spectrum of heart failure risk in the EMPA-REG 158. Neal B, Perkovic V, Matthews DR, et al.; with type 2 diabetes in the PROactive Study OUTCOME trial. Eur Heart J 2017;39:363–370 CANVAS-R Trial Collaborative Group. Rationale, (PROspective pioglitAzone Clinical Trial In 173. Hansson L, Zanchetti A, Carruthers SG, design and baseline characteristics of the macroVascular Events): a randomised con- et al.; HOT Study Group. Effects of intensive CANagliflozin cardioVascular Assessment Study- trolled trial. Lancet 2005;366:1279–1289 blood-pressure lowering and low-dose aspirin in Renal (CANVAS-R): a randomized, placebo- 166. Singh S, Loke YK, Furberg CD. Long-term patients with hypertension: principal results of controlled trial. Diabetes Obes Metab 2017; risk of cardiovascular events with rosiglitazone: the Hypertension Optimal Treatment (HOT) 19:387–393 a meta-analysis. JAMA 2007;298:1189–1195 randomised trial. Lancet 1998;351:1755–1762 159. Marso SP, Daniels GH, Brown-Frandsen K, 167. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. 174. Zoungas S, Chalmers J, Neal B, et al.; et al.; LEADER Steering Committee; LEADER Trial Pioglitazone and risk of cardiovascular events in ADVANCE-ON Collaborative Group. Follow-up of Investigators. Liraglutide and cardiovascular outpatients with type 2 diabetes mellitus: a meta- blood-pressure lowering and glucose control in comes in type 2 diabetes. N Engl J Med 2016;375: analysis of randomized trials. JAMA 2007;298: type 2 diabetes. N Engl J Med 2014;371:1392–1406 311–322 1180–1188 175. White WB, Cannon CP, Heller SR, et al.; 160. Marso SP, Bain SC, Consoli A, et al.; 168. Scirica BM, Bhatt DL, Braunwald E, et al.; EXAMINE Investigators. Alogliptin after acute SUSTAIN-6 Investigators. Semaglutide and car- SAVOR-TIMI 53 Steering Committee and Inves- coronary syndrome in patients with type 2 di- diovascular outcomes in patients with type 2 tigators. Saxagliptin and cardiovascular outcomes abetes. N Engl J Med 2013;369:1327–1335 diabetes. N Engl J Med 2016;375:1834–1844 in patients with type 2 diabetes mellitus. N Engl J 176. Cefalu WT, Kaul S, Gerstein HC, et al. 161. Pfeffer MA, Claggett B, Diaz R, et al.; ELIXA Med 2013;369:1317–1326 Cardiovascular outcomes trials in type 2 diabe- Investigators. Lixisenatide in patients with type 2 169. U.S. Food and Drug Administration. FDA tes: where do we go from here? Reflections diabetes and acute coronary syndrome. N Engl Drug Safety Communication: FDA adds warn- from a Diabetes Care Editors’ Expert Forum. J Med 2015;373:2247–2257 ings about heart failure risk to labels of type 2 Diabetes Care 2018;41:14–31 S124 Diabetes Care Volume 42, Supplement 1, January 2019

11. Microvascular Complications American Diabetes Association and Foot Care: Standards of Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S124–S138 | https://doi.org/10.2337/dc19-S011

For prevention and management of diabetes complications in children and adolescents, please refer to Section 13 “Children and Adolescents.” CHRONIC KIDNEY DISEASE 11. MICROVASCULAR COMPLICATIONS AND FOOT CARE Recommendations

Screening 11.1 At least once a year, assess urinary albumin (e.g., spot urinary albumin-to- creatinine ratio) and estimated glomerular ﬁltration rate in patients with type 1 diabetes with duration of $5 years, in all patients with type 2 diabetes, and in all patients with comorbid hypertension. B Treatment 11.2 Optimize glucose control to reduce the risk or slow the progression of chronic kidney disease. A 11.3 For patients with type 2 diabetes and chronic kidney disease, consider use of a sodium–glucose cotransporter 2 inhibitor or glucagon-like peptide 1 receptor agonist shown to reduce risk of chronic kidney disease progression, cardiovascular events, or both (Table 9.1). C 11.4 Optimize blood pressure control to reduce the risk or slow the progression of chronic kidney disease. A 11.5 For people with nondialysis-dependent chronic kidney disease, dietary Suggested citation: American Diabetes Association. protein intake should be approximately 0.8 g/kg body weight per day 11. Microvascular complications and foot care: Standards of Medical Care in Diabetesd2019. (the recommended daily allowance). For patients on dialysis, higher levels of Diabetes Care 2019;42(Suppl. 1):S124–S138 dietary protein intake should be considered. B 11.6 © 2018 by the American Diabetes Association. In nonpregnant patients with diabetes and hypertension, either an ACE Readers may use this article as long as the work inhibitor or an angiotensin receptor blocker is recommended for those with is properly cited, the use is educational and not modestly elevated urinary albumin-to-creatinine ratio (30–299 mg/g creatinine) for proﬁt, and the work is not altered. More infor- B and is strongly recommended for those with urinary albumin-to-creatinine mation is available at http://www.diabetesjournals .org/content/license. care.diabetesjournals.org Microvascular Complications and Foot Care S125

develops after diabetes duration of 10 Diagnosis of Diabetic Kidney Disease ratio $300 mg/g creatinine years in type 1 diabetes but may be present Diabetic kidney disease is usually a clin- and/or estimated glomerular at diagnosis of type 2 diabetes. CKD ical diagnosis made based on the pres- filtration rate ,60 mL/min/ can progress to end-stage renal disease ence of albuminuria and/or reduced 1.73 m2. A (ESRD) requiring dialysis or kidney trans- eGFRintheabsenceofsignsorsymptoms 11.7 Periodically monitor serum cre- plantation and is the leading cause of of other primary causes of kidney dam- atinine and potassium levels for ESRD in the U.S. (6). In addition, among age. The typical presentation of diabetic the development of increased people with type 1 or 2 diabetes, the kidney disease is considered to include creatinine or changes in potas- presence of CKD markedly increases car- a long-standing duration of diabetes, sium when ACE inhibitors, an- diovascular risk and health care costs (7). retinopathy, albuminuria without hema- giotensin receptor blockers, or turia, and gradually progressive loss of diuretics are used. B eGFR. However, signs of CKD may 11.8 Continued monitoring of urinary Assessment of Albuminuria and be present at diagnosis or without ret- albumin-to-creatinine ratio in pa- Estimated Glomerular Filtration Rate Screening for albuminuria can be most inopathy in type 2 diabetes, and reduced tients with albuminuria treated easily performed by urinary albumin-to- eGFR without albuminuria has been fre- with an ACE inhibitor or an an- creatinine ratio (UACR) in a random quently reported in type 1 and type 2 giotensin receptor blocker is spot urine collection (1,2). Timed or 24-h diabetes and is becoming more common reasonable to assess the re- collections are more burdensome and over time as the prevalence of diabetes sponsetotreatmentandprogres- add little to prediction or accuracy. Mea- increases in the U.S. (3,4,11,12). sion of chronic kidney disease. E surement of a spot urine sample for al- An active urinary sediment (containing 11.9 An ACE inhibitor or an angioten- bumin alone (whether by immunoassay or red or white blood cells or cellular casts), sin receptor blocker is not rec- by using a sensitive dipstick test specificfor rapidly increasing albuminuria or ne- ommended for the primary albuminuria) without simultaneously mea- phrotic syndrome, rapidly decreasing prevention of chronic kidney suring urine creatinine (Cr) is less expen- eGFR, or the absence of retinopathy disease in patients with diabetes sive but susceptible to false-negative and (in type 1 diabetes) may suggest alter- who have normal blood pres- false-positive determinations as a result native or additional causes of kidney sure, normal urinary albumin- of variation in urine concentration due to disease. For patients with these features, to-creatinine ratio (,30 mg/g hydration. referral to a nephrologist for further creatinine), and normal estimated Normal UACR is generally defined diagnosis, including the possibility of glomerular filtration rate. B as ,30 mg/g Cr, and increased urinary kidney biopsy, should be considered. It is 11.10 When estimated glomerular fil- albumin excretion is defined as $30 mg/g rare for patients with type 1 diabetes tration rate is ,60 mL/min/ Cr. However, UACR is a continuous to develop kidney disease without ret- 1.73 m2, evaluate and manage measurement, and differences within the inopathy. In type 2 diabetes, retinopathy potentialcomplicationsofchronic normal and abnormal ranges are associated is only moderately sensitive and specific kidney disease. E with renal and cardiovascular outcomes for CKD caused by diabetes, as confirmed 11.11 Patients should be referred for (7–9). Furthermore, because of biological by kidney biopsy (13). evaluation for renal replace- variability in urinary albumin excretion, two ment treatment if they have of three specimens of UACR collected an estimated glomerular filtra- Staging of Chronic Kidney Disease within a 3- to 6-month period should be Stages 1–2 CKD have been defined by tion rate ,30 mL/min/1.73 m2. A abnormal before considering a patient to evidence of kidney damage (usually al- 11.12 Promptly refer to a physician have albuminuria. Exercise within 24 h, buminuria) with eGFR $60 mL/min/ experienced in the care of kid- infection, fever, congestive heart failure, 1.73 m2, while stages 3–5 CKD have ney disease for uncertainty about marked hyperglycemia, menstruation, been defined by progressively lower the etiology of kidney disease, and marked hypertension may elevate ranges of eGFR (14) (Table 11.1). At difficult management issues, and UACR independently of kidney damage. any eGFR, the degree of albuminuria rapidly progressing kidney dis- eGFR should be calculated from se- is associated with risk of CKD progres- ease. B rum Cr using a validated formula. The sion, cardiovascular disease (CVD), and Chronic Kidney Disease Epidemiology mortality (7). Therefore, Kidney Disease: Epidemiology of Diabetes and Chronic Collaboration (CKD-EPI) equation is gener- Improving Global Outcomes (KDIGO) Kidney Disease ally preferred (2). eGFR is routinely re- recommends a more comprehensive Chronic kidney disease (CKD) is diag- ported by laboratories with serum Cr, CKD staging that incorporates albumin- nosed by the persistent presence of and eGFR calculators are available from uria at all stages of eGFR; this system is elevated urinary albumin excretion (al- www.nkdep.nih.gov. An eGFR ,60 mL/ more closely associated with risk but is buminuria), low estimated glomerular min/1.73 m2 is generally considered also more complex and does not trans- filtration rate (eGFR), or other manifesta- abnormal, though optimal thresholds late directly to treatment decisions (2). tions of kidney damage (1,2). In this for clinical diagnosis are debated (10). Regardless of classification scheme, both section, the focus will be on CKD attrib- Urinary albumin excretion and eGFR eGFR and albuminuria should be quanti- uted to diabetes (diabetic kidney dis- each vary within people over time, and fied to guide treatment decisions: CKD ease),whichoccursin20–40% of patients abnormal results should be confirmed to complications (Table 11.2)correlate with diabetes (1,3–5). CKD typically stage CKD (1,2). with eGFR, many drugs are limited to S126 Microvascular Complications and Foot Care Diabetes Care Volume 42, Supplement 1, January 2019

Table 11.1—CKD stages and corresponding focus of kidney-related care CKD stage† Focus of kidney-related care Evidence of Evaluate and treat risk Prepare for renal eGFR kidney Diagnose cause factors for CKD Evaluate and treat CKD replacement Stage (mL/min/1.73 m2) damage* of kidney injury progression** complications*** therapy No clinical evidence of CKD $60 2 1 $90 1 UU 260–89 1 UU 330–59 1/2 UU U 415–29 1/2 UUU 5 ,15 1/2 UU CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate. †CKD stages 1 and 2 are defined by evidence of kidney damage (1), while CKD stages 3–5 are defined by reduced eGFR with or without evidence of kidney damage (1/2). At any stage of CKD, the degree of albuminuria, observed history of eGFR loss, and cause of kidney damage (including possible causes other than diabetes) may also be used to characterize CKD, gauge prognosis, and guide treatment decisions. *Kidney damage is most often manifest as albuminuria (UACR $30 mg/g Cr) but can also include glomerular hematuria, other abnormalities of the urinary sediment, radiographic abnormalities, and other presentations. **Risk factors for CKD progression include elevated blood pressure, hyperglycemia, and albuminuria. ***See Table 11.2.

acceptable eGFR ranges, and the de- nonsteroidal anti-inflammatory drugs), Surveillance gree of albuminuria may influence and the use of medications that alter Albuminuria and eGFR should be mon- choice of antihypertensive (see Section renal blood flow and intrarenal hemo- itored regularly to enable timely diagno- 10 “Cardiovascular Disease and Risk dynamics. In particular, many antihyper- sis of CKD, monitor progression of CKD, Management”)orglucose-lowering tensive medications (e.g., diuretics, ACE detect superimposed kidney diseases medications (see below). Observed his- inhibitors, and angiotensin receptor including AKI, assess risk of CKD compli- tory of eGFR loss (which is also associated blockers [ARBs]) can reduce intravascu- cations, dose drugs appropriately, and with risk of CKD progression and other lar volume, renal blood flow, and/or determine whether nephrology referral adverse health outcomes) and cause of glomerular filtration. There is a con- is needed. Among people with existing kidney damage (including possible causes cern that sodium–glucose cotransporter kidney disease, albuminuria and eGFR other than diabetes) may also affect 2 (SGLT2) inhibitors may promote AKI may change due to progression of CKD, these decisions (15). through volume depletion, particu- development of a separate superim- larly when combined with diuretics posed cause of kidney disease, AKI, or Acute Kidney Injury or other medications that reduce glo- other effects of medications, as noted Acute kidney injury (AKI) is usually di- merular filtration. However, existing above. Serum potassium should also be agnosed by a rapid increase in serum Cr, evidence from clinical trials and obser- monitored for patients treated with ACE which is also reflectedasarapiddecrease vational studies suggests that SGLT2 inhibitors, ARBs, and diuretics because in eGFR, over a relatively short period of inhibitors do not significantly increase these medications can cause hyperkale- time. People with diabetes are at higher AKI (17–19). Timely identification and mia or hypokalemia, which are associated risk of AKI than those without diabetes treatment of AKI are important because with cardiovascular risk and mortality (16). Other risk factors for AKI include AKI is associated with increased risks of (21–23). For patients with eGFR ,60 preexisting CKD, the use of medica- progressive CKD and other poor health mL/min/1.73 m2, appropriate medications that cause kidney injury (e.g., outcomes (20). tion dosing should be verified, exposure to nephrotoxins (e.g., nonsteroidal anti-inflammatory drugs and iodinated Table 11.2—Selected complications of CKD contrast) should be minimized, and Complication Medical and laboratory evaluation potential CKD complications should Table 11.2 Elevated blood pressure Blood pressure, weight be evaluated ( ). Volume overload History, physical examination, weight The need for annual quantitative as- Electrolyte abnormalities Serum electrolytes sessment of albumin excretion after diagnosis of albuminuria, institution of ACE Metabolic acidosis Serum electrolytes inhibitors or ARB therapy, and achieving Anemia Hemoglobin; iron testing if indicated blood pressure control is a subject of Metabolic bone disease Serum calcium, phosphate, PTH, vitamin 25(OH)D debate. Continued surveillance can as- Complications of chronic kidney disease (CKD) generally become prevalent when estimated sess both response to therapy and dis- glomerular filtrationratefalls below60 mL/min/1.73 m2 (stage3CKD orgreater)andbecomemore common and severe as CKD progresses. Evaluation of elevated blood pressure and volume easeprogressionandmayaidinassessing overload should occur at every clinical contact possible; laboratory evaluations are adherence to ACE inhibitor or ARB ther- generally indicated every 6–12 months for stage 3 CKD, every 3–5 months for stage 4 CKD, apy. In addition, in clinical trials of ACE – and every 1 3 months for stage 5 CKD, or as indicated to evaluate symptoms or changes in inhibitors or ARB therapy in type 2 therapy. PTH, parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D. diabetes, reducing albuminuria from care.diabetesjournals.org Microvascular Complications and Foot Care S127

levels $300 mg/g Cr has been associated Glycemic Targets Selection of Glucose-Lowering Medications with improved renal and cardiovascular Intensive glycemic control with the goal for Patients With Chronic Kidney Disease outcomes, leading some to suggest that of achieving near-normoglycemia has For patients with type 2 diabetes and medications should be titrated to min- been shown in large prospective random- established CKD, special considerations imize UACR. However, this approach has ized studies to delay the onset and pro- for the selection of glucose-lowering med- not been formally evaluated in prospec- gression of albuminuria and reduced ications include limitations to available tive trials. In type 1 diabetes, remission of eGFR in patients with type 1 diabetes medications when eGFR is diminished albuminuria may occur spontaneously (27,28) and type 2 diabetes (1,29–34). and a desire to mitigate high risks of CKD and cohort studies evaluating associa- Insulin alone was used to lower blood progression, CVD, and hypoglycemia tions of change in albuminuria with glucose in the Diabetes Control and (48,49). Drug dosing may require modifi- 2 clinical outcomes have reported incon- Complications Trial (DCCT)/Epidemiol- cation with eGFR ,60 mL/min/1.73 m (1). sistent results (24,25). ogy of Diabetes Interventions and Com- TheU.S. Food and Drug Administration The prevalence of CKD complications plications (EDIC) study of type 1 (FDA) revised its guidance for the use correlates with eGFR (25a). When eGFR diabetes, while a variety of agents metformin in CKD in 2016 (50), recom- is ,60 mL/min/1.73 m2, screening for were used in clinical trials of type 2 mending use of eGFR instead of serum Cr complications of CKD is indicated (Table diabetes, supporting the conclusion to guide treatment and expanding the 11.2). Early vaccination against hepati- that glycemic control itself helps pre- pool of patients with kidney disease for tis B virus is indicated in patients likely vent CKD and its progression. The ef- whom metformin treatment should be to progress to ESRD (see Section 4 fects of glucose-lowering therapies on considered. The revised FDA guidance “Comprehensive Medical Evaluation and CKD have helped define A1C targets states that metformin is contraindicated Assessment of Comorbidities” for further (see Table 6.2). in patients with an eGFR ,30 mL/min/ 2 information on immunization). The presence of CKD affects the risks 1.73 m , eGFR should be monitored while and benefits of intensive glycemic con- taking metformin, the benefits and risks trol and a number of specific glucose- of continuing treatment should be re- Interventions lowering medications. In the Action to assessed when eGFR falls ,45 mL/min/ 2 Nutrition Control Cardiovascular Risk in Diabetes 1.73 m , metformin should not be initi- For people with nondialysis-dependent (ACCORD) trial of type 2 diabetes, ad- ated for patients with an eGFR ,45 mL/ CKD, dietary protein intake should be verse effects of intensive glycemic con- min/1.73 m2, and metformin should be approximately 0.8 g/kg body weight per trol (hypoglycemia and mortality) were temporarily discontinued at the time of day (the recommended daily allowance) increased among patients with kidney or before iodinated contrast imaging (1). Compared with higher levels of di- disease at baseline (35,36). Moreover, procedures in patients with eGFR 30– etary protein intake, this level slowed there is a lag time of at least 2 years in 60 mL/min/1.73 m2. Within these con- GFR decline with evidence of a greater type 2 diabetes to over 10 years in type 1 straints, metformin should be considered effect over time. Higher levels of dietary diabetes for the effects of intensive the first-line treatment for all patients with protein intake (.20% of daily calories glucose control to manifest as improved type 2 diabetes, including those with CKD. from protein or .1.3 g/kg/day) have eGFR outcomes (33,37,38). Therefore, in SGLT2 inhibitors and GLP-1 RA should been associated with increased albumin- some patients with prevalent CKD and be considered for patients with type 2 uria, more rapid kidney function loss, and substantial comorbidity, target A1C lev- diabetes and CKD who require another CVD mortality and therefore should be els may be less intensive (1,39). drug added to metformin to attain target avoided. Reducing the amount of dietary A1C or cannot use or tolerate metfor- protein below the recommended daily Direct Renal Effects of Glucose-Lowering min. SGLT2 inhibitors and GLP-1 RA are allowance of 0.8 g/kg/day is not recom- Medications suggested because they appear to reduce mended because it does not alter glycemic Some glucose-lowering medications also risks of CKD progression, CVD events, measures, cardiovascular risk measures, have effects on the kidney that are direct, and hypoglycemia. or the course of GFR decline. i.e., not mediated through glycemia. For A number of large cardiovascular Restriction of dietary sodium (to example, SGLT2 inhibitors reduce renal outcomes trials in patients with type 2 ,2,300 mg/day) may be useful to control tubular glucose reabsorption, weight, diabetes at high risk for CVD or with blood pressure and reduce cardiovascu- systemic blood pressure, intraglomerular existing CVD examined kidney effects lar risk (26), and restriction of dietary pressure, and albuminuria and slow GFR as secondary outcomes. These trials in- potassium may be necessary to control loss through mechanisms that appear clude EMPA-REG OUTCOME [BI 10773 serum potassium concentration (16,21–23). independent of glycemia (18,40–43). (Empagliflozin) Cardiovascular Outcome These interventions may be most impor- Glucagon-like peptide 1 receptor ago- Event Trial in Type 2 Diabetes Mellitus tant for patients with reduced eGFR, for nists (GLP-1 RA) also have direct effects Patients], CANVAS (Canagliflozin Car- whom urinary excretion of sodium and on the kidney and have been reported diovascular Assessment Study), LEADER potassium may be impaired. Recom- to improve renal outcomes compared (Liraglutide Effect and Action in Diabetes: mendations for dietary sodium and with placebo (44–47). Renal effects Evaluation of Cardiovascular Outcome potassium intake should be individual- should be considered when selecting Results), and SUSTAIN-6 (Trial to Evaluate ized on the basis of comorbid condi- antihyperglycemia agents (see Section 9 Cardiovascular and Other Long-term tions, medication use, blood pressure, “Pharmacologic Approaches to Glycemic Outcomes With Semaglutide in Subjects and laboratory data. Treatment”). With Type 2 Diabetes) (42,44,47,51). S128 Microvascular Complications and Foot Care Diabetes Care Volume 42, Supplement 1, January 2019

Specifically, compared with placebo, em- was stopped early due to positive efficacy, reduction of ASCVD than for CKD pro- pagliflozin reduced the risk of incident with detailed results expected in 2019. gression or heart failure. or worsening nephropathy (a composite Inaddition torenal effects, some SGLT2 of progression to UACR .300 mg/g Cr, inhibitors and GLP-1 RA have demon- Cardiovascular Disease and Blood Pressure doubling of serum Cr, ESRD, or death strated cardiovascular benefits. Namely, Hypertension is a strong risk factor for from ESRD) by 39% and the risk of in EMPA-REG OUTCOME, CANVAS, and the development and progression of CKD doubling of serum Cr accompanied by LEADER, empagliflozin, canagliflozin, and (56). Antihypertensive therapy reduces eGFR #45 mL/min/1.73 m2 by 44%; liraglutide, respectively, each reduced the risk of albuminuria (57–60), and canagliflozin reduced the risk of pro- cardiovascular events, evaluated as pri- among patients with type 1 or 2 diabetes gression of albuminuria by 27% and the mary outcomes, compared with placebo with established CKD (eGFR ,60 mL/ risk of reduction in eGFR, ESRD, or death (see Section 10 “Cardiovascular Disease min/1.73 m2 and UACR $300 mg/g Cr), from ESRD by 40%; liraglutide reduced and Risk Management” for further dis- ACE inhibitor or ARB therapy reduces the risk of new or worsening nephrop- cussion). The glucose-lowering effects of the risk of progression to ESRD (61–63). athy (a composite of persistent macro- SGLT2 inhibitors are blunted with eGFR Moreover, antihypertensive therapy re- albuminuria, doubling of serum Cr, ESRD, (18,51). However, the cardiovascular ben- duces risks of cardiovascular events or death from ESRD) by 22%; and sem- efits of empagliflozin, canagliflozin, and (57). aglutide reduced the risk of new or liraglutide were similar among partici- Blood pressure levels ,140/90 mmHg worsening nephropathy (a composite pants with and without kidney disease at are generally recommended to reduce of persistent UACR .300 mg/g Cr, dou- baseline (42,44,51,55). Most participants CVD mortality and slow CKD progression bling of serum Cr, or ESRD) by 36% (each with CKD in these trials also had diagnosed among people with diabetes (60). Lower P , 0.01). ASCVD at baseline, though approximately blood pressure targets (e.g., ,130/ These analyses were limited by eval- 28% of CANVAS participants with CKD 80 mmHg) may be considered for pa- uation of study populations not selected did not have diagnosed ASCVD (19). tients based on individual anticipated primarily for CKD and examination of Important caveats limit the strength of benefits and risks. Patients with CKD renal effects as secondary outcomes. evidence supporting the recommenda- are at increased risk of CKD progression However, all of these trials included large tion of SGLT2 inhibitors and GLP-1 RA in (particularly those with albuminuria) and numbers of people with kidney disease patients with type 2 diabetes and CKD. CVD and therefore may be suitable in some (for example, the baseline prevalence As noted above, published data address cases for lower blood pressure targets. of albuminuria in EMPA-REG OUTCOME a limited group of CKD patients, mostly ACE inhibitors or ARBs are the pre- was 53%), and some of the cardiovascular with coexisting ASCVD. Renal events ferred first-line agent for blood pressure outcomes trials (CANVAS and LEADER) have been examined primarily as sec- treatment among patients with diabetes, were enriched with patients with kidney ondary outcomes in published large hypertension, eGFR ,60 mL/min/1.73 disease through eligibility criteria based trials. Also, adverse event profiles of m2, and UACR $300 mg/g Cr because of on albuminuria or reduced eGFR. In these agents must be considered. Please their proven benefits for prevention of addition, subgroup analyses of CANVAS refer to Table 9.1 for drug-specificfac- CKD progression (61–64). In general, ACE and LEADER suggested that the renal tors, including adverse event infor- inhibitors and ARBs are considered to benefits of canagliflozin and liraglutide mation, for these agents. Therefore, have similar benefits (65,66) and risks. In were as great or greater for participants additional clinical trials are needed to the setting of lower levels of albumin- with CKD at baseline (19,46) and in more rigorously assess the benefits and uria (30–299 mg/g Cr), ACE inhibitor or CANVAS were similar for participants risks of these classes of drugs among ARB therapy has been demonstrated to with or without atherosclerotic cardio- people with CKD. reduce progression to more advanced vascular disease (ASCVD) at baseline (52). For patients with type 2 diabetes and albuminuria ($300 mg/g Cr) and car- Smaller, shorter-term trials also demon- CKD, the selection of specific agents may diovascular events but not progression strate favorable renal effects of medica- depend on comorbidity and CKD stage. to ESRD (64,67). While ACE inhibitors or tions in these classes (53, 53a). Together, SGLT2 inhibitors may be more useful ARBs are often prescribed for albumin- these consistent results suggest likely for patients at high risk of CKD progres- uria without hypertension, clinical trials renal benefits of both drug classes. sion (i.e., with albuminuria or a history have not been performed in this setting Several large clinical trials of SGLT2 of documented eGFR loss) (Fig. 9.1) to determine whether this improves inhibitors focused on patients with CKD, because they appear to have large ben- renal outcomes. and assessment of primary renal out- eficial effects on CKD incidence. Empagli- Absent kidney disease, ACE inhibitors comes are completed or ongoing. Can- flozin and canagliflozin are only approved or ARBs are useful to control blood agliflozin and Renal Endpoints in by the FDA for use with eGFR $45 mL/ pressure but may not be superior to Diabetes with Established Nephropa- min/1.73 m2 (though pivotal trials for alternative proven classes of antihyper- thy Clinical Evaluation (CREDENCE), a each included participants with eGFR tensive therapy, including thiazide-like placebo-controlled trial of canagliflozin $30 mL/min/1.73 m2 and demonstrated diuretics and dihydropyridine calcium among 4,401 adults with type 2 diabetes, benefit in subgroups with low eGFR) channel blockers (68). In a trial of people UACR $300 mg/g, and eGFR 30–90 (18,19), and dapagliflozin is only ap- with type 2 diabetes and normal urine mL/min/1.73 m2, has a primary composite proved for eGFR $60 mL/min/1.73 m2. albumin excretion, an ARB reduced or end point of ESRD, doubling of serum Cr, Some GLP-1 RA may be used with lower suppressed the development of albu- or renal or cardiovascular death (54). It eGFR and may have greater benefits for minuria but increased the rate of care.diabetesjournals.org Microvascular Complications and Foot Care S129

cardiovascular events (69). In a trial of potential need for renal replacement trimester in patients with pre- people with type 1 diabetes exhibiting therapy. existing type 1 or type 2 diabetes, neither albuminuria nor hypertension, DIABETIC RETINOPATHY and then patients should be mon- ACE inhibitors or ARBs did not prevent itored every trimester and for 1- the development of diabetic glomerulop- Recommendations year postpartum as indicated by athy assessed by kidney biopsy (70). 11.13 Optimize glycemic control to the degree of retinopathy. B Therefore, ACE inhibitors or ARBs are reduce the risk or slow the not recommended for patients without progression of diabetic reti- Treatment 11.21 hypertension to prevent the development nopathy. A Promptly refer patients with of CKD. 11.14 Optimize blood pressure and any level of macular edema, Two clinical trials studied the combi- serum lipid control to reduce severe nonproliferative dia- nations of ACE inhibitors and ARBs and the risk or slow the progression betic retinopathy (a precursor found no benefits on CVD or CKD, and of diabetic retinopathy. A of proliferative diabetic reti- the drug combination had higher ad- nopathy), or any proliferative Screening verse event rates (hyperkalemia and/or diabetic retinopathy to an 11.15 Adults with type 1 diabetes AKI) (71,72). Therefore, the combined use ophthalmologist who is knowl- should have an initial dilated of ACE inhibitors and ARBs should be edgeable and experienced in and comprehensive eye exam- avoided. the management of diabetic ination by an ophthalmologist A Mineralocorticoid receptor antago- retinopathy. or optometrist within 5 years 11.22 nists (spironolactone, eplerenone, and The traditional standard treat- after the onset of diabetes. B finerenone) in combination with ACE ment, panretinal laser photo- 11.16 Patients with type 2 diabetes inhibitors or ARBs remain an area of coagulation therapy, is indicated should have an initial dilated and great interest. Mineralocorticoid recep- to reduce the risk of vision loss in comprehensive eye examina- tor antagonists are effective for manage- patients with high-risk prolifera- tion by an ophthalmologist or ment of resistant hypertension, have tive diabetic retinopathy and, in optometrist at the time of been shown to reduce albuminuria some cases, severe nonprolifer- the diabetes diagnosis. B A in short-term studies of CKD, and may ative diabetic retinopathy. 11.17 If there is no evidence of ret- 11.23 – have additional cardiovascular benefits Intravitreous injections of anti inopathy for one or more an- (73–75). There has been, however, an vascular endothelial growth fac- nual eye exam and glycemia is increase in hyperkalemic episodes in tor ranibizumab are not inferior well controlled, then exams those on dual therapy, and larger, to traditional panretinal laser every 1–2 years may be con- longer trials with clinical outcomes photocoagulation and are also sidered. If any level of diabetic are needed before recommending indicated to reduce the risk of retinopathy is present, subse- such therapy. vision loss in patients with pro- quent dilated retinal examina- liferative diabetic retinopathy. A tions should be repeated at 11.24 Intravitreous injections of anti– Referral to a Nephrologist least annually by an ophthal- Consider referral to a physician experi- vascular endothelial growth mologist or optometrist. If enced in the care of kidney disease when factor are indicated for central- retinopathy is progressing or there is uncertainty about the etiology of involved diabetic macular edema, sight-threatening, then exami- kidney disease, difficult management which occurs beneath the foveal nations will be required more issues (anemia, secondary hyperparathy- center and may threaten reading frequently. B A roidism, metabolic bonedisease, resistant vision. 11.18 Telemedicine programs that 11.25 hypertension, or electrolyte disturban- The presence of retinopathy is use validated retinal photog- ces), or advanced kidney disease (eGFR not a contraindication to aspi- raphy with remote reading by ,30 mL/min/1.73 m2) requiring discus- rin therapy for cardioprotection, an ophthalmologist or optome- sion of renal replacement therapy for as aspirin does not increase the trist and timely referral for a A ESRD. The threshold for referral may risk of retinal hemorrhage. comprehensive eye examina- vary depending on the frequency with tion when indicated can be an which a provider encounters patients Diabetic retinopathy is a highly specific appropriate screening strategy with diabetes and kidney disease. Con- vascular complication of both type 1 for diabetic retinopathy. B sultation with a nephrologist when stage and type 2 diabetes, with prevalence 11.19 Women with preexisting type 4 CKD develops (eGFR ,30 mL/min/ strongly related to both the duration 1 or type 2 diabetes who are 1.73 m2) has been found to reduce of diabetes and the level of glycemic planning pregnancy or who cost, improve quality of care, and delay control (77). Diabetic retinopathy is are pregnant should be coun- dialysis (76). However, other specialists the most frequent cause of new cases seled on the risk of develop- and providers should also educate their of blindness among adults aged 20–74 ment and/or progression of patients about the progressive nature years in developed countries. Glaucoma, diabetic retinopathy. B of CKD, the kidney preservation bene- cataracts, and other disorders of the 11.20 Eye examinations should occur fits of proactive treatment of blood eye occur earlier and more frequently before pregnancy or in the first pressure and blood glucose, and the in people with diabetes. S130 Microvascular Complications and Foot Care Diabetes Care Volume 42, Supplement 1, January 2019

In addition to diabetes duration, fac- are not readily available (82,83). High- prevent loss of vision and to intervene tors that increase the risk of, or are asso- quality fundus photographs can detect with treatment when vision loss can be ciated with, retinopathy include chronic most clinically significant diabetic reti- prevented or reversed. hyperglycemia (78), nephropathy (79), hy- nopathy. Interpretation of the images Photocoagulation Surgery pertension (80), and dyslipidemia (81). should be performed by a trained eye Two large trials, the Diabetic Retinopathy Intensive diabetes management with the care provider. Retinal photography may Study (DRS) in patients with PDR and the fi goal of achieving near-normoglycemia also enhance ef ciency and reduce costs Early Treatment Diabetic Retinopathy has been shown in large prospective ran- when the expertise of ophthalmologists Study (ETDRS) in patients with macular domized studies to prevent and/or delay can be used for more complex examina- edema, provide the strongest support for the onset and progression of diabetic ret- tions and for therapy (90,91). In-person the therapeutic benefits of photocoag- inopathy and potentially improve patient- exams are still necessary when the ulation surgery. The DRS (96) showed in – reported visual function (30,82 84). retinal photos are of unacceptable 1978 that panretinal photocoagulation Several case series and a controlled quality and for follow-up if abnormal- surgery reduced the risk of severe vision prospective study suggest that preg- ities are detected. Retinal photos are loss from PDR from 15.9% in untreated nancy in patients with type 1 diabetes not a substitute for comprehensive eyes to 6.4% in treated eyes with the may aggravate retinopathy and threaten eye exams, which should be performed greatest benefit ratio in those with more vision, especially when glycemic control at least initially and at intervals there- advanced baseline disease (disc neovas- is poor at the time of conception (85,86). after as recommended by an eye care cularization or vitreous hemorrhage). In Laser photocoagulation surgery can mini- professional. Results of eye examina- 1985, the ETDRS also verified the benefits mize the risk of vision loss (86). tions should be documented and trans- of panretinal photocoagulation for high- mitted to the referring health care risk PDR and in older-onset patients with professional. severe nonproliferative diabetic retinop- Screening athy or less-than-high-risk PDR. Panretinal The preventive effects of therapy and Type 1 Diabetes Because retinopathy is estimated to take laser photocoagulation is still commonly the fact that patients with proliferative at least 5 years to develop after the onset used to manage complications of diabe- diabetic retinopathy (PDR) or macular of hyperglycemia, patients with type 1 tic retinopathy that involve retinal neo- edema may be asymptomatic provide diabetes should have an initial dilated and vascularization and its complications. strong support for screening to detect comprehensive eye examination within diabetic retinopathy. Anti–Vascular Endothelial Growth Factor 5 years after the diagnosis of diabetes (92). An ophthalmologist or optometrist Treatment who is knowledgeable and experienced Type 2 Diabetes Recent data from the Diabetic Retinop- in diagnosing diabetic retinopathy should Patients with type 2 diabetes who may athy Clinical Research Network and perform the examinations. Youth with have had years of undiagnosed diabetes others demonstrate that intravitreal in- type 1 or type 2 diabetes are also at and have a significant risk of prevalent jections of anti–vascular endothelial riskforcomplicationsandneedtobe diabetic retinopathy at the time of di- growth factor (anti-VEGF) agent, specif- screened for diabetic retinopathy (87). If agnosis should have an initial dilated and ically ranibizumab, resulted in visual diabetic retinopathy is present, prompt comprehensive eye examination at the acuity outcomes that were not inferior referral to an ophthalmologist is recom- time of diagnosis. to those observed in patients treated mended. Subsequent examinations for with panretinal laser at 2 years of follow- patients with type 1 or type 2 diabetes Pregnancy up (97). In addition, it was observed are generally repeated annually for pa- Pregnancy is associated with a rapid that patients treated with ranibizumab tients with minimal to no retinopathy. progression of diabetic retinopathy tended to have less peripheral visual field Exams every 1–2yearsmaybecost- (93,94). Women with preexisting type 1 loss, fewer vitrectomy surgeries for sec- effective after one or more normal eye or type 2 diabetes who are planning ondary complications from their prolif- exams, and in a population with well- pregnancy or who have become pregnant erative disease, and a lower risk of controlled type 2 diabetes, there was should be counseled on the risk of de- developing diabetic macular edema. essentially no risk of development of velopment and/or progression of diabetic However, a potential drawback in using significant retinopathy with a 3-year in- retinopathy. In addition, rapid implemen- anti-VEGF therapy to manage prolifera- terval after a normal examination (88). tation of intensive glycemic management tive disease is that patients were re- Less frequent intervals have been found in the setting of retinopathy is associated quired to have a greater number of in simulated modeling to be potentially with early worsening of retinopathy (86). visits and received a greater number effective in screening for diabetic reti- Womenwhodevelopgestationaldiabetes of treatments than is typically required nopathy in patients without diabetic mellitus do not require eye examinations for management with panretinal laser, retinopathy (89). More frequent exami- during pregnancy and do not appear to be which may not be optimal for some nations by the ophthalmologist will be at increased risk of developing diabetic patients. Other emerging therapies for required if retinopathy is progressing. retinopathy during pregnancy (95). retinopathy that may use sustained intra- Retinal photography with remote vitreal delivery of pharmacologic agents reading by experts has great potential Treatment are currently under investigation. The FDA to provide screening services in areas Two of the main motivations for screen- approved ranibizumab for the treatment where qualified eye care professionals ing for diabetic retinopathy are to of diabetic retinopathy in 2017. care.diabetesjournals.org Microvascular Complications and Foot Care S131

While the ETDRS (98) established the Specific treatment for the underlying 11.27 Assessment for distal symmet- benefit of focal laser photocoagulation nerve damage, other than improved ric polyneuropathy should in- surgery in eyes with clinically significant glycemic control, is currently not avail- clude a careful history and macular edema (defined as retinal able. Glycemic control can effectively assessment of either tempera- edema located at or within 500 mm prevent DPN and cardiac autonomic ture or pinprick sensation (small- of the center of the macula), current data neuropathy (CAN) in type 1 diabetes fiber function) and vibration from well-designed clinical trials demon- (105,106) and may modestly slow their sensation using a 128-Hz tuning strate that intravitreal anti-VEGF agents progression in type 2 diabetes (32), but fork (for large-fiber function). provide a more effective treatment reg- does not reverse neuronal loss. Thera- All patients should have annual imen for central-involved diabetic mac- peutic strategies (pharmacologic and 10-g monofilament testing to ular edema than monotherapy or even nonpharmacologic) for the relief of pain- identify feet at risk for ulcera- combination therapy with laser (99–101). ful DPN and symptoms of autonomic tion and amputation. B There are currently three anti-VEGF neuropathy can potentially reduce pain 11.28 Symptoms and signs of auto- agents commonly used to treat eyes (107) and improve quality of life. nomic neuropathy should be with central-involved diabetic macular assessed in patients with mi- edemadbevacizumab, ranibizumab, and crovascular complications. E Diagnosis aflibercept (77). Diabetic Peripheral Neuropathy Treatment In both the DRS and the ETDRS, laser 11.29 Optimize glucose control to Patients with type 1 diabetes for 5 or photocoagulation surgery was benefi- prevent or delay the develop- more years and all patients with type 2 cial in reducing the risk of further visual ment of neuropathy in patients diabetes should be assessed annually for loss in affected patients but generally with type 1 diabetes A and to DPN using the medical history and simple not beneficial in reversing already di- slow the progression of neu- clinical tests. Symptoms vary according minished acuity. Anti-VEGF therapy fi ropathy in patients with type 2 to the class of sensory bers involved. improves vision and has replaced the diabetes. B The most common early symptoms are need for laser photocoagulation in the 11.30 Assess and treat patients to induced by the involvement of small vast majority of patients with diabetic fi reduce pain related to diabetic bers and include pain and dysesthesia macular edema (102). Most patients re- peripheral neuropathy B and (unpleasant sensations of burning and quire near-monthly administration of fi symptoms of autonomic neu- tingling). The involvement of large bers intravitreal therapy with anti-VEGF agents ropathy and to improve quality may cause numbness and loss of pro- during the first 12 months of treatment, of life. E tective sensation (LOPS). LOPS indicates with fewer injections needed in subse- 11.31 Pregabalin, duloxetine, or the presence of distal sensorimotor poly- quent years to maintain remission from gabapentin are recommended neuropathy and is a risk factor for diabetic central-involved diabetic macular edema. asinitial pharmacologic treat- foot ulceration. The following clinical tests ments for neuropathic pain in may be used to assess small- and large- Adjunctive Therapy fiber function and protective sensation: Lowering blood pressure has been shown diabetes. A to decrease retinopathy progression, al- 1. Small-fiber function: pinprick and tem- though tight targets (systolic blood The diabetic neuropathies are a hetero- perature sensation , pressure 120 mmHg) do not impart geneous group of disorders with diverse 2. Large-fiber function: vibration per- fi additional bene t (83). ACE inhibitors clinical manifestations. The early recog- ception and 10-g monofilament and ARBs are both effective treatments nition and appropriate management of 3. Protective sensation: 10-g monofila- in diabetic retinopathy (103). In patients neuropathy in the patient with diabetes ment with dyslipidemia, retinopathy progres- is important. sion may be slowed by the addition of These tests not only screen for the fenofibrate, particularly with very mild 1. Diabetic neuropathy is a diagnosis of presence of dysfunction but also predict nonproliferative diabetic retinopathy at exclusion. Nondiabetic neuropathies future risk of complications. Electrophys- baseline (81,104). may be present in patients with di- iologicaltestingorreferraltoaneurologist abetes and may be treatable. is rarely needed, except in situations 2. Numerous treatment options exist for where the clinical features are atypical NEUROPATHY symptomatic diabetic neuropathy. or the diagnosis is unclear. Recommendations 3. Up to 50% of diabetic peripheral In all patients with diabetes and DPN, neuropathy (DPN) may be asymptom- causes of neuropathy other than diabe- Screening atic. If not recognized and if preven- tes should be considered, including 11.26 All patients should be assessed tive foot care is not implemented, toxins (e.g., alcohol), neurotoxic med- for diabetic peripheral neurop- patients are at risk for injuries to their ications (e.g., chemotherapy), vitamin athy starting at diagnosis of insensate feet. B12 deficiency, hypothyroidism, renal type 2 diabetes and 5 years 4. Recognition and treatment of auto- disease, malignancies (e.g., multiple after the diagnosis of type 1 nomic neuropathy may improve myeloma, bronchogenic carcinoma), in- diabetes and at least annually symptoms, reduce sequelae, and im- fections (e.g., HIV), chronic inflamma- thereafter. B prove quality of life. tory demyelinating neuropathy, inherited S132 Microvascular Complications and Foot Care Diabetes Care Volume 42, Supplement 1, January 2019

neuropathies, and vasculitis (108). See genitourinary disturbances, including the U.S. and Canada, but the evidence the American Diabetes Association (ADA) sexual dysfunction and bladder dysfunc- of its use is weaker (120). Comparative position statement “Diabetic Neuropa- tion. In men, diabetic autonomic neu- effectiveness studies and trials that in- thy” for more details (107). ropathy may cause erectile dysfunction clude quality-of-life outcomes are rare, and/or retrograde ejaculation (107). Fe- so treatment decisions must consider Diabetic Autonomic Neuropathy male sexual dysfunction occurs more each patient’s presentation and comor- The symptoms and signs of autonomic frequently in those with diabetes and bidities and often follow a trial-and-error neuropathy should be elicited carefully presents as decreased sexual desire, in- approach. Given the range of partially during the history and physical exami- creased pain during intercourse, de- effective treatment options, a tailored nation. Major clinical manifestations of creased sexual arousal, and inadequate and stepwise pharmacologic strategy diabetic autonomic neuropathy include lubrication (111). Lower urinary tract with careful attention to relative symp- hypoglycemia unawareness, resting tachy- symptoms manifest as urinary inconti- tom improvement, medication adher- cardia, orthostatic hypotension, gastro- nence and bladder dysfunction (nocturia, ence, and medication side effects is paresis, constipation, diarrhea, fecal frequent urination, urination urgency, recommended to achieve pain reduction incontinence, erectile dysfunction, neu- and weak urinary stream). Evaluation and improve quality of life (121–123). rogenic bladder,andsudomotor dysfunc- of bladder function should be performed Pregabalin, a calcium channel a2-d tion with either increased or decreased for individuals with diabetes who have subunit ligand, is the most extensively sweating. recurrent urinary tract infections, pyelo- studied drug for DPN. The majority of Cardiac Autonomic Neuropathy. CAN is nephritis, incontinence, or a palpable studies testing pregabalin have reported associated with mortality independently bladder. favorable effects on the proportion of of other cardiovascular risk factors participants with at least 30–50% im- (109,110). In its early stages, CAN may Treatment provement in pain (120,122,124–127). be completely asymptomatic and de- Glycemic Control However, not all trials with pregabalin tected only by decreased heart rate Near-normal glycemic control, imple- have been positive (120,122,128,129), variability with deep breathing. Ad- mented early in the course of diabetes, especially when treating patients with vanced disease may be associated has been shown to effectively delay or advanced refractory DPN (126). Adverse with resting tachycardia (.100 bpm) prevent the development of DPN and effects may be more severe in older and orthostatic hypotension (a fall in CAN in patients with type 1 diabetes patients (130) and may be attenuated systolic or diastolic blood pressure (112–115). Although the evidence for by lower starting doses and more gradual by .20 mmHg or .10 mmHg, respec- the benefit of near-normal glycemic con- titration. The related drug, gabapentin, tively, upon standing without an appro- trol is not as strong for type 2 diabetes, has also shown efficacy for pain control in priate increase in heart rate). CAN some studies have demonstrated a mod- diabetic neuropathy and may be less treatment is generally focused on alle- est slowing of progression without re- expensive, although it is not FDA ap- viating symptoms. versal of neuronal loss (32,116). Specific proved for this indication (131). glucose-lowering strategies may have Duloxetine is a selective norepineph- Gastrointestinal Neuropathies. Gastroin- rine and serotonin reuptake inhibitor. testinal neuropathies may involve any different effects. In a post hoc analysis, Doses of 60 and 120 mg/day showed portion of the gastrointestinal tract with participants, particularly men, in the efficacy in the treatment of pain associ- manifestations including esophageal Bypass Angioplasty Revascularization In- ated with DPN in multicenter random- dysmotility, gastroparesis, constipation, vestigation in Type 2 Diabetes (BARI 2D) ized trials, although some of these had diarrhea, and fecal incontinence. Gastro- trial treated with insulin sensitizers had a high drop-out rates (120,122,127,129). paresis should be suspected in individ- lower incidence of distal symmetric poly- Duloxetine also appeared to improve uals with erratic glycemic control or with neuropathy over 4 years than those neuropathy-related quality of life (132). upper gastrointestinal symptoms with- treated with insulin/sulfonylurea (117). In longer-term studies, a small increase in out another identified cause. Exclusion Neuropathic Pain A1C was reported in people with diabetes of organic causes of gastric outlet Neuropathic pain can be severe and can treated with duloxetine compared with obstruction or peptic ulcer disease impact quality of life, limit mobility, and placebo (133). Adverse events may be (with esophagogastroduodenoscopy contribute to depression and social dys- more severe in older people but may be or a barium study of the stomach) is function (118). No compelling evidence attenuated with lower doses and slower needed before considering a diagnosis of exists in support of glycemic control or titrations of duloxetine. or specialized testing for gastroparesis. lifestyle management as therapies for Tapentadol is a centrally acting opioid The diagnostic gold standard for gastro- neuropathic pain in diabetes or predia- analgesic that exerts its analgesic effects paresis is the measurement of gastric betes, which leaves only pharmaceutical through both m-opioid receptor agonism emptying with scintigraphy of digestible interventions (119). and noradrenaline reuptake inhibition. solids at 15-min intervals for 4 h after Pregabalin and duloxetine have re- Extended-release tapentadol was ap- food intake. The use of 13C octanoic ceived regulatory approval by the FDA, proved by the FDA for the treatment acid breath test is emerging as a viable Health Canada, and the European Med- of neuropathic pain associated with di- alternative. icines Agency for the treatment of neu- abetes based on data from two multi- Genitourinary Disturbances. Diabetic au- ropathic pain in diabetes. The opioid center clinical trials in which participants tonomic neuropathy may also cause tapentadol has regulatory approval in titrated to an optimal dose of tapentadol care.diabetesjournals.org Microvascular Complications and Foot Care S133

were randomly assigned to continue that may also improve intestinal motility and renal disease and assess dose or switch to placebo (134,135). (136,140). In cases of severe gastropa- current symptoms of neurop- However, both used a design enriched resis, pharmacologic interventions are athy (pain, burning,numbness) for patients who responded to tapentadol needed. Only metoclopramide, a proki- and vascular disease (leg fa- and therefore their results are not gen- netic agent, is approved by the FDA for tigue, claudication). B eralizable. A recent systematic review the treatment of gastroparesis. How- 11.35 The examination should include and meta-analysis by the Special Interest ever, the level of evidence regarding inspection of the skin, assessment Group on Neuropathic Pain of the In- the benefits of metoclopramide for of foot deformities, neurological ternational Association for the Study the management of gastroparesis is assessment (10-g monofilament of Pain found the evidence support- weak, and given the risk for serious testing with at least one other ing the effectiveness of tapentadol in adverse effects (extrapyramidal signs assessment: pinprick, tempera- reducing neuropathic pain to be incon- such as acute dystonic reactions, ture, vibration), and vascular as- clusive (120). Therefore, given the high drug-induced parkinsonism, akathisia, sessment including pulses in the risk for addiction and safety concerns and tardive dyskinesia), its use in the legs and feet. B compared with the relatively modest treatment of gastroparesis beyond 11.36 Patients with symptoms of pain reduction, the use of extended- 12 weeks is no longer recommended claudication or decreased or release tapentadol is not generally rec- by the FDA or the European Medicines absent pedal pulses should be ommended as a first- or second-line Agency. It should be reserved for se- referred for ankle-brachial in- therapy. The use of any opioids for vere cases that are unresponsive dex and for further vascular management of chronic neuropathic to other therapies (140). Other treat- assessment as appropriate. C pain carries the risk of addiction and ment options include domperidone 11.37 A multidisciplinary approach is should be avoided. (available outside of the U.S.) and eryth- recommended for individuals Tricyclic antidepressants, venlafaxine, romycin, which is only effective for with foot ulcers and high-risk carbamazepine, and topical capsaicin, al- short-term use due to tachyphylaxis feet (e.g., dialysis patients and though not approved for the treatment (141,142). Gastric electrical stimulation those with Charcot foot or of painful DPN, may be effective and using a surgically implantable device prior ulcers or amputation). B considered for the treatment of painful has received approval from the FDA, 11.38 Refer patients who smoke or DPN (107,120,122). although its efficacyis variableanduse is who have histories of prior limited to patients with severe symp- lower-extremity complications, Orthostatic Hypotension toms that are refractory to other treat- loss of protective sensation, Treating orthostatic hypotension is chal- ments (143). lenging. The therapeutic goal is to min- structural abnormalities, or pe- imize postural symptoms rather than to Erectile Dysfunction ripheral arterial disease to foot restore normotension. Most patients re- In addition to treatment of hypogonad- care specialists for ongoing pre- quire both nonpharmacologic measures ism if present, treatments for erectile ventive care and lifelong sur- (e.g., ensuringadequate saltintake,avoid- dysfunction may include phosphodies- veillance. C ing medications that aggravate hypoten- terase type 5 inhibitors, intracorporeal or 11.39 Provide general preventive sion, or using compressive garments over intraurethral prostaglandins, vacuum de- foot self-care education to all the legs and abdomen) and pharmaco- vices, or penile prostheses. As with DPN patients with diabetes. B logic measures. Physical activity and ex- treatments, these interventions do not 11.40 The use of specialized thera- ercise should be encouraged to avoid change the underlying pathology and peutic footwear is recommen- deconditioning, which is known to exac- natural history of the disease process ded for high-risk patients with erbate orthostatic intolerance, and vol- but may improve the patient’s quality diabetes including those with ume repletion with fluids and salt is of life. severe neuropathy, foot de- critical. Midodrine and droxidopa are formities, or history of ampu- approved by the FDA for the treatment tation. B FOOT CARE of orthostatic hypotension. Recommendations Gastroparesis Foot ulcers and amputation, which 11.32 Perform a comprehensive foot Treatment for diabetic gastroparesis may are consequences of diabetic neuropa- evaluation at least annually to be very challenging. A low-fiber, low-fat thy and/or peripheral arterial disease identify risk factors for ulcers eating plan provided in small frequent (PAD), are common and represent major and amputations. B meals with a greater proportion of liquid causes of morbidity and mortality in 11.33 Patients with evidence of sen- calories may be useful (136–138). In people with diabetes. Early recognition sory loss or prior ulceration or addition, foods with small particle size and treatment of patients with diabetes amputation should have their may improve key symptoms (139). With- and feet at risk for ulcers and amputa- feet inspected at every visit. C drawing drugs with adverse effects tions can delay or prevent adverse 11.34 Obtain a prior history of ulcer- on gastrointestinal motility including outcomes. ation, amputation, Charcot foot, opioids, anticholinergics, tricyclic anti- The risk of ulcers or amputations is angioplasty or vascular surgery, depressants, GLP-1 RA, pramlintide, and increased in people who have the fol- cigarette smoking, retinopathy, possibly dipeptidyl peptidase 4 inhibitors lowing risk factors: S134 Microvascular Complications and Foot Care Diabetes Care Volume 42, Supplement 1, January 2019

○ Poor glycemic control (history of ulcer or amputation, defor- four eyes per side, padded tongue, qual- ○ Peripheral neuropathy with LOPS mity, LOPS, or PAD) and their families ity lightweight materials, and sufficient ○ Cigarette smoking should be provided general education size to accommodate a cushioned insole. ○ Foot deformities about risk factors and appropriate man- Use of custom therapeutic footwear can ○ Preulcerative callus or corn agement (146). Patients at risk should help reduce the risk of future foot ulcers ○ PAD understand the implications of foot de- in high-risk patients (145,147). ○ History of foot ulcer formities, LOPS, and PAD; the proper care Most diabetic foot infections are poly- ○ Amputation of the foot, including nail and skin care; microbial, with aerobic gram-positive ○ Visual impairment and the importance of foot monitoring cocci. Staphylococci and streptococci ○ CKD (especially patients on dialysis) on a daily basis. Patients with LOPS are the most common causative organ- should beeducated on ways to substitute isms. Wounds without evidence of soft Clinicians are encouraged to review ADA other sensory modalities (palpation or tissue or bone infection do not require screening recommendations for further visual inspection using an unbreakable antibiotic therapy. Empiric antibiotic details and practical descriptions of how mirror) for surveillance of early foot therapy can be narrowly targeted at to perform components of the compre- problems. gram-positive cocci in many patients hensive foot examination (144). The selection of appropriate footwear with acute infections, but those at risk and footwear behaviors at home should for infection with antibiotic-resistant Evaluation for Loss of Protective also be discussed. Patients’ understand- organisms or with chronic, previously Sensation ing of these issues and their physical treated, or severe infections require All adults with diabetes should undergo a ability to conduct proper foot surveil- broader-spectrum regimens and should comprehensive foot evaluation at least lance and care should be assessed. Pa- be referred to specialized care centers annually. Detailed foot assessments may tients with visual difficulties, physical (148). Foot ulcers and wound care may occur more frequently in patients with constraints preventing movement, or require care by a podiatrist, orthopedic histories of ulcers or amputations, foot cognitive problems that impair their abil- or vascular surgeon, or rehabilitation deformities, insensate feet, and PAD ity to assess the condition of the foot and specialist experienced in the manage- (145). To assess risk, clinicians should to institute appropriate responses will ment of individuals with diabetes (148). ask about history of foot ulcers or am- need other people, such as family mem- Hyperbaric oxygen therapy (HBOT) in putation, neuropathic and peripheral bers, to assist with their care. patients with diabetic foot ulcers has vascular symptoms, impaired vision, re- mixed evidence supporting its use as nal disease, tobacco use, and foot care Treatment an adjunctive treatment to enhance practices. A general inspection of skin People with neuropathy or evidence wound healing and prevent amputation integrity and musculoskeletal deform- of increased plantar pressures (e.g., (149–151). In a relatively high-quality ities should be performed. Vascular as- erythema, warmth, or calluses) may double-blind study of patients with chronic sessment should include inspection and be adequately managed with well-fitted diabetic foot ulcers, hyperbaric oxygen palpation of pedal pulses. walking shoes or athletic shoes that as an adjunctive therapy resulted in The neurological exam performed as cushion the feet and redistribute pres- significantly more complete healing of part of the foot examination is designed sure. People with bony deformities the index ulcer in patients treated with to identify LOPS rather than early neurop- (e.g., hammertoes, prominent metatarsal HBOT compared with placebo at 1 year athy. The 10-g monofilament is the most heads, bunions) may need extra wide or of follow-up (152). However, multiple useful test to diagnose LOPS. Ideally, the deep shoes. People with bony deform- subsequently published studies have 10-g monofilament test should be per- ities, including Charcot foot, who cannot either failed to demonstrate a benefit formed with at least one other assessment be accommodated with commercial of HBOT or have been relatively small (pinprick, temperature or vibration sensa- therapeutic footwear, will require with potential flaws in study design (150). tion using a 128-Hz tuning fork, or ankle custom-molded shoes. Special consider- A well-conducted randomized controlled reflexes). Absent monofilament sensation ation and a thorough workup should be study performed in 103 patients found suggests LOPS, while at least two normal performed when patients with neurop- that HBOT did not reduce the indication tests (and no abnormal test) rules out LOPS. athy present with the acute onset of for amputation or facilitate wound healing a red, hot, swollen foot or ankle, and compared with comprehensive wound Evaluation for Peripheral Arterial Charcot neuroarthropathy should be ex- care in patients with chronic diabetic Disease cluded. Early diagnosis and treatment of foot ulcers (153). A systematic review Initial screening for PAD should include Charcot neuroarthropathy is the best by the International Working Group on a history of decreased walking speed, leg way to prevent deformities that increase the Diabetic Foot of interventions to fatigue, claudication, and an assessment the risk of ulceration and amputation. improve the healing of chronic diabetic of the pedal pulses. Ankle-brachial index The routine prescription of therapeutic foot ulcers concluded that analysis of testing should be performed in patients footwear is not generally recommended. the evidence continues to present meth- with symptoms or signs of PAD. However, patients should be provided odological challenges as randomized adequate information to aid in selection controlled studies remain few, with a Patient Education of appropriate footwear. General foot- majority being of poor quality (150). All patients with diabetes and particu- wear recommendations include a broad HBOT also does not seem to have a larly those with high-risk foot conditions and square toe box, laces with three or significant effect on health-related quality care.diabetesjournals.org Microvascular Complications and Foot Care S135

of life in patients with diabetic foot 10. Delanaye P, Glassock RJ, Pottel H, Rule AD. diabetes: the DCCT/EDIC study. Clin J Am Soc ulcers (154,155). A recent review con- An age-calibrated definition of chronic kidney Nephrol 2016;11:1969–1977 fi cluded that the evidence to date remains disease: rationale and bene ts. Clin Biochem 25. Sumida K, Molnar MZ, Potukuchi PK, et al. Rev 2016;37:17–26 Changes in albuminuria and subsequent risk of inconclusive regarding the clinical and 11. Kramer HJ, Nguyen QD, Curhan G, Hsu C-Y. incident kidney disease. Clin J Am Soc Nephrol cost-effectiveness of HBOT as an adjunc- Renal insufficiency in the absence of albuminuria 2017;12:1941–1949 tive treatment to standard wound care and retinopathy among adults with type 2 di- 25a. Inker LA, Grams ME, Levey AS, et al.; CKD for diabetic foot ulcers (156). Results from abetes mellitus. JAMA 2003;289:3273–3277 Prognosis Consortium. Relationship of estimated 12. Molitch ME, Steffes M, Sun W, et al.; Epi- GFR and albuminuria to concurrent laboratory the recently published Dutch DAMOCLES demiology of Diabetes Interventions and Com- abnormalities: an individual participant data (Does Applying More Oxygen Cure Lower plications Study Group. Development and meta-analysis inaglobalconsortium.AmJKidney Extremity Sores?) trial demonstrated that progression of renal insufficiency with and Dis. 19 October 2018 [Epub ahead of print]. DOI: HBOT in patients with diabetes and is- without albuminuria in adults with type 1 10.1053/j.ajkd.2018.08.013 chemic wounds did not significantly im- diabetes in the Diabetes Control and Com- 26. Mills KT, Chen J, Yang W, et al.; Chronic Renal plications Trial and the Epidemiology of Di- Insufficiency Cohort (CRIC) Study Investigators. prove complete wound healing and limb abetes Interventions and Complications Sodium excretion and the risk of cardiovascular salvage (157). The Centers for Medicare & study. Diabetes Care 2010;33:1536–1543 disease in patients with chronic kidney disease. Medicaid Services currently covers HBOT 13. He F, Xia X, Wu XF, Yu XQ, Huang FX. Diabetic JAMA 2016;315:2200–2210 for diabetic foot ulcers that have failed a retinopathy in predicting diabetic nephropathy 27. DCCT/EDIC Research Group. Effect of inten- standard course of wound therapy when in patients with type 2 diabetes and renal sive diabetes treatment on albuminuria in type 1 disease: a meta-analysis. Diabetologia 2013; diabetes: long-term follow-up of the Diabetes there are no measurable signs of healing 56:457–466 Control and Complications Trial and Epidemiol- for at least 30 consecutive days (158). 14. Levey AS, Coresh J, Balk E, et al.; National ogy of Diabetes Interventions and Complications HBOT should be a topic of shared decision Kidney Foundation. National Kidney Foundation study. Lancet Diabetes Endocrinol 2014;2:793– making before treatment is considered practice guidelines for chronic kidney disease: 800 fi fi for selected patients with diabetic foot evaluation, classi cation, and strati cation. Ann 28. de Boer IH, Sun W, Cleary PA, et al.; DCCT/ Intern Med 2003;139:137–147 EDIC Research Group. Intensive diabetes therapy ulcers (158). 15. Coresh J, Turin TC, Matsushita K, et al. De- and glomerular filtration rate in type 1 diabetes. cline in estimated glomerular filtration rate and N Engl J Med 2011;365:2366–2376 subsequent risk of end-stage renal disease and 29. UK Prospective Diabetes Study (UKPDS) References mortality. JAMA 2014;311:2518–2531 Group. Effect of intensive blood-glucose control 1. Tuttle KR, Bakris GL, Bilous RW, et al. Di- 16. James MT, Grams ME, Woodward M, et al.; with metformin on complications in overweight abetic kidney disease: a report from an ADA CKD Prognosis Consortium. A meta-analysis of patients with type 2 diabetes (UKPDS 34). Lancet Consensus Conference. Diabetes Care 2014;37: the association of estimated GFR, albuminuria, 1998;352:854–865 2864–2883 diabetes mellitus, and hypertension with acute 30. UK Prospective Diabetes Study (UKPDS) 2. National Kidney Foundation. KDIGO 2012 clin- kidney injury. Am J Kidney Dis 2015;66:602–612 Group. Intensive blood-glucose control with ical practice guideline for the evaluation and 17. Nadkarni GN, Ferrandino R, Chang A, et al. sulphonylureas or insulin compared with con- management of chronic kidney disease. Kidney Acute kidney injury in patients on SGLT2 inhib- ventional treatment and risk of complications in Int Suppl 2013;3:1–150 itors: a propensity-matched analysis. Diabetes patients with type 2 diabetes (UKPDS 33). Lancet 3. Afkarian M, Zelnick LR, Hall YN, et al. Clinical Care 2017;40:1479–1485 1998;352:837–853 manifestations of kidney disease among US 18. Wanner C, Inzucchi SE, Lachin JM, et al.; 31. Patel A, MacMahon S, Chalmers J, et al.; adults with diabetes, 1988-2014. JAMA 2016; EMPA-REG OUTCOME Investigators. Empagliflo- ADVANCE Collaborative Group. Intensive blood 316:602–610 zin and progression of kidney disease in type 2 glucose control and vascular outcomes in pa- 4. de Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss diabetes. N Engl J Med 2016;375:323–334 tients with type 2 diabetes. N Engl J Med 2008; NS, Himmelfarb J. Temporal trends in the prev- 19. Neuen BL, Ohkuma T, Neal B, et al. Cardio- 358:2560–2572 alence of diabetic kidney disease in the United vascular and renal outcomes with canagliflozin 32. Ismail-Beigi F, Craven T, Banerji MA, et al.; States. JAMA 2011;305:2532–2539 according to baseline kidney function: data from ACCORDtrial group.Effectof intensivetreatment 5. de Boer IH; DCCT/EDIC Research Group. Kid- the CANVAS Program. Circulation 2018;138: of hyperglycaemia on microvascular outcomes ney disease and related findings in the Diabetes 1537–1550 in type 2 diabetes: an analysis of the ACCORD Control and Complications Trial/Epidemiology of 20. Thakar CV, Christianson A, Himmelfarb J, randomised trial. Lancet 2010;376:419–430 Diabetes Interventions and Complications study. Leonard AC. Acute kidney injury episodes and 33. Zoungas S, Chalmers J, Neal B, et al.; Diabetes Care 2014;37:24–30 chronic kidney disease risk in diabetes mellitus. ADVANCE-ON Collaborative Group. Follow-up 6. UnitedStatesRenalDataSystem.AnnualData Clin J Am Soc Nephrol 2011;6:2567–2572 of blood-pressure lowering and glucose control Report: Epidemiology of Kidney Disease in the 21. Hughes-Austin JM, Rifkin DE, Beben T, et al. in type 2 diabetes. N Engl J Med 2014;371:1392– United States. Bethesda, MD, National Institutes The relation of serum potassium concentration 1406 of Health, National Institute of Diabetes and with cardiovascular events and mortality in 34. Zoungas S, Arima H, Gerstein HC, et al.; Digestive and Kidney Diseases, 2016 community-living individuals. Clin J Am Soc Collaborators on Trials of Lowering Glucose 7. Fox CS, Matsushita K, Woodward M, et al.; Nephrol 2017;12:245–252 (CONTROL) group. Effects of intensive glucose Chronic Kidney Disease Prognosis Consortium. 22. Bandak G, Sang Y, Gasparini A, et al. Hyper- control on microvascular outcomes in patients Associations of kidney disease measures with kalemia after initiating renin-angiotensin system with type 2 diabetes: a meta-analysis of individ- mortality and end-stage renal disease in indi- blockade: the Stockholm Creatinine Measure- ual participant data from randomised controlled viduals with and without diabetes: a meta- ments (SCREAM) Project. J Am Heart Assoc 2017; trials. Lancet Diabetes Endocrinol 2017;5:431– analysis. Lancet 2012;380:1662–1673 6:e005428 437 8. Afkarian M, Sachs MC, Kestenbaum B, et al. 23. Nilsson E, Gasparini A, Arnl¨ ov¨ J, et al. In- 35. Miller ME, Bonds DE, Gerstein HC, et al.; Kidney disease and increased mortality risk in cidence and determinants of hyperkalemia and ACCORD Investigators. The effects of baseline type 2 diabetes. J Am Soc Nephrol 2013;24:302– hypokalemia in a large healthcare system. Int J characteristics, glycaemia treatment approach, 308 Cardiol 2017;245:277–284 and glycated haemoglobin concentration on the 9. Groop P-H, Thomas MC, Moran JL, et al.; 24. de Boer IH, Gao X, Cleary PA, et al.; Diabetes risk of severe hypoglycaemia: post hoc epide- FinnDiane Study Group. The presence and Control and Complications Trial/Epidemiology of miological analysis of the ACCORD study. BMJ severity of chronic kidney disease predicts Diabetes Interventions and Complications (DCCT/ 2010;340:b5444 all-cause mortality in type 1 diabetes. Diabetes EDIC) Research Group. Albuminuria changes and 36. Papademetriou V, Lovato L, Doumas M, 2009;58:1651–1658 cardiovascular and renal outcomes in type 1 et al.; ACCORD Study Group. Chronic kidney S136 Microvascular Complications and Foot Care Diabetes Care Volume 42, Supplement 1, January 2019

disease and intensive glycemic control increase cardiovascular outcomes, and mortality in study and MICRO-HOPE substudy. Lancet 2000; cardiovascular risk in patients with type 2 di- type 2 diabetes. N Engl J Med 2015;373: 355:253–259 abetes. Kidney Int 2015;87:649–659 2117–2128 65. Barnett AH, Bain SC, Bouter P, et al.; Dia- 37. Perkovic V, Heerspink HL, Chalmers J, et al.; 52. Mahaffey KW, Neal B, Perkovic V, et al.; betics Exposed to Telmisartan and Enalapril ADVANCECollaborativeGroup.Intensiveglucose CANVAS Program Collaborative Group. Cana- Study Group. Angiotensin-receptor blockade control improves kidney outcomes in patients gliflozin for primary and secondary preven- versus converting-enzyme inhibition in type 2 with type 2 diabetes. Kidney Int 2013;83:517– tion of cardiovascular events: results from the diabetes and nephropathy. N Engl J Med 2004; 523 CANVAS Program (Canagliflozin Cardiovas- 351:1952–1961 38. Wong MG, Perkovic V, Chalmers J, et al.; cular Assessment Study). Circulation 2018;137: 66. Wu H-Y, Peng C-L, Chen P-C, et al. Compar- ADVANCE-ON Collaborative Group. Long-term 323–334 ative effectiveness of angiotensin-converting benefits of intensive glucose control for prevent- 53. Tuttle KR, Lakshmanan MC, Rayner B, et al. enzyme inhibitors versus angiotensin II receptor ing end-stage kidney disease: ADVANCE-ON. Dulaglutide versus insulin glargine in patients blockers for major renal outcomes in patients Diabetes Care 2016;39:694–700 with type 2 diabetes and moderate-to-severe with diabetes: a 15-year cohort study. PLoS One 39. National Kidney Foundation. KDOQI clinical chronic kidney disease (AWARD-7): a multi- 2017;12:e0177654 practice guideline for diabetes and CKD: 2012 up- centre, open-label, randomised trial. Lancet 67. Parving HH, Lehnert H, Brochner-Mortensen¨ date. Am J Kidney Dis 2012;60:850–886 Diabetes Endocrinol 2018;6:605–617 J, Gomis R, Andersen S, Arner P; Irbesartan in 40. CherneyDZI,Perkins BA, SoleymanlouN,etal. 53a. Lambers-Heerspink HJ, Desai M, Jardine M, Patients with Type 2 Diabetes and Microalbu- Renal hemodynamic effect of sodium-glucose et al. Canagliflozin slows progression of renal minuria Study Group. The effect of irbesartan cotransporter 2 inhibition in patients with function decline independent of glycemic ef- on the development of diabetic nephropathy type 1 diabetes mellitus. Circulation 2014;129: fects. J Am Soc Nephrol 2017;28:368–375 in patients with type 2 diabetes. N Engl J Med 587–597 54. Jardine MJ, Mahaffey KW, Neal B, et al.; 2001;345:870–878 41. Heerspink HJL, Desai M, Jardine M, Balis D, CREDENCE study investigators. The Canagliflozin 68. Bangalore S, Fakheri R, Toklu B, Messerli FH. Meininger G, Perkovic V. Canagliflozin slows and Renal Endpoints in Diabetes with Established Diabetes mellitus as a compelling indication progression of renal function decline indepen- Nephropathy Clinical Evaluation (CREDENCE) for use of renin angiotensin system blockers: dently of glycemic effects. J Am Soc Nephrol study rationale, design, and baseline character- systematic review and meta-analysis of random- 2017;28:368–375 PubMed istics. Am J Nephrol 2017;46:462–472 ized trials. BMJ 2016;352:i438 42. Neal B, Perkovic V, Mahaffey KW, et al.; 55. Wanner C, Lachin JM, Inzucchi SE, et al.; 69. HallerH,ItoS,IzzoJLJr,etal.;ROADMAPTrial CANVAS Program Collaborative Group. Canagli- EMPA-REG OUTCOME Investigators. Empagliflo- Investigators. Olmesartan for the delay or pre- flozin and cardiovascular and renal events in zin and clinical outcomes in patients with type 2 vention of microalbuminuria in type 2 diabetes. type 2 diabetes. N Engl J Med 2017;377:644–657 diabetes, established cardiovascular disease and N Engl J Med 2011;364:907–917 43. Zelniker TA, Braunwald E. Cardiac and renal chronic kidney disease. Circulation 2018;137: 70. Mauer M, Zinman B, Gardiner R, et al. Renal effects of sodium-glucose co-transporter 2 inhib- 119–129 and retinal effects of enalapril and losartan in itors in diabetes: JACC state-of-the-art review. 56. Leehey DJ, Zhang JH, Emanuele NV, et al.; VA type 1 diabetes. N Engl J Med 2009;361:40–51 J Am Coll Cardiol 2018;72:1845–1855 NEPHRON-D Study Group. BP and renal out- 71. Yusuf S, Teo KK, Pogue J, et al.; ONTARGET 44. Marso SP, Daniels GH, Brown-Frandsen K, comes in diabetic kidney disease: the Veterans Investigators. Telmisartan, ramipril, or both in et al.; LEADER Steering Committee; LEADER Trial Affairs Nephropathy in Diabetes Trial. Clin J Am patients at high risk for vascular events. N Engl J Investigators. Liraglutide and cardiovascular out- Soc Nephrol 2015;10:2159–2169 Med 2008;358:1547–1559 comes in type 2 diabetes. N Engl J Med 2016; 57. Emdin CA, Rahimi K, Neal B, Callender T, 72. Fried LF, Emanuele N, Zhang JH, et al.; VA 375:311–322 Perkovic V, Patel A. Blood pressure lowering in NEPHRON-D Investigators. Combined angioten- 45. Cooper ME, Perkovic V, McGill JB, et al. type 2 diabetes: a systematic review and meta- sin inhibition for the treatment of diabetic Kidney disease end points in a pooled analysis analysis. JAMA 2015;313:603–615 nephropathy. N Engl J Med 2013;369:1892–1903 of individual patient-level data from a large 58. Cushman WC, Evans GW, Byington RP, et al.; 73. Bakris GL, Agarwal R, Chan JC, et al.; Min- clinical trials program of the dipeptidyl peptidase ACCORD Study Group. Effects of intensive blood- eralocorticoid Receptor Antagonist Tolerability 4 inhibitor linagliptin in type 2 diabetes. Am J pressure control in type 2 diabetes mellitus. N Study–Diabetic Nephropathy (ARTS-DN) Study Kidney Dis 2015;66:441–449 Engl J Med 2010;362:1575–1585 Group. Effect of finerenone on albuminuria in 46. Mann JFE, Ørsted DD, Brown-Frandsen K, 59. UK Prospective Diabetes Study Group. Tight patients with diabetic nephropathy: a random- et al.; LEADER Steering Committee and Inves- blood pressure control and risk of macrovascular ized clinical trial. JAMA 2015;314:884–894 tigators. Liraglutide and renal outcomes in type 2 and microvascular complications in type 2 di- 74. Williams B, MacDonald TM, Morant S, et al.; diabetes. N Engl J Med 2017;377:839–848 abetes: UKPDS 38. BMJ 1998;317:703–713 British Hypertension Society’s PATHWAY Studies 47. Marso SP, Bain SC, Consoli A, et al.; SUSTAIN- 60. de Boer IH, Bangalore S, Benetos A, et al. Group. Spironolactone versus placebo, bis- 6 Investigators. Semaglutide and cardiovascular Diabetes and hypertension: a position statement oprolol, and doxazosin to determine the opti- outcomes in patients with type 2 diabetes. N by the American Diabetes Association. Diabetes maltreatment for drug-resistanthypertension Engl J Med 2016;375:1834–1844 Care 2017;40:1273–1284 (PATHWAY-2): a randomised, double-blind, 48. Karter AJ, Warton EM, Lipska KJ, et al. De- 61. Brenner BM, Cooper ME, de Zeeuw D, et al.; crossover trial. Lancet 2015;386:2059–2068 velopment and validation of a tool to identify RENAAL Study Investigators. Effects of losartan 75. Filippatos G, Anker SD, Bohm¨ M, et al. A patients with type 2 diabetes at high risk of on renal and cardiovascular outcomes in patients randomized controlled study of finerenone vs. hypoglycemia-related emergency department with type 2 diabetes and nephropathy. N Engl J eplerenone in patients with worsening chronic or hospital use. JAMA Intern Med 2017;177: Med 2001;345:861–869 heart failure and diabetes mellitus and/or 1461–1470 62. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD; chronic kidney disease. Eur Heart J 2016;37: 49. Moen MF, Zhan M, Hsu VD, et al. Frequency The Collaborative Study Group. The effect of 2105–2114 of hypoglycemia and its significance in chronic angiotensin-converting-enzyme inhibition on di- 76. Smart NA, Dieberg G, Ladhani M, Titus T. kidney disease. Clin J Am Soc Nephrol 2009;4: abetic nephropathy. N Engl J Med 1993;329: Early referral to specialist nephrology services for 1121–1127 1456–1462 preventing the progression to end-stage kidney 50. U.S. Food and Drug Administration. FDA 63. Lewis EJ, Hunsicker LG, Clarke WR, et al.; disease. Cochrane Database Syst Rev 2014;6: drug safety communication: FDA revises warn- Collaborative Study Group. Renoprotective ef- CD007333 ings regarding use of the diabetes medicine fect of the angiotensin-receptor antagonist ir- 77. Solomon SD, Chew E, Duh EJ, et al. Diabetic metformin in certain patients with reduced besartan in patients with nephropathy due to retinopathy: a position statement by the Amer- kidney function [Internet], 2016. Available type 2 diabetes. N Engl J Med 2001;345:851–860 ican Diabetes Association. Diabetes Care 2017; from http://www.fda.gov/Drugs/DrugSafety/ 64. Heart Outcomes Prevention Evaluation 40:412–418 ucm493244.htm. Accessed 14 October 2016 Study Investigators. Effects of ramipril on car- 78. Klein R. Hyperglycemia and microvascular 51. ZinmanB, WannerC,LachinJM, et al.; EMPA- diovascular and microvascular outcomes in peo- and macrovascular disease in diabetes. Di- REG OUTCOME Investigators. Empagliflozin, ple with diabetes mellitus: results of the HOPE abetes Care 1995;18:258–268 care.diabetesjournals.org Microvascular Complications and Foot Care S137

79. Estacio RO, McFarling E, Biggerstaff S, Jeffers based clinical practice guidelines for the man- by the American Diabetes Association. Diabetes BW, Johnson D, Schrier RW. Overt albuminuria agement of diabetic retinopathy. Can J Ophthal- Care 2017;40:136–154 predicts diabetic retinopathy in Hispanics with mol 2012;47(Supp. 1):S1–S30 108. Freeman R. Not all neuropathy in diabetes NIDDM. Am J Kidney Dis 1998;31:947–953 93. Axer-Siegel R, Hod M, Fink-Cohen S, et al. is of diabetic etiology: differential diagnosis of 80. Leske MC, Wu S-Y, Hennis A, et al.; Barbados Diabetic retinopathy during pregnancy. Ophthal- diabetic neuropathy. Curr Diab Rep 2009;9:423–431 Eye Study Group. Hyperglycemia, blood pres- mology 1996;103:1815–1819 109. Pop-Busui R, Evans GW, Gerstein HC, et al.; sure, and the 9-year incidence of diabetic 94. Best RM, Chakravarthy U. Diabetic retinopathy Action to Control Cardiovascular Risk in Diabetes retinopathy: the Barbados Eye Studies. Oph- in pregnancy. Br J Ophthalmol 1997;81:249–251 Study Group. Effects of cardiac autonomic dys- thalmology 2005;112:799–805 95. Gunderson EP, Lewis CE, Tsai A-L, et al. A function on mortality risk in the Action to Control 81. Chew EY, Davis MD, Danis RP, et al.; Action 20-year prospective study of childbearing and Cardiovascular Risk in Diabetes (ACCORD) trial. to Control Cardiovascular Risk in Diabetes Eye incidence of diabetes in young women, control- Diabetes Care 2010;33:1578–1584 Study Research Group. The effects of medical ling for glycemia before conception: the Coro- 110. Pop-Busui R, Cleary PA, Braffett BH, et al.; management on the progression of diabetic nary Artery Risk Development in Young Adults DCCT/EDIC Research Group. Association be- retinopathy in persons with type 2 diabetes: the (CARDIA) Study. Diabetes 2007;56:2990–2996 tween cardiovascular autonomic neuropathy Action to Control Cardiovascular Risk in Di- 96. The Diabetic Retinopathy Study Research and left ventricular dysfunction: DCCT/EDIC abetes (ACCORD) Eye Study. Ophthalmology Group. Preliminary report on effects of photo- study (Diabetes Control and Complications Trial/ 2014;121:2443–2451 coagulation therapy. Am J Ophthalmol 1976;81: Epidemiology of Diabetes Interventions and Com- 82. Nathan DM, Genuth S, Lachin J, et al.; Di- 383–396 plications). J Am Coll Cardiol 2013;61:447–454 abetes Control and Complications Trial Research 97. Gross JG, Glassman AR, Jampol LM, et al.; 111. Smith AG, Lessard M, Reyna S, Doudova M, Group. The effect of intensive treatment of di- Writing Committee for the Diabetic Retinop- Singleton JR. The diagnostic utility of Sudoscan abetes on the development and progression of athy Clinical Research Network. Panretinal for distal symmetric peripheral neuropathy. J long-term complications in insulin-dependent di- photocoagulation vs intravitreous ranibizumab Diabetes Complications 2014;28:511–516 abetes mellitus. N Engl J Med 1993;329:977–986 for proliferative diabetic retinopathy: a random- 112. Diabetes Control and Complications Trial 83. Chew EY, Ambrosius WT, Davis MD, et al.; ized clinical trial. JAMA 2015;314:2137–2146 (DCCT) Research Group. Effect of intensive di- ACCORD Study Group; ACCORD Eye Study 98. Early Treatment Diabetic Retinopathy Study abetes treatment on nerve conduction in the Group. Effects of medical therapies on reti- Research Group. Photocoagulation for diabetic Diabetes Control and Complications Trial. Ann nopathy progression in type 2 diabetes. N Engl macular edema. Early Treatment Diabetic Ret- Neurol 1995;38:869–880 J Med 2010;363:233–244 inopathy Study report number 1. Arch Ophthal- 113. CDC Study Group. The effect of intensive 84. Gubitosi-Klug RA, Sun W, Cleary PA, et al.; mol 1985;103:1796–1806 diabetes therapy on measures of autonomic Writing Team for the DCCT/EDIC Research 99. Elman MJ, Aiello LP, Beck RW, et al.; Dia- nervous system function in the Diabetes Control Group. Effects of prior intensive insulin therapy betic Retinopathy Clinical Research Network. and Complications Trial (DCCT). Diabetologia and risk factors on patient-reported visual func- Randomized trial evaluating ranibizumab plus 1998;41:416–423 tion outcomes in the Diabetes Control and prompt or deferred laser or triamcinolone plus 114. Albers JW, Herman WH, Pop-Busui R, et al.; Complications Trial/Epidemiology of Diabetes prompt laser for diabetic macular edema. Oph- Diabetes Control and Complications Trial /Epi- Interventions and Complications (DCCT/EDIC) thalmology 2010;117:1064–1077.e35 demiology of Diabetes Interventions and Com- cohort. JAMA Ophthalmol 2016;134:137–145 100. Mitchell P, Bandello F, Schmidt-Erfurth U, plications Research Group. Effect of prior 85. Fong DS, Aiello LP, Ferris FL 3rd, Klein R. et al.; RESTORE study group. The RESTORE study: intensive insulin treatment during the Diabetes Diabetic retinopathy. Diabetes Care 2004;27: ranibizumab monotherapy or combined with Control and Complications Trial (DCCT) on pe- 2540–2553 laser versus laser monotherapy for diabetic mac- ripheral neuropathy in type 1 diabetes during 86. Diabetes Control and Complications Trial ular edema. Ophthalmology 2011;118:615–625 the Epidemiology of Diabetes Interventions and Research Group. Effect of pregnancy on micro- 101. Elman MJ, Bressler NM, Qin H, et al.; Di- Complications (EDIC) study. Diabetes Care 2010; vascular complications in the diabetes control abetic Retinopathy Clinical Research Network. 33:1090–1096 and complications trial. Diabetes Care 2000;23: Expanded 2-year follow-up of ranibizumab plus 115. Pop-Busui R, Low PA, Waberski BH, et al.; 1084–1091 prompt or deferred laser or triamcinolone plus DCCT/EDIC Research Group. Effects of prior in- 87. Dabelea D, Stafford JM, Mayer-Davis EJ, prompt laser for diabetic macular edema. Oph- tensive insulin therapy on cardiac autonomic et al.; SEARCH for Diabetes in Youth Research thalmology 2011;118:609–614 nervous system function in type 1 diabetes Group. Association of type 1 diabetes vs type 2 102. Nguyen QD, Brown DM, Marcus DM, et al.; mellitus: the Diabetes Control and Complications diabetes diagnosed during childhood and ado- RISE and RIDE Research Group. Ranibizumab for Trial/Epidemiology of Diabetes Interventions lescence with complications during teenage diabetic macular edema: results from 2 phase III and Complications study (DCCT/EDIC). Circula- years and young adulthood. JAMA 2017;317: randomized trials:RISEandRIDE.Ophthalmology tion 2009;119:2886–2893 825–835 2012;119:789–801 116. Callaghan BC,Little AA, FeldmanEL, Hughes 88. Agardh E, Tababat-Khani P. Adopting 3-year 103. Shih C-J, Chen H-T, Kuo S-C, et al. Com- RAC. Enhanced glucose control for preventing screening intervals for sight-threatening retinal parative effectiveness of angiotensin-converting- and treating diabetic neuropathy. Cochrane Da- vascular lesions in type 2 diabetic subjects with- enzyme inhibitors and angiotensin II receptor tabase Syst Rev 2012;6:CD007543 out retinopathy. Diabetes Care 2011;34:1318– blockers in patients with type 2 diabetes and 117. Pop-Busui R, Lu J, Brooks MM, et al.; BARI 1319 retinopathy. CMAJ 2016;188:E148–E157 2D Study Group. Impact of glycemic control 89. Nathan DM, Bebu I, Hainsworth D, et al.; 104. Shi R, Zhao L, Wang F, et al. Effects of lipid- strategies on the progression of diabetic periph- DCCT/EDIC Research Group. Frequency of evi- lowering agents on diabetic retinopathy: a meta- eral neuropathy in the Bypass Angioplasty Re- dence-based screening for retinopathy in type 1 analysis and systematic review. Int J Ophthalmol vascularization Investigation 2 Diabetes (BARI diabetes. N Engl J Med 2017;376:1507–1516 2018;11:287–295 2D) cohort. Diabetes Care 2013;36:3208–3215 90. Daskivich LP, Vasquez C, Martinez C Jr, Tseng 105. Ang L, Jaiswal M, Martin C, Pop-Busui R. 118. Sadosky A, Schaefer C, Mann R, et al. C-H, Mangione CM. Implementation and evalu- Glucosecontrolanddiabeticneuropathy: lessons Burden of illness associated with painful diabetic ation of a large-scale teleretinal diabetic reti- from recent large clinical trials. Curr Diab Rep peripheral neuropathy among adults seeking nopathy screening program in the Los Angeles 2014;14:528 treatment in the US: results from a retrospective County Department of Health Services. JAMA 106. Martin CL, Albers JW, Pop-Busui R; DCCT/ chartreviewandcross-sectionalsurvey.Diabetes Intern Med 2017;177:642–649 EDIC Research Group. Neuropathy and related Metab Syndr Obes 2013;6:79–92 91. Sim DA, Mitry D, Alexander P, et al. The ﬁndings in the Diabetes Control and Complica- 119. Waldfogel JM, Nesbit SA, Dy SM, et al. evolution of teleophthalmology programs in the tions Trial/Epidemiology of Diabetes Interven- Pharmacotherapy for diabetic peripheral neu- United Kingdom: beyond diabetic retinopathy tions and Complications study. Diabetes Care ropathy pain and quality of life: a systematic screening. J Diabetes Sci Technol 2016;10:308–317 2014;37:31–38 review. Neurology 2017;88:1958–1967 92. Hooper P, Boucher MC, Cruess A, et al. 107. Pop-Busui R, Boulton AJM, Feldman EL, 120. Finnerup NB, Attal N, Haroutounian S, et al. Canadian Ophthalmological Society evidence- et al. Diabetic neuropathy: a position statement Pharmacotherapy for neuropathic pain in adults: S138 Microvascular Complications and Foot Care Diabetes Care Volume 42, Supplement 1, January 2019

a systematic review and meta-analysis. Lancet neuropathic pain impact glycemic control? Di- 146. Bonner T, Foster M, Spears-Lanoix E. Type Neurol 2015;14:162–173 abetes Care 2007;30:21–26 2 diabetes-related foot care knowledge and foot 121. Bril V, England J, Franklin GM, et al.; Amer- 134. Schwartz S, Etropolski M, Shapiro DY, et al. self-care practice interventions in the United ican Academy of Neurology; American Associa- Safety and efficacy of tapentadol ER in patients States: a systematic review of the literature. tion of Neuromuscular and Electrodiagnostic with painful diabetic peripheral neuropathy: Diabet Foot Ankle 2016;7:29758 Medicine; American Academy of Physical Med- results of a randomized-withdrawal, placebo- 147. Rizzo L, Tedeschi A, Fallani E, et al. Custom- icine and Rehabilitation. Evidence-based guide- controlled trial. Curr Med Res Opin 2011;27: made orthesis and shoes in a structured line: treatment of painful diabetic neuropathy: 151–162 follow-up program reduces the incidence of report of the American Academy of Neurology, 135. Vinik AI, Shapiro DY, Rauschkolb C, et al. neuropathic ulcers in high-risk diabetic foot the American Association of Neuromuscular and A randomized withdrawal, placebo-controlled patients. Int J Low Extrem Wounds 2012;11:59– Electrodiagnostic Medicine, and the American study evaluating the efficacy and tolerability 64 Academy of Physical Medicine and Rehabilita- of tapentadol extended release in patients 148. Lipsky BA, Berendt AR, Cornia PB, et al.; tion [published correction appears in Neurology with chronic painful diabetic peripheral Infectious Diseases Society of America. 2012 2011;77:603]. Neurology 2011;76:1758–1765 neuropathy. Diabetes Care 2014;37:2302– Infectious Diseases Society of America clinical 122. Griebeler ML, Morey-Vargas OL, Brito JP, 2309 practice guideline for the diagnosis and treat- et al. Pharmacologic interventions for painful 136. Camilleri M, Parkman HP, Shafi MA, Abell ment of diabetic foot infections. Clin Infect Dis diabetic neuropathy: an umbrella systematic TL, Gerson L; American College of Gastroenter- 2012;54:e132–e173 review and comparative effectiveness network ology. Clinical guideline: management of gastro- 149. Elraiyah T, Tsapas A, Prutsky G, et al. A meta-analysis. Ann Intern Med 2014;161:639– paresis. Am J Gastroenterol 2013;108:18–37; systematic review and meta-analysis of adjunc- 649 quiz 38 tive therapies in diabetic foot ulcers. J Vasc Surg 123. Ziegler D, Fonseca V. From guideline to 137. Parrish CR, Pastors JG. Nutritional manage- 2016;63(2 Suppl.):46S–58S.e1–2 patient: a review of recent recommendations for ment of gastroparesis in people with diabetes. 150. Game FL, Apelqvist J, Attinger C, et al.; pharmacotherapy of painful diabetic neuropa- Diabetes Spectr 2007;20:231–234 International Working Group on the Diabetic thy. J Diabetes Complications 2015;29:146–156 138. Parkman HP, Yates KP, Hasler WL, et al.; Foot. Effectiveness of interventions to enhance 124. Freeman R, Durso-Decruz E, Emir B. Effi- NIDDK Gastroparesis Clinical Research Consor- healing of chronic ulcers of the foot in diabetes: cacy, safety, and tolerability of pregabalin treat- tium. Dietary intake and nutritional deficiencies a systematic review. Diabetes Metab Res Rev ment for painful diabetic peripheral neuropathy: in patients with diabetic or idiopathic gastro- 2016;32(Suppl. 1):154–168 findings from seven randomized, controlled trials paresis. Gastroenterology 2011;141:486–498, 151. Kranke P, Bennett MH, Martyn-St James M, across a range of doses. Diabetes Care 2008;31: 498.e1–7 Schnabel A, Debus SE, Weibel S. Hyperbaric 1448–1454 139. Olausson EA, Storsrud¨ S, Grundin H, oxygen therapy for chronic wounds. Cochrane 125. Moore RA, Straube S, Wiffen PJ, Derry S, Isaksson M, Attvall S, Simren´ M. A small particle Database Syst Rev 2015;6:CD004123 McQuayHJ.Pregabalinforacuteandchronicpain size diet reduces upper gastrointestinal symp- 152. Londahl¨ M, Katzman P, Nilsson A, in adults. Cochrane Database Syst Rev 2009;3: toms in patients with diabetic gastroparesis: Hammarlund C. Hyperbaric oxygen therapy CD007076 arandomized controlledtrial. AmJGastroenterol facilitates healing of chronic foot ulcers in 126. Raskin P, Huffman C, Toth C, et al. Pre- 2014;109:375–385 patients with diabetes. Diabetes Care 2010; gabalin in patients with inadequately treated 140. Umpierrez GE, Ed. Therapy for Diabetes 33:998–1003 painful diabetic peripheral neuropathy: a ran- Mellitus and Related Disorders. 6th ed. Alex- 153. Fedorko L, Bowen JM, Jones W, et al. domized withdrawal trial. Clin J Pain 2014;30: andria, VA, American Diabetes Association, Hyperbaric oxygen therapy does not reduce 379–390 2014 indications for amputation in patients with di- 127. Tesfaye S, Wilhelm S, Lledo A, et al. Dulox- 141. Sugumar A, Singh A, Pasricha PJ. A system- abetes with nonhealing ulcers of the lower limb: etine and pregabalin: high-dose monotherapy atic review of the efficacy of domperidone for the a prospective, double-blind, randomized con- or their combination? The “COMBO-DN study”– treatment of diabetic gastroparesis. Clin Gastro- trolled clinical trial. Diabetes Care 2016;39: a multinational, randomized, double-blind, enterol Hepatol 2008;6:726–733 392–399 parallel-group study in patients with diabetic 142. Maganti K, Onyemere K, Jones MP. Oral 154. Li G, Hopkins RB, Levine MAH, et al. Re- peripheral neuropathic pain. Pain 2013;154: erythromycin and symptomatic relief of gastro- lationship between hyperbaric oxygen therapy 2616–2625 paresis: a systematic review. Am J Gastroenterol and quality of life in participants with chronic 128. Ziegler D, Duan WR, An G, Thomas JW, 2003;98:259–263 diabetic foot ulcers: data from a randomized Nothaft W. A randomized double-blind, placebo-, 143. McCallum RW, Snape W, Brody F, Wo J, controlled trial. Acta Diabetol 2017;54:823– and active-controlled study of T-type calcium Parkman HP, Nowak T. Gastric electrical stimu- 831 channel blocker ABT-639 in patients with diabetic lation with Enterra therapy improves symptoms 155. Boulton AJM. The Diabetic Foot [Internet], peripheralneuropathicpain.Pain2015;156:2013– from diabetic gastroparesis in a prospective 2000. South Dartmouth, MA, MDText.com, Inc. 2020 study. Clin Gastroenterol Hepatol 2010;8:947– Available from http://www.ncbi.nlm.nih.gov/ 129. Quilici S, Chancellor J, Lothgren¨ M, et al. 954; quiz e116 books/NBK409609/. Accessed 5 October 2017 Meta-analysis of duloxetine vs. pregabalin and 144. Boulton AJM, Armstrong DG, Albert SF, 156. Health Quality Ontario. Hyperbaric oxygen gabapentin in the treatment of diabetic periph- et al.; American Diabetes Association; American therapy for the treatment of diabetic foot ulcers: eral neuropathic pain. BMC Neurol 2009;9:6 Association of Clinical Endocrinologists. Compre- a health technology assessment. Ont Health 130. Dworkin RH, Jensen MP, Gammaitoni AR, hensive foot examination and risk assessment: Technol Assess Ser 2017;17:1–142 Olaleye DO, Galer BS. Symptom profiles differ in a report of the Task Force of the Foot Care 157. Stoekenbroek RM, Santema TB, Koelemay patients with neuropathic versus non-neuro- Interest Group of the American Diabetes Asso- MJ, et al. Is additional hyperbaric oxygen therapy pathic pain. J Pain 2007;8:118–126 ciation, with endorsement by the American cost-effective for treating ischemic diabetic ul- 131. Wiffen PJ, Derry S, Bell RF, et al. Gabapentin Association of Clinical Endocrinologists. Diabetes cers? Study protocol for the Dutch DAMOCLES for chronic neuropathic pain in adults. Cochrane Care 2008;31:1679–1685 multicenter randomized clinical trial? J Diabetes Database Syst Rev 2017;6:CD007938 145. Hingorani A, LaMuraglia GM, Henke P, et al. 2015;7:125–132 132. Wernicke JF, Pritchett YL, D’Souza DN, et al. The management of diabetic foot: a clinical 158. Huang ET, Mansouri J, Murad MH, et al.; A randomized controlled trial of duloxetine in practice guideline by the Society for Vascular UHMS CPG Oversight Committee. A clinical diabetic peripheral neuropathic pain. Neurology Surgery in collaboration with the American Po- practice guideline for the use of hyperbaric 2006;67:1411–1420 diatric Medical Association and the Society for oxygen therapy in the treatment of diabetic 133. Hardy T, Sachson R, Shen S, Armbruster M, Vascular Medicine. J Vasc Surg 2016;63(Suppl.): foot ulcers. Undersea Hyperb Med 2015;42: BoultonAJM.Doestreatmentwithduloxetine for 3S–21S 205–247 Diabetes Care Volume 42, Supplement 1, January 2019 S139

12. Older Adults: Standards of American Diabetes Association Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S139–S147 | https://doi.org/10.2337/dc19s012

Care annually, or more frequently as warranted. For a detailed description of ADA ADULTS OLDER 12. standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Recommendations 12.1 Consider the assessment of medical, psychological, functional (self- management abilities), and social geriatric domains in older adults to provide a framework to determine targets and therapeutic approaches for diabetes management. C 12.2 Screening for geriatric syndromes may be appropriate in older adults experiencing limitations in their basic and instrumental activities of daily living as they may affect diabetes self-management and be related to health- related quality of life. C

Diabetes is an important health condition for the aging population; approximately one-quarter of people over the age of 65 years have diabetes and one-half of older adults have prediabetes (1), and this proportion is expected to increase rapidly in the coming decades. Older individuals with diabetes have higher rates of premature death, functional disability, accelerated muscle loss, and coexisting illnesses, such as hypertension, coronary heart disease, and stroke, than those without diabetes. Older adults with diabetes also are at greater risk than other older adults for several common geriatric syndromes, such as polypharmacy, cognitive impairment, urinary incontinence, injurious falls, and persistent pain. These conditions may impact older adults’ diabetes self-management abilities (2). See Section 4 “Comprehensive Medical Evaluation and Assessment of Comorbidities” for comorbidities to consider when caring for older adult patients with diabetes. Suggested citation: American Diabetes Associ- Screening for diabetes complications in older adults should be individualized and ation. 12. Older adults: Standards of Medical periodically revisited, as the results of screening tests may impact therapeutic Care in Diabetesd2019. Diabetes Care 2019;42 approaches and targets (2–4). Older adults are at increased risk for depression and (Suppl. 1):S139–S147 should therefore be screened and treated accordingly (5). Diabetes management may © 2018 by the American Diabetes Association. require assessment of medical, psychological, functional, and social domains. This Readers may use this article as long as the work is properly cited, the use is educational and not may provide a framework to determine targets and therapeutic approaches, including for proﬁt, and the work is not altered. More infor- whether referral for diabetes self-management education is appropriate (when mation is available at http://www.diabetesjournals complicating factors arise or when transitions in care occur) or whether the current .org/content/license. S140 Older Adults Diabetes Care Volume 42, Supplement 1, January 2019

regimen is too complex for the patient’s Poor glycemic control is associated insulin deficiency necessitating insulin self-management ability. Particular at- with a decline in cognitive function therapy and progressive renal insuffi- tention should be paid to complications (13), and longer duration of diabetes is ciency. In addition, older adults tend to that can develop over short periods of associated with worsening cognitive havehigherratesofunidentifiedcognitive time and/or would significantly impair function. There are ongoing studies eval- deficits, causing difficulty in complex self- functional status, such as visual and uating whether preventing or delaying care activities (e.g., glucose monitoring, lower-extremity complications. Please diabetes onset may help to maintain adjusting insulin doses, etc.). These cog- refer to the American Diabetes Associ- cognitive function in older adults. How- nitive deficits have been associated with ation (ADA) consensus report “Diabe- ever, studies examining the effects of increased risk of hypoglycemia, and, con- tes in Older Adults” for details (2). intensive glycemic and blood pressure versely, severe hypoglycemia has been control to achieve specific targets have linked to increased risk of dementia (20). not demonstrated a reduction in brain Therefore, it is important to routinely NEUROCOGNITIVE FUNCTION function decline (14,15). screen older adults for cognitive dys- Recommendation Older adults with diabetes should function and discuss findings with the 12.3 Screening for early detection of be carefully screened and monitored patients and their caregivers. mild cognitive impairment or for cognitive impairment (2) (see Ta- Hypoglycemic events should be dili- dementia and depression is in- ble 4.1 for depression and cognitive gently monitored and avoided, whereas dicated for adults 65 years of age screening recommendations). Sev- glycemic targets and pharmacologic in- or older at the initial visit and eral organizations have released simple terventions may need to be adjusted to annually as appropriate. B assessment tools, such as the Mini- accommodate for the changing needs of Mental State Examination (16) and the the older adult (2). Of note, it is impor- Older adults with diabetes are at higher Montreal Cognitive Assessment (17), tant to prevent hypoglycemia to reduce risk of cognitive decline and institution- which may help to identify patients the risk of cognitive decline (20) and alization (6,7). The presentation of cog- requiring neuropsychological evalua- other major adverse outcomes. Intensive nitive impairment ranges from subtle tion, particularly those in whom de- glucose control in the Action to Control executive dysfunction to memory loss mentia is suspected (i.e., experiencing Cardiovascular Risk in Diabetes-Memory and overt dementia. People with diabe- memory loss and decline in their basic in Diabetes study (ACCORD MIND) was tes have higher incidences of all-cause and instrumental activities of daily liv- not found to benefit brain structure or dementia, Alzheimer disease, and vascu- ing). Annual screening for cognitive cognitive function during follow-up (14). lar dementia than people with normal impairment is indicated for adults In the Diabetes Control and Complica- glucose tolerance (8). The effects of hy- 65 years of age or older for early de- tions Trial (DCCT), no significant long- perglycemia and hyperinsulinemia on tection of mild cognitive impairment or term declines in cognitive function were the brain are areas of intense research. dementia (4,18). Screening for cogni- observed, despite participants’ relatively Clinical trials of specific interventionsd tive impairment should additionally be high rates of recurrent severe hypogly- including cholinesterase inhibitors and considered in the presence of a signif- cemia (21). To achieve the appropriate glutamatergic antagonistsdhave not icant decline in clinical status, inclusive balance between glycemic control and shown positive therapeutic benefitin of increased difficulty with self-care risk for hypoglycemia, it is important to maintaining or significantly improving activities, such as errors in calculating carefully assess and reassess patients’ cognitive function or in preventing insulin dose, difficulty counting carbo- risk for worsening of glycemic control cognitive decline (9). Pilot studies in hydrates, skipping meals, skipping in- and functional decline. patients with mild cognitive impair- sulin doses, and difficulty recognizing, ment evaluating the potential benefits preventing, or treating hypoglycemia. of intranasal insulin therapy and met- People who screen positive for cognitive TREATMENT GOALS formin therapy provide insights for impairment should receive diagnostic as- Recommendations future clinical trials and mechanistic sessment as appropriate, including refer- 12.5 Older adults who are other- studies (10–12). ral to a behavioral health provider for wise healthy with few coexisting The presence of cognitive impairment formal cognitive/neuropsychological chronic illnesses and intact cog- can make it challenging for clinicians to evaluation (19). nitive function and functional help their patients reach individualized status should have lower gly- glycemic, blood pressure, and lipid tar- cemic goals (such as A1C ,7.5% gets. Cognitive dysfunction makes it dif- HYPOGLYCEMIA [58 mmol/mol]), while those ficult for patients to perform complex Recommendation with multiple coexisting chronic self-care tasks, such as glucose monitor- 12.4 Hypoglycemia should be avoided illnesses,cognitiveimpairment,or ing and adjusting insulin doses. It also in older adults with diabetes. It functional dependence should hinders their ability to appropriately should be assessed and managed have less stringent glycemic goals maintain the timing and content of diet. by adjusting glycemic targets and (such as A1C ,8.0–8.5% [64–69 When clinicians are managing patients B pharmacologic interventions. mmol/mol]). C with cognitive dysfunction, it is critical 12.6 Glycemic goals for some older to simplify drug regimens and to involve Older adults are at higher risk of hypo- adults might reasonably be caregivers in all aspects of care. glycemia for many reasons, including care.diabetesjournals.org Older Adults S141

diabetes but may have limitations in with poorly controlled diabetes may relaxed as part of individualized patients who have medical conditions be subject to acute complications of care, but hyperglycemia leading that impact red blood cell turnover (see diabetes, including dehydration, poor to symptoms or risk of acute hy- Section 2 “Classification and Diagnosis of wound healing, and hyperglycemic perglycemia complications should Diabetes” for additional details on the hyperosmolar coma. Glycemic goals be avoided in all patients. C limitations of A1C) (26). Many conditions at a minimum should avoid these 12.7 Screening for diabetes compli- associated with increased red blood cell consequences. cations should be individualized turnover, such as hemodialysis, recent in older adults. Particular atten- blood loss or transfusion, or erythropoi- Vulnerable Patients at the End of Life tion should be paid to compli- etintherapy,arecommonlyseeninolder For patients receiving palliative care and cations that would lead to adults with functional limitations, which end-of-life care, the focus should be to functional impairment. C can falsely increase or decrease A1C. In avoid symptoms and complications from 12.8 Treatment of hypertension to these instances, plasma blood glucose glycemic management. Thus, when or- individualized target levels is fi gan failure develops, several agents will C and ngerstick readings should be used indicated in most older adults. Table 12.1 have to be downtitrated or discontinued. 12.9 for goal setting ( ). Treatment of other cardiovas- For the dying patient, most agents for cular risk factors should be type 2 diabetes may be removed (27). individualized in older adults Healthy Patients With Good Functional There is, however, no consensus for the considering the time frame of Status management of type 1 diabetes in this fi There are few long-term studies in older bene t. Lipid-lowering therapy scenario (28). See END-OF-LIFE CARE below, fi adults demonstrating the benefits of in- and aspirin therapy may bene t for additional information. those with life expectancies at tensive glycemic, blood pressure, and lipid control. Patients who can be ex- least equal to the time frame of Beyond Glycemic Control primary prevention or second- pected to live long enough to reap the Although hyperglycemia control may be fi ary intervention trials. E bene ts of long-term intensive diabetes important in older individuals with di- management, who have good cognitive abetes, greater reductions in morbidity and physical function, and who choose to The care of older adults with diabetes is and mortality are likely to result from do so via shared decision making may be control of other cardiovascular risk fac- complicated by their clinical, cognitive, treated using therapeutic interventions and functional heterogeneity. Some tors rather than from tight glycemic and goals similar to those for younger control alone. There is strong evidence older individuals may have developed Table 12.1 adults with diabetes ( ). from clinical trials of the value of treating diabetes years earlier and have signifi- As with all patients with diabetes, di- cant complications, others are newly hypertension in older adults (29,30). abetes self-management education and There is less evidence for lipid-lowering diagnosed and may have had years of ongoing diabetes self-management sup- undiagnosed diabetes with resultant therapy and aspirin therapy, although port are vital components of diabetes fi complications, and still other older adults the bene ts of these interventions for care for older adults and their caregivers. primary prevention and secondary in- may have truly recent-onset disease with Self-management knowledge and skills few or no complications (22). Some older tervention are likely to apply to older should be reassessed when regimen adults whose life expectancies equal or adults with diabetes have other under- changes are made or an individual’s lying chronic conditions, substantial exceed the time frames of the clinical functional abilities diminish. In addition, trials. diabetes-related comorbidity, limited declining or impaired ability to perform cognitive or physical functioning, or diabetes self-care behaviors may be an LIFESTYLE MANAGEMENT frailty (23,24). Other older individuals indication for referral of older adults with with diabetes have little comorbidity diabetes for cognitive and physical func- Recommendation and are active. Life expectancies are tional assessment using age-normalized 12.10 Optimal nutrition and protein in- highly variable but are often longer evaluation tools (3,19). take is recommended for older than clinicians realize. Providers caring adults; regular exercise, includ- for older adults with diabetes must take Patients With Complications and ing aerobic activity and re- this heterogeneity into consideration Reduced Functionality sistance training, should be when setting and prioritizing treat- For patients with advanced diabetes encouraged in all older adults ment goals (25) (Table 12.1). In addition, complications, life-limiting comorbid ill- who can safely engage in such older adults with diabetes should be as- nesses, or substantial cognitive or func- activities. B sessed for disease treatment and self- tional impairments, it is reasonable to set management knowledge, health literacy, less intensive glycemic goals (Table 12.1). Diabetes in the aging population is as- and mathematical literacy (numeracy) at Factors to consider in individualizing sociated with reduced muscle strength, the onset of treatment. See Fig. 6.1 for glycemic goals are outlined in Fig. poor muscle quality, and accelerated loss patient- and disease-related factors to 6.1. These patients are less likely to of muscle mass, resulting in sarcopenia. consider when determining individual- benefit from reducing the risk of mi- Diabetes is also recognized as an inde- ized glycemic targets. crovascular complications and more pendent risk factor for frailty. Frailty is A1C is used as the standard biomarker likely to suffer serious adverse effects characterized by decline in physical perfor glycemic control in all patients with from hypoglycemia. However, patients formance and an increased risk of poor S142 Older Adults Diabetes Care Volume 42, Supplement 1, January 2019

health outcomes due to physiologic vulnerability to clinical, functional, or psychosocial stressors. Inadequate nutritional intake, particularly inadequate t with ve ﬁ

ﬁ protein intake, can increase the risk of sarcopenia and frailty in older adults. contraindicated or not tolerated statin (secondary prevention more so than primary) of bene contraindicated or not tolerated Management of frailty in diabetes includes optimal nutrition with adequate protein intake combined with an exercise program that includes aerobic and resistance training (31,32). 150/90 mmHg Consider likelihood 140/90 mmHg Statin unless 140/90 mmHg Statin unless , , , PHARMACOLOGIC THERAPY

Recommendations

ing. 12.11 In older adults at increased risk cer, congestive heart failure, depression,

. The patient characteristic categories are general of hypoglycemia, medication A1C of 8.5% (69 mmol/mol) equates to an of treatment individualization. Additionally, a

† classes with low risk of hypoglycemia are preferred. B 200 mg/dL 180 mg/dL 12.12 150 mg/dL 8.3 mmol/L)

means at least three, but many patients may have Overtreatment of diabetes is – – 11.1 mmol/L) 10.0 mmol/L) – – – – ”

90 common in older adults and 110 100 (5.0 (6.1 (5.6 should be avoided. B 12.13 ﬁ ﬁ

Multiple Deintensi cation (or simpli ca- “ tion) of complex regimens is recommended to reduce the risk of hypoglycemia, if it can be

cantly reduce life expectancy. achieved within the individu- ﬁ alized A1C target. B

Special care is required in prescribing and and dyslipidemia in older adults with diabetes 180 mg/dL 130 mg/dL 150 mg/dL 7.2 mmol/L) 8.3 mmol/L) glucose Bedtime glucose Blood pressure Lipids – 10.0 mmol/L) – – – –

– monitoring pharmacologic therapies in 100 (5.0 (5.0 Fig. 9.1

(5.6 older adults (33). See for general Fasting or preprandial recommendations regarding antihyperglycemia treatment for adults with type 2 4 congestive heart failure or oxygen-dependent lung disease, chronic kidney disease requiring dialysis, or Table 9.1

2 diabetes and for patient- and

‡ drug-speciﬁc factors to consider when selecting antihyperglycemia agents. Cost

† may be an important consideration, es-

8.5% pecially as older adults tend to be on

, many medications. See Tables 9.2 and A lower A1C goal may be set for an individual if achievable without recurrent or severe hypoglycemia or undue treatment (69 mmol/mol) ‡ 9.3 for median monthly cost of noninsulin 7.5% (58 mmol/mol) 90 8.0% (64 mmol/mol) 90 , , glucose-lowering agents and insulin in the U.S., respectively. It is important to treatment goals for glycemia, blood pressure, match complexity of the treatment

cant symptoms or impairment of functional status and signi regimen to the self-management abil- ﬁ ity of an older patient. Many older t uncertain

ﬁ adults with diabetes struggle to maintain the frequent blood glucose test- life expectancy remaining life expectancy, high treatment burden, hypoglycemia vulnerability, fall risk expectancy makes bene ing and insulin injection regimens they Longer remaining Intermediate Limited remaining life

200 mg/dL (11.1 mmol/L). Looser A1C targets above 8.5% (69 mmol/mol) are not recommended aspreviously they may expose patients to more frequent higher glucose followed, perhaps for many

; decades, as they develop medical conditions that may impair their ability to follow their regimen safely. Individ- ualized glycemic goals should be established (Fig. 6.1) and periodically Framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia in older adults with diabetes (2)

— adjusted based on coexisting chronic illnesses, cognitive function, and func- s health status and preferences may change over time. ’ instrumental ADL ADL dependencies) tional status (2). Tight glycemic control 1 1 illnesses, intact cognitive and functional status) coexisting chronic illnesses* or 2 impairments or mild-to- moderate cognitive impairment) (LTC or end-stage chronic illnesses** or moderate-to- severe cognitive impairment or 2 in older adults with multiple medical Table 12.1 Patient characteristics/ health statusHealthy (few coexisting chronic Rationale Reasonable A1C goal or more (54). **The presence ofestimated a single average end-stage glucose chronic of illness, such as stage 3 uncontrolled metastatic cancer, may cause signi values and the acute risks from glycosuria, dehydration, hyperglycemic hyperosmolar syndrome, and poor wound healing. ADL, activities of daily liv Complex/intermediate (multiple This represents a consensusconcepts. framework Not for every considering patientpatient will clearly fall into a particular category. Consideration of patient and caregiver preferences is an important aspect burden. *Coexisting chronicemphysema, illnesses falls, are hypertension, conditions incontinence, serious stage enough 3 to or require worse medications chronic or kidney lifestyle disease, management myocardial and infarction, may include and stroke. arthritis, can Very complex/poor health conditions is considered overtreatment care.diabetesjournals.org Older Adults S143

Fig. 12.1—Algorithm to simplify insulin regimen for older patients with type 2 diabetes. eGFR, estimated glomerular filtration rate. *Basal insulins: glargine U-100 and U-300, detemir, degludec, and human NPH. **See Table 12.1. UMealtime insulins: short-acting (regular human insulin) or rapid- acting (lispro, aspart, and glulisine). §Premixed insulins: 70/30, 75/25, and 50/50 products. Adapted with permission from Munshi and colleagues (39,55,56). and is associated with an increased simplification may be appropriate in Insulin Secretagogues risk of hypoglycemia; unfortunately, older adults. Sulfonylureas and other insulin secre- overtreatment is common in clinical tagogues are associated with hypo- practice (34–38). Deintensification of Metformin glycemiaandshouldbeusedwith regimens in patients taking noninsu- Metformin is the first-line agent for older caution. If used, shorter-duration sul- lin glucose-lowering medications can adults with type 2 diabetes. Recent stud- fonylureas, such as glipizide, are pre- be achieved by either lowering the ies have indicated that it may be used ferred. Glyburide is a longer-duration dose or discontinuing some medica- safely in patients with estimated glomer- sulfonylurea and contraindicated in tions, so long as the individualized ular filtration rate $30 mL/min/1.73 m2 older adults (43). A1C target is maintained. When pa- (42). However, it is contraindicated in tients are found to have an insulin patients with advanced renal insuffi- Incretin-Based Therapies regimen with complexity beyond their ciency and should be used with caution Oral dipeptidyl peptidase 4(DPP-4)inhib- self-management abilities, lowering the in patients with impaired hepatic func- itors have few side effects and minimal dose of insulin may not be adequate. tion or congestive heart failure due hypoglycemia, but their costs may be a Simplification of the insulin regimen to to the increased risk of lactic acidosis. barrier to some older patients. DPP-4 matchanindividual’s self-management Metformin may be temporarily discon- inhibitors do not increase major adverse abilities in these situations has been tinued before procedures, during hospi- cardiovascular outcomes (44). shown to reduce hypoglycemia and talizations, and when acute illness may Glucagon-like peptide 1 (GLP-1) re- disease-related distress without wors- compromise renal or liver function. ceptor agonists are injectable agents, ening glycemic control (39–41). Figure which require visual, motor, and cog- 12.1 depicts an algorithm that can be Thiazolidinediones nitive skills for appropriate adminis- used to simplify the insulin regimen Thiazolidinediones, if used at all, should tration.Theymaybeassociatedwith (39). Table 12.2 provides examples of be used very cautiously in those with, or nausea, vomiting, and diarrhea. Also, and rationale for situations where de- at risk for, congestive heart failure and weight loss with GLP-1 receptor ago- intensification and/or insulin regimen those at risk for falls or fractures. nists may not be desirableinsomeolder S144 Older Adults Diabetes Care Volume 42, Supplement 1, January 2019

Table 12.2—Considerations for treatment regimen simplification and deintensification/deprescribing in older adults with diabetes (39,55) When may treatment Patient characteristics/ Reasonable A1C/ When may regimen deintensification/ health status treatment goal Rationale/considerations simplification be required? deprescribing be required? Healthy (few coexisting A1C ,7.5% c Patients can generally c If severe or recurrent c If severe or recurrent chronic illnesses, intact (58 mmol/mol) perform complex tasks to hypoglycemia occurs in hypoglycemia occurs in cognitive and functional maintain good glycemic patients on insulin therapy patients on noninsulin status) control when health is (even if A1C is appropriate) therapies with high risk stable c If wide glucose excursions of hypoglycemia (even if c During acute illness, are observed A1C is appropriate) patients may be more at c If cognitive or functional c If wide glucose excursions risk for administration or decline occurs following are observed dosing errors that can acute illness c In the presence of result in hypoglycemia, polypharmacy falls, fractures, etc. Complex/intermediate A1C ,8.0% c Comorbidities may affect c If severe or recurrent c If severe or recurrent (multiple coexisting (64 mmol/mol) self-management abilities hypoglycemia occurs in hypoglycemia occurs in chronic illnesses or and capacity to avoid patients on insulin therapy patients on noninsulin 21 instrumental ADL hypoglycemia (even if A1C is appropriate) therapies with high risk impairments or mild-to- c Long-acting medication c If unable to manage of hypoglycemia (even if moderate cognitive formulations may complexity of an insulin A1C is appropriate) impairment) decrease pill burden and regimen c If wide glucose excursions complexity of medication c If there is a significant are observed regimen change in social c In the presence of circumstances, such as loss polypharmacy of caregiver, change in living situation, or financial difficulties Community-dwelling Avoid reliance on A1C c Glycemic control is c If treatment regimen c If the hospitalization for patients receiving care in important for recovery, increased in complexity acute illness resulted in askillednursing facilityfor wound healing, hydration, during hospitalization, it is weight loss, anorexia, short-term rehabilitation and avoidance of reasonable, in many cases, short-term cognitive infections to reinstate the decline, and/or loss of Glucose target: c Patients recovering from prehospitalization physical functioning 100–200 mg/dL illness may not have medication regimen (5.55–11.1 mmol/L) returned to baseline during the rehabilitation cognitive function at the time of discharge c Consider the type of support the patient will receive at home Very complex/poor health A1C ,8.5% c No benefits of tight c If on an insulin regimen c If on noninsulin agents (long-term care or end- (69 mmol/)† glycemic control in this and the patient would like with a high hypoglycemia stage chronic illnesses or population to decrease the number of risk in the context moderate-to-severe c Hypoglycemia should be injections and fingerstick of cognitive dysfunction, cognitive impairment or avoided blood glucose monitoring depression, anorexia, or 21 ADL dependencies) c Most important outcomes events each day inconsistent eatingpattern are maintenance of c If the patient has an c If taking any medications cognitive and functional inconsistent eatingpattern without clear benefits status Patients at end of life Avoid hypoglycemia c Goal is to provide comfort c If there is pain or c If taking any medications and symptomatic and avoid tasks or discomfort caused by without clear benefits in hyperglycemia interventions that cause treatment (e.g., injections improving symptoms pain or discomfort or fingersticks) and/or comfort c Caregivers are important c If there is excessive in providing medical care caregiver stress due to and maintaining quality of treatment complexity life Treatment regimen simplification refers to changing strategy to decrease the complexity of a medication regimen, e.g., fewer administration times, fewer fingerstick readings, decreasing the need for calculations (such as sliding scale insulin calculations or insulin-carbohydrate ratio calculations). Deintensification/deprescribing refers to decreasing the dose or frequency of administration of a treatment or discontinuing a treatment altogether. ADL, activities of daily living. †Consider adjustment of A1C goal if the patient has a condition that may interfere with erythrocyte life span/turnover. care.diabetesjournals.org Older Adults S145

patients, particularly those with ca- centers) may rely completely on the lead to decreased food intake and con- chexia. In patients with established care plan and nursing support. Those tribute to unintentional weight loss and atherosclerotic cardiovascular disease, receiving palliative care (with or without undernutrition. Diets tailored to a pa- GLP-1 receptor agonists have shown hospice) may require an approach that tient’s culture, preferences, and per- cardiovascular benefits (44). emphasizes comfort and symptom man- sonal goals may increase quality of life, agement, while de-emphasizing strict satisfaction with meals, and nutrition Sodium2Glucose Cotransporter metabolic and blood pressure control. status (48). 2 Inhibitors Sodium2glucose cotransporter 2 inhibi- TREATMENT IN SKILLED NURSING Hypoglycemia tors are administered orally, which may FACILITIES AND NURSING HOMES Older adults with diabetes in LTC are be convenient for older adults with di- especially vulnerable to hypoglycemia. abetes; however, long-term experience Recommendations 12.14 Consider diabetes education They have a disproportionately high in this population is limited despite the for the staff of long-term care number of clinical complications and initial efficacy and safety data reported facilities to improve the man- comorbidities that can increase hypo- with these agents. In patients with es- agement of older adults with glycemia risk: impaired cognitive and tablished atherosclerotic cardiovascu- diabetes. E renal function, slowed hormonal regular disease, these agents have shown 12.15 Patients with diabetes residing lation and counterregulation, suboptimal cardiovascular benefits (44). in long-term care facilities need hydration, variable appetite and nutri- careful assessment to establish tional intake, polypharmacy, and slowed Insulin Therapy glycemic goals and to make ap- intestinal absorption (49). Oral agents The use of insulin therapy requires that propriate choices of glucose- may achieve similar glycemic outcomes patients or their caregivers have good lowering agents based on in LTC populations as basal insulin visual and motor skills and cognitive their clinical and functional (34,50). ability. Insulin therapy relies on the abil- status. E Another consideration for the LTC ity of the older patient to administer setting is that, unlike the hospital setting, insulin on their own or with the assis- Management of diabetes in the long- medical providers are not required to tance of a caregiver. Insulin doses should term care (LTC) setting (i.e., nursing evaluate the patients daily. According to be titrated to meet individualized glyce- homes and skilled nursing facilities) is federal guidelines, assessments should mic targets and to avoid hypoglycemia. unique. Individualization of health care is be done at least every 30 days for the first Once-daily basal insulin injection ther- important in all patients; however, prac- 90 days after admission and then at least apy is associated with minimal side effects tical guidance is needed for medical once every 60 days. Although in practice and may be a reasonable option in many providers as well as the LTC staff and the patients may actually be seen more older patients. Multiple daily injections of caregivers (46). Training should include frequently, the concern is that patients insulin may be too complex for the older diabetes detection and institutional may have uncontrolled glucose levels or patient with advanced diabetes compli- quality assessment. LTC facilities should wide excursions without the practitioner cations, life-limiting coexisting chronic develop their own policies and proce- being notified. Providers may make ad- illnesses, or limited functional status. dures for prevention and management justments to treatment regimens by Figure 12.1 provides a potential ap- of hypoglycemia. telephone, fax, or in person directly at proach to insulin regimen simplification. the LTC facilities provided they are given timely notification of blood glucose man- Other Factors to Consider Resources agement issues from a standardized alert The needs of older adults with diabetes Staff of LTC facilities should receive ap- system. and their caregivers should be evaluated propriate diabetes education to improve The following alert strategy could be to construct a tailored care plan. Im- the management of older adults with considered: paired social functioning may reduce diabetes. Treatments for each patient their quality of life and increase the should be individualized. Special man- 1. Call provider immediately: in case of risk of functional dependency (45). The agement considerations include the low blood glucose levels (#70 mg/dL patient’s living situation must be con- need to avoid both hypoglycemia and [3.9 mmol/L]). sidered as it may affect diabetes man- the complications of hyperglycemia (2,47). 2. Call as soon as possible: a) glucose agement and support needs. Social and For more information, see the ADA po- values between 70 and 100 mg/dL (3.9 instrumental support networks (e.g., sition statement “Management of Dia- and 5.6 mmol/L) (regimen may need adult children, caretakers) that provide betes in Long-term Care and Skilled to be adjusted), b)glucosevalues instrumental or emotional support for Nursing Facilities” (46). greater than 250 mg/dL (13.9 mmol/L) older adults with diabetes should be in- within a 24-h period, c) glucose values cluded in diabetes management discus- Nutritional Considerations greater than 300 mg/dL (16.7 mmol/L) sions and shared decision making. An older adult residing in an LTC facility over 2 consecutive days, d) when any Older adults in assisted living facilities may have irregular and unpredictable reading is too high for the glucom- may not have support to administer their meal consumption, undernutrition, an- eter, or e) the patient is sick, with own medications, whereas those living orexia, and impaired swallowing. Further- vomiting, symptomatic hyperglyce- in a nursing home (community living more, therapeutic diets may inadvertently mia, or poor oral intake. S146 Older Adults Diabetes Care Volume 42, Supplement 1, January 2019

END-OF-LIFE CARE focus on the prevention of hypogly- and cognitive impairment. Neurology 2014;82: cemia and the management of hy- 1132–1141 Recommendations perglycemia using blood glucose 8. Xu WL, von Strauss E, Qiu CX, Winblad B, 12.16 When palliative care is needed Fratiglioni L. Uncontrolled diabetes increases testing, keeping levels below the re- in older adults with diabetes, the risk of Alzheimer’s disease: a population- nal threshold of glucose. There is strict blood pressure control based cohort study. Diabetologia 2009;52: very little role for A1C monitoring 1031–1039 may not be necessary, and and lowering. 9. Ghezzi L, Scarpini E, Galimberti D. Disease- withdrawal of therapy may modifying drugs in Alzheimer’s disease. Drug Des 2. A patient with organ failure: pre- be appropriate. Similarly, the Devel Ther 2013;7:1471–1478 venting hypoglycemia is of greater intensity of lipid management 10. CraftS,Baker LD, MontineTJ,etal. Intranasal significance. Dehydration must be insulin therapy for Alzheimer disease and can be relaxed, and withdrawal prevented and treated. In people amnestic mild cognitive impairment: a pilot clin- of lipid-lowering therapy may – with type 1 diabetes, insulin admin- ical trial. Arch Neurol 2012;69:29 38 be appropriate. E 11. Freiherr J, Hallschmid M, Frey WH 2nd, et al. istration may be reduced as the oral 12.17 Overall comfort,prevention Intranasal insulin as a treatment for Alzheimer’s intake of food decreases but should of distressing symptoms, and disease: a review of basic research and clinical not be stopped. For those with type 2 evidence. CNS Drugs 2013;27:505–514 preservation of quality of life diabetes, agents that may cause hy- 12. Alagiakrishnan K, Sankaralingam S, Ghosh M, and dignity are primary goals poglycemia should be downtitrated. Mereu L, Senior P. Antidiabetic drugs and their for diabetes management at potential role in treating mild cognitive impair- The main goal is to avoid hypoglyce- the end of life. E ment and Alzheimer’s disease. Discov Med 2013; mia, allowing for glucose values in the 16:277–286 upper level of the desired target 13. Yaffe K, Falvey C, Hamilton N, et al. Diabetes, The management of the older adult at glucose control, and 9-year cognitive decline the end of life receiving palliative med- range. 3. A dying patient: for patients with among older adults without dementia. Arch icine or hospice care is a unique situation. Neurol 2012;69:1170–1175 Overall, palliative medicine promotes type 2 diabetes, the discontinuation 14. Launer LJ, Miller ME, Williamson JD, et al.; comfort, symptom control and preven- of all medications may be a reasonable ACCORD MIND investigators. Effects of intensive glucose lowering on brain structure and function tion (pain, hypoglycemia, hyperglycemia, approach, as patients are unlikely to have any oral intake. In patients with in people with type 2 diabetes (ACCORD MIND): and dehydration), and preservation of a randomized open-label substudy. Lancet Neu- type 1 diabetes, there is no consen- dignity and quality of life in patients with rol 2011;10:969–977 limited life expectancy (47,51). A patient sus, but a small amount of basal 15. Murray AM, Hsu F-C, Williamson JD, et al.; has the right to refuse testing and treat- insulin may maintain glucose levels Action to Control Cardiovascular Risk in Diabetes Follow-On Memory in Diabetes (ACCORDION ment, whereas providers may consider and prevent acute hyperglycemic complications. MIND) Investigators. ACCORDION MIND: results withdrawing treatment and limiting di- of the observational extension of the ACCORD agnostic testing, including a reduction in MIND randomised trial. Diabetologia 2017;60: the frequency of fingerstick testing (52). 69–80 Glucose targets should aim to prevent References 16. Cummings JL, Frank JC, Cherry D, et al. 1. Centers for Disease Control and Prevention. Guidelines for managing Alzheimer’s disease: hypoglycemia and hyperglycemia. Treat- National Diabetes Statistics Report [Internet], part I. Assessment. Am Fam Physician 2002; ment interventions need to be mindful of 2017. Available from https://www.cdc.gov/ 65:2263–2272 quality of life. Careful monitoring of oral diabetes/data/statistics/statistics-report.html. 17. Nasreddine ZS, Phillips NA, Bedirian´ V, et al. intake is warranted. The decision process Accessed 20 September 2018 The Montreal Cognitive Assessment, MoCA: may need to involve the patient, family, 2. Kirkman MS, Briscoe VJ, Clark N, et al. Di- a brief screening tool for mild cognitive impair- abetes in older adults. Diabetes Care 2012;35: ment. J Am Geriatr Soc 2005;53:695–699 and caregivers, leading to a care plan that 2650–2664 18. Moreno G, Mangione CM, Kimbro L, is both convenient and effective for the 3. Young-Hyman D, de Groot M, Hill-Briggs F, Vaisberg E; American Geriatrics Society Expert goals of care (53). The pharmacologic Gonzalez JS, Hood K, Peyrot M. Psychosocial care Panel on Care of Older Adults with Diabetes therapy may include oral agents as first for people with diabetes: a position statement of Mellitus. Guidelines abstracted from the Amer- line, followed by a simplified insulin the American Diabetes Association. Diabetes ican Geriatrics Society guidelines for improving Care 2016;39:2126–2140 the care of older adults with diabetes mellitus: regimen. If needed, basal insulin can 4. Institute of Medicine of the National Acad- 2013 update. J Am Geriatr Soc 2013;61:2020– be implemented, accompanied by oral emies. Cognitive Aging: Progress in Understand- 2026 agents and without rapid-acting insulin. ing and Opportunities for Action [Internet], 2015. 19. American Psychological Association. Guide- Agents that can cause gastrointestinal Available from http://nationalacademies.org/ lines for the Evaluation of Dementia and Age- Related Cognitive Change [Internet], 2011. symptoms such as nausea or excess hmd/Reports/2015/Cognitive-Aging.aspx. Ac- cessed 20 September 2018 Available from http://www.apa.org/practice/ weight loss may not be good choices 5. Kimbro LB, Mangione CM, Steers WN, et al. guidelines/dementia.aspx. Accessed 20 Sep- in this setting. As symptoms progress, Depression and all-cause mortality in persons tember 2018 some agents may be slowly tapered and with diabetes mellitus: are older adults at higher 20. Feinkohl I, Aung PP, Keller M, et al.; Edin- discontinued. risk? Results from the Translating Research Into burgh Type 2 Diabetes Study (ET2DS) Investiga- Action for Diabetes Study. J Am Geriatr Soc 2014; tors. Severe hypoglycemia and cognitive decline Different patient categories have been 62:1017–1022 in older people with type 2 diabetes: the Edin- proposed for diabetes management in 6. Cukierman T, Gerstein HC, Williamson JD. burgh Type 2 Diabetes Study. Diabetes Care those with advanced disease (28). Cognitive decline and dementia in diabetes– 2014;37:507–515 systematic overview of prospective observa- 21. Jacobson AM, Musen G, Ryan CM, et al.; tional studies. Diabetologia 2005;48:2460–2469 Diabetes Control and Complications Trial/ 1. A stable patient: continue with the 7. Roberts RO, Knopman DS, Przybelski SA, et al. Epidemiology of Diabetes Interventions and patient’s previous regimen, with a Association of type 2 diabetes with brain atrophy Complications Study Research Group. Long- care.diabetesjournals.org Older Adults S147

term effect of diabetes and its treatment on glycemic control. Diabetes Res Clin Pract 2014; 46. Munshi MN, Florez H, Huang ES, et al. cognitive function. N Engl J Med 2007;356: 105:102–109 Management of diabetes in long-term care 1842–1852 35. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, and skilled nursing facilities: a position state- 22. Selvin E, Coresh J, Brancati FL. The burden Steinman MA. Potential overtreatment of dia- ment of the American Diabetes Association. Di- and treatment of diabetes in elderly individuals betes mellitus in older adults with tight glycemic abetes Care 2016;39:308–318 in the U.S. Diabetes Care 2006;29:2415–2419 control. JAMA Intern Med 2015;175:356–362 47. Sinclair A, Morley JE, Rodriguez-Manas~ L, 23. Bandeen-Roche K, Seplaki CL, Huang J, et al. 36. Thorpe CT, Gellad WF, Good CB, et al. Tight et al. Diabetes mellitus in older people: position Frailty in older adults: a nationally representative glycemic control and use of hypoglycemic med- statement on behalf of the International Asso- profile in the United States. J Gerontol A Biol Sci ications in older veterans with type 2 diabetes ciation of Gerontology and Geriatrics (IAGG), the Med Sci 2015;70:1427–1434 and comorbid dementia. Diabetes Care 2015; European Diabetes Working Party for Older 24. Kalyani RR, Tian J, Xue Q-L, et al. Hypergly- 38:588–595 People (EDWPOP), and the International Task cemia and incidence of frailty and lower extrem- 37. McAlister FA, Youngson E, Eurich DT. Treat- Force of Experts in Diabetes. J Am Med Dir Assoc ity mobility limitations in older women. J Am ment deintensification is uncommon in adults 2012;13:497–502 Geriatr Soc 2012;60:1701–1707 with type 2 diabetes mellitus: a retrospective 48. Dorner B, Friedrich EK, Posthauer ME. Prac- 25. Blaum C, Cigolle CT, Boyd C, et al. Clinical cohort study. Circ Cardiovasc Qual Outcomes tice paper of the American Dietetic Association: complexity in middle-aged and older adults with 2017;10:e003514 individualized nutrition approaches for older diabetes: the Health and Retirement Study. Med 38. Arnold SV, Lipska KJ, Wang J, Seman L, Mehta adults in health care communities. J Am Diet Care 2010;48:327–334 SN, Kosiborod M. Use of intensive glycemic Assoc 2010;110:1554–1563 26. NGSP. Factorsthat Interfere with HbA1c Test management in older adults with diabetes mel- 49. Migdal A, Yarandi SS, Smiley D, Umpierrez Results [Internet], 2018. Available from http:// litus. J Am Geriatr Soc 2018;66:1190–1194 GE. Update on diabetes in the elderly and in www.ngsp.org/factors.asp. Accessed 20 Sep- 39. Munshi MN, Slyne C, Segal AR, Saul N, Lyons nursing home residents. J Am Med Dir Assoc tember 2018 C, Weinger K. Simplification of insulin regimen in 2011;12:627–632.e2 27. Sinclair A, Dunning T, Colagiuri S. IDF Global older adults and risk of hypoglycemia. JAMA 50. Pasquel FJ, Powell W, Peng L, et al. A Guideline For Managing Older People With Intern Med 2016;176:1023–1025 randomized controlled trial comparing treat- Type 2 Diabetes. International Diabetes Feder- 40. Sussman JB, Kerr EA, Saini SD, et al. Rates of ment with oral agents and basal insulin in elderly ation, Brussels, Belgium, 2013 deintensification of blood pressure and glycemic patients with type 2 diabetes in long-term care 28. Angelo M, Ruchalski C, Sproge BJ. An ap- medication treatment based on levels of control facilities. BMJ Open Diabetes Res Care 2015; proach to diabetes mellitus in hospice and and life expectancy in older patients with di- 3:e000104 palliative medicine. J Palliat Med 2011;14: abetes mellitus. JAMA Intern Med 2015;175: 51. Quinn K, Hudson P, Dunning T. Diabetes 83–87 1942–1949 management in patients receiving palliative care. 29. Beckett NS, Peters R, Fletcher AE, et al.; 41. Abdelhafiz AH, Sinclair AJ. Deintensifica- J Pain Symptom Manage 2006;32:275–286 HYVET Study Group. Treatment of hypertension tion of hypoglycaemic medications-use of a 52. Ford-Dunn S, Smith A, Quin J. Management in patients 80 years of age or older. N Engl J Med systematic review approach to highlight safety of diabetes during the last days of life: attitudes 2008;358:1887–1898 concerns in older people with type 2 diabetes. of consultant diabetologists and consultant pal- 30. de Boer IH, Bangalore S, Benetos A, et al. J Diabetes Complications 2018;32:444–450 liative care physicians in the UK. Palliat Med Diabetes and hypertension: a position statement 42. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, 2006;20:197–203 by the American Diabetes Association. Diabetes McGuire DK. Metformin in patients with type 2 53. Mallery LH, Ransom T, Steeves B, Cook B, Care 2017;40:1273–1284 diabetes and kidney disease: a systematic re- Dunbar P, Moorhouse P. Evidence-informed 31. Sinclair AJ, Abdelhafiz A, Dunning T, et al. An view. JAMA 2014;312:2668–2675 guidelines for treating frail older adults with international position statement on the man- 43. American Geriatrics Society 2015 Beers Cri- type 2 diabetes: from the Diabetes Care Program agement of frailty in diabetes mellitus: summary teria Update Expert Panel. American Geriatrics of Nova Scotia (DCPNS) and the Palliative and of recommendations 2017. J Frailty Aging 2018; Society 2015 updated Beers criteria for poten- Therapeutic Harmonization (PATH) program. 7:10–20 tially inappropriate medication use in older J Am Med Dir Assoc 2013;14:801–808 32. Castro-Rodr´ıguez M, Carnicero JA, Garcia- adults. J Am Geriatr Soc 2015;63:2227–2246 54. LaiteerapongN,IveniukJ,JohnPM,Laumann Garcia FJ, et al. Frailty as a major factor in the 44. Davies MJ, D’Alessio DA, Fradkin J. Manage- EO, Huang ES. Classification of older adults who increased risk of death and disability in older ment of hyperglycemia in type 2 diabetes, 2018. have diabetes by comorbid conditions, United people with diabetes. J Am Med Dir Assoc 2016; A consensus report by the American Diabetes States, 2005-2006. Prev Chronic Dis 2012;9:E100 17:949–955 Association (ADA) and the European Association 55. Munshi MN, Slyne C, Segal AR, Saul N, Lyons 33. Valencia WM, Florez H. Pharmacological for the Study of Diabetes (EASD). Diabetes Care C, Weinger K. Liberating A1C goals in older adults treatment of diabetes in older people. Diabetes 2018;41:2669–2701 may not protect against the risk of hypogycemia. Obes Metab 2014;16:1192–1203 45. Laiteerapong N, Karter AJ, Liu JY, et al. J Diabetes Complications 2017;31:1197–1199 34. Andreassen LM, Sandberg S, Kristensen GBB, Correlates of quality of life in older adults 56. Leung E, Wongrakpanich S, Munshi MN. Sølvik UØ, Kjome RLS. Nursing home patients with diabetes: the Diabetes & Aging Study. Di- Diabetes management in the elderly. Diabetes with diabetes: prevalence, drug treatment and abetes Care 2011;34:1749–1753 Spectr 2018;31:245–253 S148 Diabetes Care Volume 42, Supplement 1, January 2019

13. Children and Adolescents: American Diabetes Association Standards of Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S148–S164 | https://doi.org/10.2337/dc19-S013

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. 13. CHILDREN AND ADOLESCENTS The management of diabetes in children and adolescents cannot simply be derived from care routinely provided to adults with diabetes. The epidemiology, pathophysiology,developmental considerations, andresponsetotherapy inpediatric-onset diabetes are different from adult diabetes. There are also differences in recommended care for children and adolescents with type 1 as opposed to type 2 diabetes. This section ﬁrst addresses care for children and adolescents with type 1 diabetes and next addresses care for children and adolescents with type 2 diabetes. Figure 13.1 provides guidance on managing new-onset diabetes in overweight youth before type 1 or type 2 diabetes is diagnosed and so applies to all overweight youth. Lastly, guidance is provided in this section on transition of care from pediatric to adult providers to ensure that the continuum of care is appropriate as the child with diabetes develops into adulthood. Due to the nature of clinical research in children, the recommendations for children and adolescents with diabetes 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 statements “Type 1 Diabetes in Children and Adolescents” (1) and “Eval- uation and Management of Youth-Onset Type 2 Diabetes” (2). The ADA consensus report “Youth-Onset Type 2 Diabetes Consensus Report: Current Status, Challenges, and Priorities” (3) characterizes type 2 diabetes in children and evaluates treatment options as well, but also discusses knowledge gaps and recruitment challenges in Suggested citation: American Diabetes Associa- clinical and translational research in youth-onset type 2 diabetes. tion. 13. Children and adolescents: Standards of Medical Care in Diabetesd2019. Diabetes Care TYPE 1 DIABETES 2019;42(Suppl. 1):S148–S164 Type 1 diabetes is the most common form of diabetes in youth (4), although recent data © 2018 by the American Diabetes Association. suggestthatit mayaccountfora largeproportionofcasesdiagnosed inadultlife (5).The Readers may use this article as long as the work is properly cited, the use is educational and not provider must consider the unique aspects of care and management of children and for proﬁt, and the work is not altered. More infor- adolescents with type 1 diabetes, such as changes in insulin sensitivity related to physical mation is available at http://www.diabetesjournals growth and sexual maturation, ability to provide self-care, supervision in the child care .org/content/license. care.diabetesjournals.org Children and Adolescents S149

and school environment, neurological vul- and family to overcome barriers or reactivity daily, with vigorous nerability to hypoglycemia and hypergly- define goals as appropriate. Diabetes muscle-strengthening and bone- cemia in young children, as well as self-management education and support strengthening activities at least possible adverse neurocognitive effects requires periodic reassessment, espe- 3 days per week. C of diabetic ketoacidosis (DKA) (6,7). Atten- cially as the youth grows, develops, 13.6 Education about frequent pat- tion to family dynamics, developmental and acquires the need for greater in- terns of glycemia during and stages, and physiologic differences related dependent self-care skills. In addition, it after exercise, which may to sexual maturity is essential in develop- is necessary to assess the educational include initial transient hyper- ing and implementing an optimal diabetes needs and skills of day care providers, glycemia followed by hypo- treatment plan (8). school nurses, or other school personnel glycemia, is essential. Families A multidisciplinary team of specialists who participate in the care of the young should also receive education trained in pediatric diabetes manage- child with diabetes (9). on prevention and management and sensitive to the challenges ment of hypoglycemia during of children and adolescents with type 1 and after exercise, including diabetes and their families should Nutrition Therapy ensuring patients have a pre- provide care for this population. It is Recommendations exercise glucose level of 90– essential that diabetes self-management 13.2 Individualized medical nutrition 250 mg/dL (5–13 mmol/L) education and support, medical nutri- therapy is recommended for and accessible carbohydrates tion therapy, and psychosocial support children and adolescents with before engaging in activity, in- be provided at diagnosis and regularly type 1 diabetes as an essential dividualized according to the thereafter in a developmentally appro- component of the overall treat- type/intensity of the planned priate format that builds on prior knowl- ment plan. A physical activity. E edge by individuals experienced with the 13.3 Monitoring carbohydrate in- 13.7 Patients should be educated on educational, nutritional, behavioral, and take, whether by carbohydrate strategies to prevent hypogly- emotional needs of the growing child and counting or experience-based cemia during exercise, after ex- family. The appropriate balance between estimation, is key to achieving ercise, and overnight following adult supervision and independent self- optimal glycemic control. B exercise, which may include re- fi fi care should be de ned at the rst inter- 13.4 Comprehensive nutrition edu- ducing prandial insulin dosing action and reevaluated at subsequent vis- cation at diagnosis, with annual for the meal/snack preceding its, with the expectation that it will evolve updates, by an experienced (and, if needed, following) ex- as the adolescent gradually becomes an registered dietitian is recom- ercise, increasing carbohy- emerging young adult. mended to assess caloric and drate intake, eating bedtime nutrition intake in relation to snacks,using continuous glucose Diabetes Self-management Education weight status and cardiovascu- monitoring, and/or reducing and Support lar disease risk factors and to in- basal insulin doses. C form macronutrient choices. E 13.8 Frequent glucose monitoring Recommendation before, during, and after exer- 13.1 Youth with type 1 diabetes and Dietary management should be indi- cise, with or without use of con- parents/caregivers (for patients vidualized: family habits, food pre- tinuous glucose monitoring, is aged ,18 years) should receive ferences, religious or cultural needs, important to prevent, detect, culturally sensitive and develop- schedules, physical activity, and the pa- and treat hypoglycemia and hy- mentally appropriate individual- ’ ’ tient s and family s abilities in numeracy, perglycemia with exercise. C ized diabetes self-management literacy, and self-management should education and support according be considered. Dietitian visits should in- to national standards at diagnosis clude assessment for changes in food Exercise positively affects insulin sensi- and routinely thereafter. B preferences over time, access to food, tivity, physical fitness, strength building, growth and development, weight sta- weight management, social interaction, No matter how sound the medical tus, cardiovascular risk, and potential for mood, self-esteem building, and crea- regimen, it can only be effective if the eating disorders. Dietary adherence is tion of healthful habits for adulthood, family and/or affected individuals are associated with better glycemic control but it also has the potential to cause able to implement it. Family involvement in youth with type 1 diabetes (10). both hypoglycemia and hyperglycemia. is a vital component of optimal diabetes See below for strategies to mitigate management throughout childhood and hypoglycemia risk and minimize hyper- adolescence. Health care providers in the Physical Activity and Exercise glycemia with exercise. For an in-depth diabetes care team who care for chil- discussion, see recently published re- Recommendations dren and adolescents must be capable of views and guidelines (11–13). 13.5 Exercise is recommended for all evaluating the educational, behavioral, Overall, it is recommended that youth youth with type 1 diabetes with emotional, and psychosocial factors that with type 1 diabetes participate in 60 min the goal of 60 min of moderate- impact implementation of a treatment of moderate- (e.g., brisk walking, dancing) to vigorous-intensity aerobic plan and must work with the individual to vigorous- (e.g., running, jumping rope) S150 Children and Adolescents Diabetes Care Volume 42, Supplement 1, January 2019

intensity aerobic activity daily, includ- status and encourage a healthy diet, care for all girls of childbearing ing resistance and flexibility training (14). exercise, and healthy weight as key com- potential. A Although uncommon in the pediatric pop- ponents of pediatric type 1 diabetes care. 13.16 Begin screening youth with ulation, patients should be medically eval- type 1 diabetes for eating uated for comorbid conditions or diabetes disorders between 10 and complicationsthatmayrestrictparticipation School and Child Care As a large portion of a child’sdayisspent 12 years of age. The Diabetes in an exercise program. As hyperglycemia in school, close communication with and Eating Problems Survey- can occur before, during, and after physical the cooperation of school or day care Revised (DEPS-R) is a reliable, activity, it is important to ensure that the personnel are essential for optimal di- valid, and brief screening tool elevated glucose level is not related to abetes management, safety, and maximal for identifying disturbed eat- insulin deficiencythatwouldleadtowors- academic opportunities. Refer to the ADA ing behavior. B ening hyperglycemia with exercise and position statements “Diabetes Care in the ketosis risk. Intense activity should School Setting” (26) and “Care of Young be postponed with marked hyperglyce- Rapid and dynamic cognitive, devel- Children With Diabetes in the Child mia (glucose $350 mg/dL [19.4 mmol/L]), opmental, and emotional changes oc- Care Setting” (27) for additional details. moderate to large urine ketones, and/or cur during childhood, adolescence, and b-hydroxybutyrate (B-OHB) .1.5 mmol/L. emerging adulthood. Diabetes manage- Caution may be needed when B-OHB Psychosocial Issues ment during childhood and adolescence $ levels are 0.6 mmol/L (10,11). Recommendations places substantial burdens on the youth The prevention and treatment of hy- 13.9 At diagnosis and during routine and family, necessitating ongoing assess- poglycemia associated with physical ac- follow-up care, assess psycho- ment of psychosocial status and diabetes tivity include decreasing the prandial social issues and family stresses distress in the patient and the caregiver – insulin for the meal/snack before exer- that could impact diabetes man- during routine diabetes visits (28 34). cise and/or increasing food intake. Pa- agement and provide appropri- Early detection of depression, anxiety, tients on insulin pumps can lower basal ate referrals to trained mental eating disorders, and learning disabilities ; – rates by 10 50% or more or suspend for health professionals, preferably can facilitate effective treatment options – 1 2 h during exercise (15). Decreasing experienced in childhood dia- and help minimize adverse effects on basal rates or long acting insulin doses betes. E diabetes management and disease out- ; by 20% after exercise may reduce 13.10 Mental health professionals comes (33,35). There are validated tools, delayed exercise-induced hypoglycemia should be considered integral such as the Problem Areas in Diabetes- (16). Accessible rapid-acting carbohy- members of the pediatric dia- Teen (PAID-T) and Parent (P-PAID-Teen) drates and frequent blood glucose mon- betes multidisciplinary team. E (34), that can be used in assessing fi itoring before, during, and after exercise, 13.11 Encourage developmentally ap- diabetes-speci c distress in youth start- with or without continuous glucose mon- propriate family involvement in ing at age 12 years and in their parent itoring, maximize safety with exercise. diabetes management tasks for caregivers. Furthermore, the complex- Blood glucose targets prior to exer- children and adolescents, rec- ities of diabetes management require – – cise should be 90 250 mg/dL (5.0 13.9 ognizing that premature trans- ongoing parental involvement in care mmol/L). Consider additional carbohy- fer of diabetes care to the child throughout childhood with developmen- drate intake during and/or after exercise, tally appropriate family teamwork be- can result in diabetes burn-out depending on the duration and intensity tween the growing child/teen and parent nonadherence and deteriora- of physical activity, to prevent hypogly- in order to maintain adherence and to tion in glycemic control. A cemia. For low- to moderate-intensity prevent deterioration in glycemic control 13.12 Providers should consider asking aerobic activities (30260 min), and if (36,37). As diabetes-specific family conflict youth and their parents about the patient is fasting, 10215 g of car- is related to poorer adherence and glyce- social adjustment (peer relation- bohydrate may prevent hypoglycemia mic control, it is appropriate to inquire ships) and school performance (17). After insulin boluses (relative hy- about such conflict during visits and to to determine whether further perinsulinemia), consider 0.5–1.0 g of either help to negotiate a plan for res- intervention is needed. B carbohydrates/kg per hour of exercise olution or refer to an appropriate men- 13.13 Assess youth with diabetes (;30260 g), which is similar to carbo- tal health specialist (38). Monitoring for psychosocial and diabetes- hydrate requirements to optimize per- of social adjustment (peer relationships) related distress, generally start- formance in athletes without type 1 and school performance can facilitate ing at 7–8 years of age. B diabetes (18–20). both well-being and academic achieve- 13.14 Offer adolescents time by In addition, obesity is as common in ment (39). Suboptimal glycemic control themselves with their care children and adolescents with type 1 di- is a risk factor for underperformance at provider(s) starting at age abetes as in those without diabetes. It is school and increased absenteeism (40). 12 years, or when develop- associated with higher frequency of car- Shared decision making with youth mentally appropriate. E diovascular risk factors, and it dispropor- regarding the adoption of regimen com- 13.15 Starting at puberty, precon- tionately affects racial/ethnic minorities ponents and self-management behaviors ception counseling should be in- in the U.S. (21–25). Therefore, diabetes can improve diabetes self-efficacy, adher- corporated into routine diabetes care providers should monitor weight ence, and metabolic outcomes (22,41). care.diabetesjournals.org Children and Adolescents S151

Although cognitive abilities vary, the ethical eating behaviors using available screen- should be considered in chil- position often adopted is the “mature ing tools (28,45). With respect to disor- dren with type 1 diabetes. B minor rule,” whereby children after age dered eating, it is important to recognize 13.21 An A1C target of ,7.5% (58 12 or 13 years who appear to be “mature” the unique and dangerous disordered mmol/mol) should be consid- have the right to consent or withhold eating behavior of insulin omission for ered in children and adoles- consent to general medical treatment, weight control in type 1 diabetes (50). cents with type 1 diabetes except in cases in which refusal would The presence of a mental health pro- but should be individualized significantly endanger health (42). fessional on pediatric multidisciplinary based on the needs and situa- Beginning at the onset of puberty or at teams highlights the importance of at- tion of the patient and family. E diagnosis of diabetes, all adolescent girls tending to the psychosocial issues of di- and women with childbearing potential abetes. These psychosocial factors are should receive education about the risks significantly related to self-management Please refer to Section 7 “Diabetes of malformations associated with poor difficulties, suboptimal glycemic control, Technology” for more information on metabolic control and the use of effec- reduced quality of life, and higher rates of the use of blood glucose meters, contin- tive contraception to prevent unplanned acute and chronic diabetes complications. uous glucose monitors, and insulin pumps. pregnancy. Preconception counseling us- More information on insulin injection ing developmentally appropriate educa- technique can be found in Section 9 tional tools enables adolescent girls to Glycemic Control “Pharmacologic Approaches to Glycemic make well-informed decisions (43). Pre- Treatment,” p. S90. Recommendations conception counseling resources tailored Current standards for diabetes manage- 13.17 The majority of children and for adolescents are available at no cost ment reflect the need to lower glucose as adolescents with type 1 dia- through the ADA (44). Refer to the ADA safely as possible. This should be done with betes should be treated with position statement “Psychosocial Care stepwise goals. When establishing individ- intensive insulin regimens, for People With Diabetes” for further ualized glycemic targets, special consid- either via multiple daily injec- details (35). eration should be given to the risk of tions or continuous subcuta- Youth with type 1 diabetes have , neous insulin infusion. A hypoglycemia in young children (aged 6 an increased risk of disordered eating 13.18 All children and adolescents years) who are often unable to recognize, behavior as well as clinical eating disorders with type 1 diabetes should articulate, and/or manage hypoglycemia. with serious short-term and long- self-monitor glucose levels However, registry data indicate that lower term negative effects on diabetes out- A1C can be achieved in children, including multiple times daily (up to comes and health in general. Therefore, those ,6 years, without increased risk of 6–10 times/day), including it is important to screen for eating dis- severe hypoglycemia (51,52). premeal, prebedtime, and as orders in youth with type 1 diabetes us- Type 1 diabetes can be associated needed for safety in specific ing tools such as the Diabetes Eating with adverse effects on cognition dur- situations such as exercise, Problems Survey-Revised (DEPS-R) to ing childhood and adolescence. Factors driving, or the presence of that contribute to adverse effects on allow for early diagnosis and interven- symptoms of hypoglycemia. B tion (45–48). 13.19 Continuous glucose monitor- brain development and function include ing should be considered in all young age or DKA at onset of type 1 , Screening children and adolescents with diabetes, severe hypoglycemia at 6 Screening for psychosocial distress and type 1 diabetes, whether us- years of age, and chronic hyperglycemia mental health problems is an important (53,54). However, meticulous use of new ing injections or continuous component of ongoing care. It is impor- therapeutic modalities such as rapid- and subcutaneous insulin infusion, tant to consider the impact of diabetes on long-acting insulin analogs, technologi- as an additional tool to help quality of life as well as the development cal advances (e.g., continuous glucose mon- improve glucose control. Ben- of mental health problems related to itors, low-glucose suspend insulin pumps, efits of continuous glucose diabetes distress, fear of hypoglycemia and automated insulin delivery systems), monitoring correlate with ad- (and hyperglycemia), symptoms of anxi- and intensive self-management education herence to ongoing use of the ety, disordered eating behaviors as well now make it more feasible to achieve device. B as eating disorders, and symptoms of 13.20 Automated insulin delivery excellent glycemic control while reduc- depression (49). Consider assessing youth systems appear to improve ingtheincidenceofseverehypoglycemia for diabetes distress, generally starting – glycemic control and reduce (55 64). Intermittently scanned continuous at 7 or 8 years of age (35). Consider hypoglycemia in children and glucose monitors (sometimes referred to as screening for depression and disordered “flash” continuous glucose monitors) are

Table 13.1—Blood glucose and A1C targets for children and adolescents with type 1 diabetes Blood glucose goal range Before meals Bedtime/overnight A1C Rationale 90–130 mg/dL (5.0–7.2 mmol/L) 90–150 mg/dL (5.0–8.3 mmol/L) ,7.5% (58 mmol/mol) A lower goal (,7.0% [53 mmol/mol]) is reasonable if it can be achieved without excessive hypoglycemia S152 Children and Adolescents Diabetes Care Volume 42, Supplement 1, January 2019

not currently approved for use in children diabetes, screening for thyroid dysfunc- misleading (euthyroid sick syndrome) and adolescents. A strong relationship exists tion and celiac disease should be consid- if performed at the time of diagnosis between frequency of blood glucose mon- ered (72,73). Periodic screening in owing to the effect of previous hy- itoring and glycemic control (57–66). asymptomatic individuals has been rec- perglycemia, ketosis or ketoacidosis, The Diabetes Control and Complica- ommended, but the optimal frequency weight loss, etc. Therefore, if performed tions Trial (DCCT), which did not enroll of screening is unclear. at diagnosis and slightly abnormal, thyroid children ,13 years of age, demonstrated Although much less common than thy- function tests should be repeated soon that near normalization of blood glucose roid dysfunction and celiac disease, other after a period of metabolic stability and levels was more difficult to achieve in autoimmune conditions, such as Addison good glycemic control. Subclinical hy- adolescents than in adults. Nevertheless, disease (primary adrenal insufficiency), pothyroidism may be associated with the increased use of basal-bolus regimens, autoimmune hepatitis, autoimmune gas- increased risk of symptomatic hypogly- insulin pumps, frequent blood glucose tritis, dermatomyositis, and myasthenia cemia (79) and reduced linear growth monitoring, goal setting, and improved gravis, occur more commonly in the pop- rate. Hyperthyroidism alters glucose patient education in youth from infancy ulation with type 1 diabetes than in the metabolism and usually causes dete- through adolescence has been associated general pediatric population and should rioration of glycemic control. with more children reaching the blood glu- be assessed and monitored as clinically cose targets recommended by ADA (67–70), indicated. In addition, relatives of patients Celiac Disease particularly in those families in which both should be offered testing for islet auto- Recommendations the parents and the child with diabetes antibodies through research studies (e.g., 13.25 Screen children with type 1 participate jointly to perform the required TrialNet) for early diagnosis of preclinical diabetes for celiac disease by diabetes-related tasks. Furthermore, stud- type 1 diabetes (stages 1 and 2). measuring IgA tissue transglu- ies documenting neurocognitive imaging taminase (tTG) antibodies, Thyroid Disease differences related to hyperglycemia in with documentation of normal children provide another motivation for Recommendations total serum IgA levels, soon lowering glycemic targets (6). 13.23 Consider testing children with after the diagnosis of diabe- In selecting glycemic targets, the long- type 1 diabetes for antithyroid tes, or IgG to tTG and deami- term health benefits of achieving a lower peroxidase and antithyroglob- dated gliadin antibodies if IgA A1C should be balanced against the risks ulin antibodies soon after the deficient. E of hypoglycemia and the developmental diagnosis. B 13.26 Repeat screening within 2 years burdens of intensive regimens in children 13.24 Measure thyroid-stimulating of diabetes diagnosis and then and youth. In addition, achieving lower A1C hormone concentrations at di- again after 5 years and consider levels is likely facilitated by setting lower agnosis when clinically stable more frequent screening in A1C targets (51,71). A1C and blood glucose or soon after glycemic control children who have symptoms targets are presented in Table 13.1.Lower has been established. If nor- or a first-degree relative with goals may be possible during the “honey- mal, suggest rechecking every celiac disease. B moon” phase of type 1 diabetes. 1–2 years or sooner if the 13.27 Individuals with biopsy- patient develops symptoms confirmed celiac disease should Key Concepts in Setting Glycemic Targets or signs suggestive of thyroid be placed on a gluten-free ○ Targets should be individualized, and dysfunction, thyromegaly, an diet and have a consultation lower targets may be reasonable based abnormal growth rate, or un- on a benefit-risk assessment. with a dietitian experienced in explained glycemic variabil- managing both diabetes and ○ Blood glucose targets should be modi- ity. E B fied in children with frequent hypogly- celiac disease. cemia or hypoglycemia unawareness. Autoimmune thyroid disease is the most ○ Postprandial blood glucose values common autoimmune disorder associ- Celiac disease is an immune-mediated should be measured when there is a dis- ated with diabetes, occurring in 17–30% disorder that occurs with increased crepancy between preprandial blood of patients with type 1 diabetes (74). At frequency in patients with type 1 diabe- glucose values and A1C levels and to the time of diagnosis, about 25% of tes (1.6–16.4% of individuals compared assess preprandial insulin doses in those children with type 1 diabetes have thy- with 0.3–1% in the general population) on basal-bolus or pump regimens. roid autoantibodies (75); their presence (72,73,80–83). is predictive of thyroid dysfunctiond Screening for celiac disease includes Autoimmune Conditions most commonly hypothyroidism, al- measuring serum levels of IgA and tissue Recommendation though hyperthyroidism occurs in transglutaminase antibodies, or, with IgA 13.22 Assess for additional autoim- ;0.5% of patients with type 1 diabetes deficiency, screening can include mea- mune conditions soon after (76,77). For thyroid autoantibodies, a suring IgG tissue transglutaminase anti- the diagnosis of type 1 diabe- recent study from Sweden indicated bodies or IgG deamidated gliadin peptide tes and if symptoms develop. E antithyroid peroxidase antibodies were antibodies. Because most cases of celiac more predictive than antithyroglobulin disease are diagnosed within the first Because of the increased frequency of antibodies in multivariate analysis 5 years after the diagnosis of type 1 other autoimmune diseases in type 1 (78). Thyroid function tests may be diabetes, screening should be considered care.diabetesjournals.org Children and Adolescents S153

at the time of diagnosis and repeated Normal blood pressure levels for age, Children found to have high- at 2 and then 5 years (82) or if clinical sex, and height and appropriate methods normal blood pressure (systolic symptoms indicate, such as poor growth for measurement are available online blood pressure or diastolic or increased hypoglycemia (83,84). at nhlbi.nih.gov/files/docs/resources/ blood pressure $90th percen- Although celiac disease can be diag- heart/hbp_ped.pdf. tile for age, sex, and height) nosed more than 10 years after diabetes or hypertension (systolic blood Dyslipidemia diagnosis, there are insufficient data pressure or diastolic blood pres- after 5 years to determine the optimal Recommendations sure $95th percentile for age, screening frequency. Measurement of sex, and height) should have Testing tissue transglutaminase antibody should 13.33 fi elevated blood pressure con- Obtain a fasting lipid pro le be considered at other times in patients $ firmed on 3 separate days. B in children 10 years of age with symptoms suggestive of celiac soon after the diagnosis of disease (82). Monitoring for symptoms Treatment diabetes (after glucose control should include assessment of linear 13.29 Initial treatment of high- has been established). E growth and weight gain (83,84). A normal blood pressure (sys- 13.34 If LDL cholesterol values are small-bowel biopsy in antibody-positive tolic blood pressure or diastolic within the accepted risk level children is recommended to confirm the blood pressure consistently (,100 mg/dL [2.6 mmol/L]), diagnosis (85). European guidelines on $90th percentile for age, a lipid profile repeated every screening for celiac disease in children sex, and height) includes 3–5yearsisreasonable.E (not specific to children with type 1 di- dietary modification and in- abetes) suggest that biopsy may not be creased exercise, if appropri- Treatment 13.35 necessary in symptomatic children with ate, aimed at weight control. If lipids are abnormal, initial high antibody titers (i.e., greater than If target blood pressure is not therapy should consist of op- 10 times the upper limit of normal) reachedwithin3–6 months of timizing glucose control and provided that further testing is per- initiating lifestyle interven- medical nutrition therapy us- formed (verification of endomysial anti- tion, pharmacologic treatment ing a Step 2 American Heart body positivity on a separate blood should be considered. E Association diet to decrease sample). Whether this approach may 13.30 In addition to lifestyle modifi- the amount of saturated fat be appropriate for asymptomatic chil- cation, pharmacologic treat- to 7% of total calories and die- dren in high-risk groups remains an open ment of hypertension (systolic tary cholesterol to 200 mg/day, question, though evidence is emerging blood pressure or diastolic which is safe and does not in- (86). It is also advisable to check for celiac blood pressure consistently terfere with normal growth and disease–associated HLA types in patients $95th percentile for age, sex, development. B who are diagnosed without a small in- and height) should be consid- 13.36 After the age of 10 years, ad- testinal biopsy. In symptomatic children ered as soon as hypertension is dition of a statin is suggested with type 1 diabetes and confirmed celiac confirmed. E in patients who, despite medical disease, gluten-free diets reduce symp- 13.31 ACE inhibitors or angiotensin nutrition therapy and lifestyle toms and rates of hypoglycemia (87). The receptor blockers should be changes, continue to have LDL challenging dietary restrictions associ- considered for the initial phar- cholesterol .160 mg/dL (4.1 ated with having both type 1 diabetes macologic treatment of hy- mmol/L) or LDL cholesterol fi E and celiac disease place a signi cant pertension in children and .130 mg/dL (3.4 mmol/L) burden on individuals. Therefore, a bi- adolescents, following repro- and one or more cardiovascu- opsy to confirm the diagnosis of celiac ductive counseling due to the lar disease risk factor, follow- disease is recommended, especially in potential teratogenic effects ing reproductive counseling asymptomatic children, before establish- of both drug classes. E because of the potential tera- ing a diagnosis of celiac disease (88) and 13.32 The goal of treatment is blood E endorsing significant dietary changes. A pressure consistently ,90th togenic effects of statins. 13.37 gluten-free diet was beneficial in asymp- percentile for age, sex, and The goal of therapy is an LDL , tomatic adults with positive antibodies height. E cholesterol value 100 mg/dL E confirmed by biopsy (89). (2.6 mmol/L). Blood pressure measurements should be performedusing theappropriate sizecuff Population-based studies estimate that – Management of Cardiovascular Risk with the child seated and relaxed. Hy- 14 45% of children with type 1 diabetes Factors pertension should be confirmed on at have two or more atherosclerotic car- Hypertension least 3 separate days. Evaluation should diovascular disease (ASCVD) risk factors (92–94), and the prevalence of cardio- Recommendations proceedasclinically indicated (90).Treat- ment is generally initiated with an ACE vascular disease (CVD) risk factors in- Screening inhibitor, but an angiotensin receptor creases with age (94) and among racial/ 13.28 Blood pressure should be blocker can be used if the ACE inhibitor ethnic minorities (21), with girls having measured at each routine visit. is not tolerated (e.g., due to cough) (91). a higher risk burden than boys (93). S154 Children and Adolescents Diabetes Care Volume 42, Supplement 1, January 2019

Pathophysiology. The atherosclerotic pro- function and causing regression of ca- sample preferred to avoid ef- cess begins in childhood, and although rotid intimal thickening (106,107). Sta- fects of exercise) spot urine ASCVD events are not expected to occur tins are not approved for patients aged sample for albumin-to-creatinine during childhood, observations using a ,10 years, and statin treatment should ratio should be considered at variety of methodologies show that generally not be used in children with puberty or at age .10 years, youth with type 1 diabetes may have type 1 diabetes before this age. Statins whichever is earlier, once the subclinical CVD within the first decade are contraindicated in pregnancy; there- child has had diabetes for of diagnosis (95–97). Studies of carotid fore, prevention of unplanned preg- 5years.B intima-media thickness have yielded nancies is of paramount importance inconsistent results (90,91). for postpubertal girls (see Section 14 Treatment Treatment. Pediatric lipid guidelines pro- “Management of Diabetes in Pregnancy” 13.41 An ACE inhibitor or an angio- vide some guidance relevant to chil- for more information). The multicenter, tensin receptor blocker, ti- dren with type 1 diabetes (90,98–100); randomized, placebo-controlled Ado- trated to normalization of however, there are few studies on mod- lescent Type 1 Diabetes Cardio-Renal albumin excretion, may be ifying lipid levels in children with type 1 Intervention Trial (AdDIT) provides safety considered when elevated uri- diabetes. A 6-month trial of dietary coun- data on pharmacologic treatment with nary albumin-to-creatinine ra- . seling produced a significant improve- an ACE inhibitor and statin in adolescents tio ( 30 mg/g) is documented ment in lipid levels (101); likewise, a with type 1 diabetes. (two of three urine samples lifestyle intervention trial with 6 months Smoking obtained over a 6-month in- of exercise in adolescents demonstrated terval following efforts to im- Recommendations improvement in lipid levels (102). prove glycemic control and 13.38 Elicit a smoking history at ini- E Although intervention data are sparse, normalize blood pressure). tial and follow-up diabetes the American Heart Association catego- visits; discourage smoking in Data from 7,549 participants ,20 years rizes children with type 1 diabetes in the youth who do not smoke, and of age in the T1D Exchange clinic registry highest tier for cardiovascular risk and encourage smoking cessation emphasize the importance of good gly- recommends both lifestyle and pharma- in those who do smoke. A cemic and blood pressure control, par- cologic treatment for those with ele- 13.39 e-Cigarette use should be dis- ticularly as diabetes duration increases, vated LDL cholesterol levels (100,103). couraged. B in order to reduce the risk of diabetic Initial therapy should be with a nutrition kidney disease. The data also underscore plan that restricts saturated fat to 7% of The adverse health effects of smoking are the importance of routine screening to total calories and dietary cholesterol to well recognized with respect to future ensure early diagnosis and timely treat- 200 mg/day. Data from randomized clin- cancer and CVD risk. Despite this, smok- ment of albuminuria (113). An estimation ical trials in children as young as 7 months ing rates are significantly higher among of glomerular filtration rate (GFR), calcu- of age indicate that this diet is safe and youth with diabetes than among youth lated using GFR estimating equations from does not interfere with normal growth without diabetes (108,109). In youth the serum creatinine, height, age, and sex and development (104). with diabetes, it is important to avoid (114), should be considered at baseline For children with a significant family additional CVD risk factors. Smoking in- and repeated as indicated based on clin- history of CVD, the National Heart, Lung, creases the risk of onset of albumin- ical status, age, diabetes duration, and and Blood Institute recommends ob- uria; therefore, smoking avoidance is therapies. Improved methods are needed taining a fasting lipid panel beginning important to prevent both microvascular at 2 years of age (98). Abnormal results and macrovascular complications (98, to screen for early GFR loss, since estimated . from a random lipid panel should be 110). Discouraging cigarette smoking, GFR is inaccurate at GFR 60 mL/min/ 2 confirmed with a fasting lipid panel. including e-cigarettes (111,112), is an 1.73 m (114,115). The AdDIT study in Data from the SEARCH for Diabetes in important part of routine diabetes adolescents with type 1 diabetes demon- Youth (SEARCH) study show that im- care. In younger children, it is important strated safety of ACE inhibitor treatment, proved glucose control over a 2-year to assess exposure to cigarette smoke in but the treatment did not change the period is associated with a more favor- thehomebecauseoftheadverseeffects albumin-to-creatinine ratio over the able lipid profile; however, improved of secondhand smoke and to discourage course of the study (90). glycemic control alone will not normalize youth from ever smoking if exposed to lipids in youth with type 1 diabetes and smokers in childhood. Retinopathy dyslipidemia (105). Recommendations Neither long-term safety nor cardio- 13.42 An initial dilated and compre- fi Microvascular Complications vascular outcome ef cacy of statin ther- hensive eye examination is Nephropathy apy has been established for children; recommended once youth however, studies have shown short-term Recommendations have had type 1 diabetes for safety equivalent to that seen in adults and 3–5 years, provided they are efficacy in lowering LDL cholesterol levels Screening 13.40 Annual screening for albumin- age $10 years or puberty has in familial hypercholesterolemiaorsevere uria with a random (morning started, whichever is earlier. B hyperlipidemia, improving endothelial care.diabetesjournals.org Children and Adolescents S155

Type 2 diabetes in youth has increased 13.43 After the initial examination, oral glucose tolerance test, over the past 20 years, and recent esti- annual routine follow-up is and A1C can be used to test mates suggest an incidence of ;5,000 generally recommended. Less- for prediabetes or diabetes in new cases per year in the U.S. (119). The frequent examinations, every 2 children and adolescents. B Centers for Disease Control and Preven- years,maybeacceptableonthe 13.48 Children and adolescents with tion published projections for type 2 advice of an eye care professional overweight/obesity in whom diabetes prevalence using the SEARCH the diagnosis of type 2 diabe- and based on risk factor assess- database; assuming a 2.3% annual in- E tes is being considered should ment. crease, the prevalence in those under 20 years of age will quadruple in 40 years have a panel of pancreatic autoantibodies tested to ex- Retinopathy (like albuminuria) most com- (120,121). Evidence suggests that type 2 diabetes clude the possibility of auto- monly occurs after the onset of puberty immune type 1 diabetes. B and after 5–10 years of diabetes duration in youth is different not only from type 1 (116). Referrals should be made to eye diabetes but also from type 2 diabetes in In the last decade, the incidence and prev- care professionals with expertise in di- adults and has unique features, such as a b alence of type 2 diabetes in adolescents abetic retinopathy and experience in more rapidly progressive decline in -cell function and accelerated development of has increased dramatically, especially in counseling the pediatric patient and diabetescomplications(2,122).Type2di- racial and ethnic minority populations family on the importance of prevention, abetes disproportionately impacts youth (98,127). A few recent studies suggest early detection, and intervention. of ethnic and racial minorities and can oral glucose tolerance tests or fasting plasma glucose values as more suit- Neuropathy occur in complex psychosocial and cultural environments, which may make it able diagnostic tests than A1C in the Recommendation difficult to sustain healthy lifestyle pediatric population, especially among 13.44 Consider an annual compre- changes and self-management behaviors certain ethnicities (128), although fast- hensive foot exam at the start (22,123–126). Additional risk factors as- ing glucose alone may overdiagnose of puberty or at age $10 years, sociated with type 2 diabetes in youth diabetes in children (129,130). In addi- whichever is earlier, once the include adiposity, family history of dition, many of these studies do not youth has had type 1 diabetes abetes, female sex, and low socioeco- recognize that diabetes diagnostic cri- for 5 years. B nomic status (122). teria are based on long-term health As with type 1 diabetes, youth with outcomes, and validations are not cur- Diabetic neuropathy rarely occurs in type 2 diabetes spend much of the day in rently available in the pediatric popu- – prepubertal children or after only 1 2 school. Therefore, close communication lation (131). ADA acknowledges the years of diabetes (116), although data with and the cooperation of school per- limited data supporting A1C for diag- suggest a prevalence of distal peripheral sonnel are essential for optimal diabetes nosing type 2 diabetes in children and neuropathy of 7% in 1,734 youth with management, safety, and maximal aca- adolescents. Although A1C is not rec- type 1 diabetes and associated with the demic opportunities. ommended for diagnosis of diabetes in presence of CVD risk factors (117,118). A children with cystic fibrosis or symptoms comprehensive foot exam, including in- Screening and Diagnosis suggestive of acute onset of type 1 di- spection, palpation of dorsalis pedis and abetes, and only A1C assays without posterior tibial pulses, and determina- Recommendations 13.45 Risk-based screening for pre- interference are appropriate for chil- tion of proprioception, vibration, and dren with hemoglobinopathies, ADA monofilament sensation, should be per- diabetes and/or type 2 diabetes should be considered in continues to recommend A1C for di- formed annually along with an assess- agnosis of type 2 diabetes in this pop- ment of symptoms of neuropathic pain children and adolescents after $ ulation (132,133). (118). Foot inspection can be performed the onset of puberty or 10 at each visit to educate youth regarding years of age, whichever occurs the importance of foot care (see Section earlier, who are overweight (BMI $85th percentile) or Diagnostic Challenges 11 “Microvascular Complications and Given the current obesity epidemic, dis- obese (BMI $95th percentile) Foot Care”). tinguishing between type 1 and type 2 and who have one or more diabetes in children can be difficult. additional risk factors for di- Overweight and obesity are common in abetes (see Table 2.4 for ev- TYPE 2 DIABETES children with type 1 diabetes (23), idence grading of other risk For information on testing for type 2 di- and diabetes-associated autoantibodies factors). abetes and prediabetes in children and and ketosis may be present in pediatric 13.46 If tests are normal, repeat test- adolescents, please refer to Section 2 patients with features of type 2 diabetes ing at a minimum of 3-year “Classification and Diagnosis of Diabe- (including obesity and acanthosis nigri- intervals E, or more frequently tes.” For additional support for these cans) (129). The presence of islet auto- if BMI is increasing. C recommendations, see the ADA position antibodies has been associated with 13.47 Fasting plasma glucose, 2-h statement “Evaluation and Management faster progression to insulin deficiency plasma glucose during a 75-g of Youth-Onset Type 2 Diabetes” (2). (129). At onset, DKA occurs in ;6% of S156 Children and Adolescents Diabetes Care Volume 42, Supplement 1, January 2019

youth aged 10–19 years with type 2 dense, high-quality foods and be treated initially with basal diabetes (134). Although uncommon, decreased consumption of insulin while metformin is ini- type 2 diabetes has been observed in calorie-dense, nutrient-poor tiated and titrated. B prepubertal children under the age of 10, foods, particularly sugar-added 13.61 In patients with ketosis/ and thus it should be part of the differ- beverages. B ketoacidosis, treatment with ential in children with suggestive symp- subcutaneous or intravenous toms (135). Finally, obesity (136) and Glycemic Targets 13.54 Home self-monitoring of blood insulin should be initiated to type 2 diabetes–associated genetic fac- glucose regimens should be rapidly correct the hyperglyce- tors may (137) contribute to the devel- individualized, taking into con- mia and the metabolic derange- opment of type 1 diabetes in some sideration the pharmacologic ment. Once acidosis is resolved, individuals, which further blurs the lines treatment of the patient. E metformin should be initiated between diabetes types. However, accu- 13.55 A1C should be measured every while subcutaneous insulin ther- rate diagnosis is critical, as treatment 3 months. E apy is continued. A regimens, educational approaches, die- 13.56 A reasonable A1C target for 13.62 In individuals presenting with tary advice, and outcomes differ markedly most children and adolescents severe hyperglycemia (blood between patients with the two diagnoses. with type 2 diabetes treated glucose $600 mg/dL [33.3 , Management with oral agents alone is 7% mmol/L]), consider assessment (53 mmol/mol). More strin- for hyperglycemic hyperosmo- Recommendations gent A1C targets (such lar nonketotic syndrome. A Lifestyle Management as ,6.5% [48 mmol/mol]) 13.63 If the A1C target is no longer 13.49 All youth with type 2 diabetes may be appropriate for se- met with metformin mono- and their families should re- lected individual patients if therapy, or if contraindications ceive comprehensive diabetes this can be achieved with- or intolerable side effects of self-management education out significant hypoglycemia metformin develop, basal in- and support that is specific or other adverse effects of sulin therapy should be initi- to youth with type 2 diabetes treatment. Appropriate pa- ated. B and is culturally competent. B tients might include those 13.64 Patients treated with basal 13.50 Youth with overweight/obe- with short duration of diabetes insulin up to 1.5 units/kg/day sity and type 2 diabetes and and lesser degrees of b-cell who do not meet A1C target their families should be pro- dysfunction and patients should be moved to multiple vided with developmentally treated with lifestyle or metfor- daily injections with basal and and culturally appropriate min only who achieve signifi- premeal bolus insulins. E comprehensive lifestyle pro- cant weight improvement. E 13.65 In patients initially treated grams that are integrated with 13.57 A1C targets for patients on with insulin and metformin diabetes management to achieve insulin should be individual- who are meeting glucose tar- 7–10% decrease in excess ized, taking into account the gets based on home blood weight. C relatively low rates of hypogly- glucose monitoring, insulin 13.51 Given the necessity of long- cemia in youth-onset type 2 can be tapered over 2–6 weeks term weight management diabetes. E by decreasing the insulin dose for children and adolescents Pharmacologic Management 10–30% every few days. B with type 2 diabetes, lifestyle 13.58 Initiate pharmacologic ther- 13.66 Use of medications not ap- intervention should be based apy, in addition to lifestyle proved by the U.S. Food and on a chronic care model and therapy, at diagnosis of type Drug Administration for youth offered in the context of di- 2 diabetes. A with type 2 diabetes is not abetes care. E 13.59 In incidentally diagnosed or recommended outside of re- 13.52 Youth with diabetes, like all metabolically stable patients search trials. B children, should be encour- (A1C ,8.5% [69 mmol/mol] aged to participate in at least and asymptomatic), metformin Treatment of youth-onset type 2 diabetes 30–60 min of moderate to is the initial pharmacologic should include lifestyle management, di- vigorous physical activity at treatment of choice if renal abetes self-management education, and least 5 days per week (and function is normal. A pharmacologic treatment. Initial treatment strength training on at least 13.60 Youth with marked hyper- ofyouthwithobesityanddiabetesmust 3 days/week) B and to de- glycemia (blood glucose $250 take into account that diabetes type is crease sedentary behavior. C mg/dL [13.9 mmol/L], A1C often uncertain in the first few weeks of 13.53 Nutrition for youth with type $8.5% [69 mmol/mol]) with- treatment, due to overlap in presentation, 2 diabetes, like all children, out acidosis at diagnosis who and that a substantial percentage of youth should focus on healthy eat- are symptomatic with poly- with type 2 diabetes will present with ing patterns that emphasize uria, polydipsia, nocturia, clinically significant ketoacidosis (138). consumption of nutrient- and/or weight loss should Therefore, initial therapy should address care.diabetesjournals.org Children and Adolescents S157

Figure 13.1—Management of new-onset diabetes in overweight youth (2). A1C 8.5% 5 69 mmol/mol. DKA, diabetic ketoacidosis; HHNK, hyperosmolar hyperglycemic nonketotic syndrome; MDI, multiple daily injections. the hyperglycemia and associated meta- approach to nutrition and lifestyle modi- limited to two approved drugsdinsulin bolic derangements irrespective of ulti- fication is essential in children with type 2 and metformin (2). Presentation with mate diabetes type, with adjustment of diabetes, and nutition recommendations ketoacidosis or marked ketosis requires therapy once metabolic compensation should be culturally appropriate and sen- a period of insulin therapy until fasting has been established and subsequent sitive to family resources (see Section and postprandial glycemia have been information, such as islet autoantibody 5 “Lifestyle Management”). Given the restored to normal or near-normal levels. results, becomes available. Figure 13.1 complex social and environmental con- Metformin therapy may be used as an provides an approach to initial treatment text surrounding youth with type 2 diabe- adjunct after resolution of ketosis/ of new-onset diabetes in overweight tes, individual-level lifestyle interventions ketoacidosis. Initial treatment should youth. may not be sufficienttotargetthecom- also be with insulin when the distinction Glycemic targets should be individu- plex interplay of family dynamics, mental between type 1 diabetes and type 2 alized, taking into consideration long- health, community readiness, and the diabetes is unclear and in patients who term health benefits of more stringent broader environmental system (2). have random blood glucose concentra- targets as well as risk for adverse effects, A multidisciplinary diabetes team, tions $250 mg/dL (13.9 mmol/L) and/or such as hypoglycemia. A lower target A1C including a physician, diabetes nurse A1C $8.5% (69 mmol/mol) (146). Insulin in youth with type 2 diabetes when educator, registered dietitian, and psy- is needed when the glycemic target is not compared with those recommended in chologist or social worker, is essential. In met on metformin alone, or if there is type 1 diabetes is justified by lower risk addition to blood glucose control and metformin intolerance or renal or he- of hypoglycemia and higher risk of com- self-management education (143–145), patic insufficiency (147). plications (139–142). initial treatment must include manage- When insulin treatment is not re- Patients and their families must pri- ment of comorbidities such as obesity, quired, initiation of metformin is recom- oritize lifestyle modifications such as dyslipidemia, hypertension, and micro- mended. The Treatment Options for eating a balanced diet, achieving and vascular complications. Type 2 Diabetes in Adolescents and Youth maintaining a healthy weight, and Current pharmacologic treatment op- (TODAY) study found that metformin exercising regularly. A family-centered tions for youth-onset type 2 diabetes are alone provided durable glycemic S158 Children and Adolescents Diabetes Care Volume 42, Supplement 1, January 2019

control (A1C #8% [64 mmol/mol] for including the Pediatric Bariatric Study for those with urinary albumin- 6 months) in approximately half of Group and the Teen Longitudinal Assess- to-creatinine ratio .300 mg/g the subjects (148). To date, the TODAY ment of Bariatric Surgery (Teen-LABS) creatinine and/or estimated study is the only trial combining life- Study have demonstrated the effective- glomerular ﬁltration rate style and metformin therapy in youth ness of metabolic surgery in adoles- ,60 mL/min/1.73 m2. E with type 2 diabetes; the combination did cents (155–161). 13.77 For those with nephropathy, not perform better than metformin alone continued monitoring (yearly in achieving durable glycemic control urinary albumin-to-creatinine (148). Prevention and Management of ratio, estimated glomerular Diabetes Complications Metabolic Surgery ﬁltration rate, and serum po-

Recommendations Recommendations tassium) may aid in assessing 13.67 Metabolic surgery may be adherence and detecting pro- Nephropathy gression of disease. E considered for the treatment 13.69 Blood pressure should be 13.78 Referral to nephrology is rec- of adolescents with type 2 dia- A measured at every visit. ommended in case of uncer- betes who are markedly obese 13.70 Blood pressure should be opti- . 2 tainty of etiology, worsening (BMI 35 kg/m ) and who mizedtoreduceriskand/orslow urinary albumin-to-creatinine have uncontrolled glycemia the progression of diabetic kid- ratio, or decrease in estimated and/or serious comorbidities ney disease. A glomerular filtration rate. E despite lifestyle and pharma- 13.71 If blood pressure is .95th A cologic intervention. percentile for age, sex, and 13.68 Neuropathy Metabolic surgery should be height, increased emphasis 13.79 Youth with type 2 diabetes performed only by an expe- should be placed on lifestyle should be screened for the rienced surgeon working as management to promote presence of neuropathy by part of a well-organized and weight loss. If blood pressure foot examination at diagnosis engaged multidisciplinary remains above the 95th per- and annually. The examina- team including surgeon, endo- centile after 6 months, antihy- tion should include inspec- crinologist, nutritionist, behav- pertensive therapy should be tion, assessment of foot ioral health specialist, and initiated. C pulses, pinprick and 10-g A nurse. 13.72 Initial therapeutic options in- monofilament sensation tests, clude ACE inhibitors or angio- testing of vibration sensation The results of weight-loss and lifestyle tensin receptor blockers. using 128-Hz tuning fork, and interventions for obesity in children and Other blood pressure–lowering ankle reflexes. C adolescents have been disappointing, agents may be added as 13.80 Prevention should focus on and no effective and safe pharmaco- needed. C achieving glycemic targets. C logic intervention is available or ap- 13.73 Protein intake should be at proved by the U.S. Food and Drug the recommended daily allow- Retinopathy Administration in youth. Over the 13.81 Screening for retinopathy ance of 0.8 g/kg/day. E last decade, weight-loss surgery has should be performed by di- 13.74 Urine albumin-to-creatinine been increasingly performed in adoles- lated fundoscopy or retinal ratio should be obtained at cents with obesity. Small retrospective photography at or soon after the time of diagnosis and an- analyses and a recent prospective mul- diagnosis and annually there- nually thereafter. An elevated ticenter nonrandomized study suggest after. C urine albumin-to-creatinine that bariatric or metabolic surgery may 13.82 Optimizing glycemia is recom- ratio (.30 mg/g creatinine) have benefitsinobeseadolescentswith mended to decrease the risk or should be confirmed on two type 2 diabetes similar to those ob- slow the progression of reti- of three samples. B served in adults. Teenagers experience nopathy. B 13.75 Estimated glomerular filtration similar degrees of weight loss, diabetes 13.83 Less frequent examination (ev- rate should be determined at remission, and improvement of cardi- ery 2 years) may be considered the time of diagnosis and an- ometabolic risk factors for at least 3 if there is adequate glycemic nually thereafter. E years after surgery (149). No random- control and a normal eye 13.76 In nonpregnant patients with ized trials, however, have yet compared exam. C diabetes and hypertension, ei- the effectiveness and safety of surgery ther an ACE inhibitor or an to those of conventional treatment op- Nonalcoholic Fatty Liver Disease angiotensin receptor blocker 13.84 Evaluation for nonalcoholic fatty tions in adolescents (150). The guidelines is recommended for those liver disease (by measuring used as an indication for metabolic sur- with modestly elevated uri- aspartate aminotransferase gery in adolescents generally include nary albumin-to-creatinine ra- and alanine aminotransferase) BMI .35 kg/m2 with comorbidities or tio (30–299 mg/g creatinine) D should be done at diagnosis and BMI .40 kg/m2 with or without comor- and is strongly recommended annually thereafter. B bidities (151–162). A number of groups, care.diabetesjournals.org Children and Adolescents S159

13.85 Referral to gastroenterology dietary intervention, initiate youth with type 2 diabetes, even if they should be considered for per- therapy with statin, with are being treated with insulin (165), sistently elevated or worsen- goal of LDL ,100 mg/dL. B and there are high rates of complica- ing transaminases. B 13.95 If triglycerides are .400 mg/dL tions (139–142). These diabetes comor- Obstructive Sleep Apnea (4.7 mmol/L) fasting or bidities also appear to be higher than in 13.86 Screening for symptoms of .1,000 mg/dL (11.6 mmol/L) youth with type 1 diabetes despite sleep apnea should be nonfasting, optimize glycemia shorter diabetes duration and lower done at each visit, and refer- and begin fibrate, with a goal A1C (163). In addition, the progression ral to a pediatric sleep spe- of ,400 mg/dL (4.7 mmol/L) of vascular abnormalities appears to be cialist for evaluation and a fasting (to reduce risk for pan- more pronounced in youth-onset type 2 polysomnogram, if indicated, creatitis). C diabetes compared with type 1 di- is recommended. Obstructive abetes of similar duration, including Cardiac Function Testing ischemic heart disease and stroke sleep apnea should be treated 13.96 Routine screening for heart dis- B (166). when documented. ease with electrocardiogram, Polycystic Ovary Syndrome echocardiogram, or stress test- Psychosocial Factors 13.87 Evaluate for polycystic ovary ing is not recommended in syndrome in female adoles- asymptomatic youth with type Recommendations cents with type 2 diabetes, 2diabetes.B including laboratory studies 13.97 Providers should assess social when indicated. B Comorbidities may already be present context, including potential 13.88 Oral contraceptive pills for at the time of diagnosis of type 2 di- food insecurity, housing sta- treatment of polycystic ovary abetes in youth (122,163). Therefore, bility, and financial barriers, syndrome are not contraindi- blood pressure measurement, a fast- and apply that information to cated for girls with type 2 di- ing lipid panel, assessment of ran- treatment decisions. E abetes. C dom urine albumin-to-creatinine 13.98 Use patient-appropriate stan- 13.89 Metformin in addition to life- ratio, and a dilated eye examination dardized and validated tools style modification is likely to should be performed at diagnosis. to assess for diabetes dis- improve the menstrual cyclic- Thereafter, screening guidelines and tress and mental/behavioral ity and hyperandrogenism in treatment recommendations for hy- health in youth with type 2 girls with type 2 diabetes. E pertension, dyslipidemia, urine albumin diabetes, with attention to excretion, and retinopathy are similar to symptoms of depression Cardiovascular Disease those for youth with type 1 diabetes. and eating disorders, and re- 13.90 Intensive lifestyle interven- Additional problems that may need to be fer to specialty care when tions focusing on weight loss, addressed include polycystic ovary dis- indicated. B dyslipidemia, hypertension, ease and other comorbidities associ- 13.99 When choosing glucose- and dysglycemia are impor- ated with pediatric obesity, such as lowering or other medications tant to prevent overt mac- sleep apnea, hepatic steatosis, ortho- for youth with overweight/ rovascular disease in early pedic complications, and psychoso- obesity and type 2 diabetes, adulthood. E cial concerns. The ADA position consider medication-taking “ statement Evaluation and Manage- behavior and their effect on Dyslipidemia ment of Youth-Onset Type 2 Diabe- 13.91 Lipid testing should be per- weight. E tes” (2) provides guidance on the formed when initial glycemic 13.100 Starting at puberty, precon- prevention, screening, and treatment control has been achieved and ception counseling should be of type 2 diabetes and its comorbidities annually thereafter. B incorporated into routine di- in children and adolescents. 13.92 Optimal goals are LDL choles- abetes clinic visits for all fe- Youth-onset type 2 diabetes is asso- terol ,100 mg/dL (2.6 mmol/L), males of childbearing potential ciated with significant microvascular HDL cholesterol .35 mg/dL because of the adverse preg- and macrovascular risk burden and a sub- (0.905 mmol/L), and trigly- nancy outcomes in this popu- stantial increase in the risk of cardiovas- cerides ,150 mg/dL (1.7 lation. A cular morbidity and mortality at an mmol/L). E 13.101 Patients should be screened earlier age than those diagnosed later 13.93 If LDL cholesterol is .130 for smoking and alcohol use in life (164). The higher complication mg/dL, blood glucose control at diagnosis and regularly risk in earlier-onset type 2 diabetes is should be maximized and di- thereafter. C likely related to prolonged lifetime ex- etary counseling should be posure to hyperglycemia and other provided using the American atherogenic risk factors, including in- Most youth with type 2 diabetes Heart Association Step 2 diet. E sulin resistance, dyslipidemia, hyper- come from racial/ethnic minority groups, 13.94 If LDL cholesterol remains tension, and chronic inflammation. have low socioeconomic status, and of- above goal after 6 months of There is low risk of hypoglycemia in ten experience multiple psychosocial S160 Children and Adolescents Diabetes Care Volume 42, Supplement 1, January 2019

stressors (22,35,123–126). Consider- youth with type 1 or type 2 diabetes statementbythe AmericanDiabetesAssociation. ation of the sociocultural context and throughout childhood and adolescence. Diabetes Care 2018;41:2648–2668 efforts to personalize diabetes manage- The shift from pediatric to adult health 3. Nadeau KJ, Anderson BJ, Berg EG, et al. Youth- onset type 2 diabetes consensus report: current ment are of critical importance to min- care providers, however, often occurs status, challenges, and priorities. Diabetes Care imize barriers to care, enhance abruptly as the older teen enters the next 2016;39:1635–1642 adherence, and maximize response to developmental stage, referred to as 4. Mayer-Davis EJ, Lawrence JM, Dabelea D, treatment. emerging adulthood (177), which is a et al.; SEARCH for Diabetes in Youth Study. Evidence about psychiatric disorders critical period for young people who Incidence trends of type 1 and type 2 diabetes among youths, 2002–2012. N Engl J Med 2017; and symptoms in youth with type 2 di- have diabetes. During this period of 376:1419–1429 abetes is limited (167–171), but given the major life transitions, youth begin to 5. Thomas NJ, Jones SE, Weedon MN, Shields sociocultural context for many youth and move out of their parents’ homes and BM, Oram RA, Hattersley AT. Frequency and the medical burden and obesity associ- must become fully responsible for their phenotype of type 1 diabetes in the first six ated with type 2 diabetes, ongoing sur- diabetes care. Their new responsibilities decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank. veillance of mental health/behavioral include self-management of their diabe- Lancet Diabetes Endocrinol 2018;6:122–129 health is indicated. Symptoms of depres- tes, making medical appointments, and 6. Barnea-Goraly N, Raman M, Mazaika P, et al.; sion and disordered eating are common financing health care, once they are no Diabetes Research in Children Network (Direc- and associated with poorer glycemic longer covered by their parents’ health Net). Alterations in white matter structure in control (168,172,173). insurance plans (ongoing coverage until young children with type 1 diabetes. Diabetes Care 2014;37:332–340 Many of the drugs prescribed for di- age 26 years is currently available under 7. Cameron FJ, Scratch SE, Nadebaum C, et al.; abetes and psychiatric disorders are as- provisions of the U.S. Affordable Care DKA Brain Injury Study Group. Neurological sociated with weight gain and can Act). In addition to lapses in health care, consequences of diabetic ketoacidosis at initial increase patients’ concerns about eat- this is also a period associated with de- presentation of type 1 diabetes in a prospective ing, body shape, and weight (174,175). terioration in glycemic control; increased cohort study of children. Diabetes Care 2014;37: 1554–1562 The TODAY study documented (176) occurrence of acute complications; psy- 8. Markowitz JT, Garvey KC, Laffel LMB. De- that despite disease- and age-specific chosocial, emotional, and behavioral velopmental changes in the roles of patients counseling, 10.2% of the females in challenges; and the emergence of and families in type 1 diabetes management. the cohort became pregnant over an chronic complications (178–181). The Curr Diabetes Rev 2015;11:231–238 9. Driscoll KA, Volkening LK, Haro H, et al. Are average of 3.8 years of study participa- transition period from pediatric to adult children with type 1 diabetes safe at school? tion. Of note, 26.4% of pregnancies care is prone to fragmentation in health Examining parent perceptions. Pediatr Diabetes ended in a miscarriage, stillbirth, or in- care delivery, which may adversely im- 2015;16:613–620 trauterine death, and 20.5% of the live- pact health care quality, cost, and out- 10. Mehta SN, Volkening LK, Anderson BJ, et al.; born infants had a major congenital comes (182). Family Management of Childhood Diabetes Study Steering Committee. Dietary behaviors anomaly. Although scientific evidence is limited, predict glycemic control in youth with type 1 it is clear that comprehensive and co- diabetes. Diabetes Care 2008;31:1318–1320 ordinated planning that begins in early 11. Riddell MC, Gallen IW, Smart CE, et al. TRANSITION FROM PEDIATRIC TO adolescence is necessary to facilitate a Exercise management in type 1 diabetes: a con- ADULT CARE seamless transition from pediatric to sensus statement. Lancet Diabetes Endocrinol 2017;5:377–390 Recommendations adult health care (178,179,183,184). A 12. Colberg SR, Sigal RJ, Yardley JE, et al. Physical 13.102 Pediatric diabetes providers comprehensive discussion regarding the activity/exercise and diabetes: a position state- should begin to prepare challenges faced during this period, in- ment of the American Diabetes Association. youth for transition to adult cluding specific recommendations, is Diabetes Care 2016;39:2065–2079 health care in early adoles- found in the ADA position statement 13. Robertson K, Adolfsson P, Scheiner G, Hanas “ R, Riddell MC. Exercise in children and adolescence and, at the latest, at Diabetes Care for Emerging Adults: Rec- cents with diabetes. Pediatr Diabetes 2009;10 least 1 year before the tran- ommendations for Transition From Pe- (Suppl. 12):154–168 sition. E diatric to Adult Diabetes Care Systems” 14. U.S. Department of Health and Human Serv- 13.103 Both pediatric and adult di- (179). ices. 2008 physical activity guidelines for Amer- abetes care providers should The Endocrine Society in collabora- icans: index [Internet]. Available from https:// health.gov/paguidelines/guidelines/default. provide support and resour- tion with the ADA and other organiza- aspx. Accessed 16 October 2018 ces for transitioning young tions has developed transition tools 15. Tsalikian E, Kollman C, Tamborlane WB, adults. E for clinicians and youth and families et al.; Diabetes Research in Children Network 13.104 Youth with type 2 diabetes (184). (DirecNet) Study Group. Prevention of hypogly- should be transferred to an cemia during exercise in children with type 1 diabetes by suspending basal insulin. Diabetes adult-oriented diabetes spe- – References Care 2006;29:2200 2204 cialist when deemed appro- 16. Taplin CE, Cobry E, Messer L, McFann K, 1. Chiang JL, Maahs DM, Garvey KC, et al. Type 1 priate by the patient and Chase HP, Fiallo-Scharer R. Preventing post- diabetes in children and adolescents: a position provider. E exercise nocturnal hypoglycemia in children statementbythe AmericanDiabetesAssociation. with type 1 diabetes. J Pediatr 2010;157: Diabetes Care 2018;41:2026–2044 784–788.e1 Care and close supervision of diabetes 2. Arslanian S, Bacha F, Grey M, Marcus MD, 17. Riddell MC, Milliken J. Preventing exercise- management are increasingly shifted White NH, Zeitler P. Evaluation and manage- induced hypoglycemia in type 1 diabetes using from parents and other adults to the ment of youth-onset type 2 diabetes: a position real-time continuous glucose monitoring and a care.diabetesjournals.org Children and Adolescents S161

new carbohydrate intake algorithm: an obser- [published correction appears in Diabetes 48. Saßmann H, Albrecht C, Busse-Widmann P, vational field study. Diabetes Technol Ther 2011; Care 2018;41:640]. Diabetes Care 2017;40: et al. Psychometric properties of the German 13:819–825 1002–1009 version of the Diabetes Eating Problem Survey- 18. Francescato MP, Stel G, Stenner E, Geat M. 33. Hilliard ME, De Wit M, Wasserman RM, et al. Revised: additional benefit of disease-specific Prolonged exercise in type 1 diabetes: perfor- Screening and support for emotional burdens screening in adolescents with type 1 diabetes. mance of a customizable algorithm to estimate of youth with type 1 diabetes: strategies for Diabet Med 2015;32:1641–1647 the carbohydrate supplements to minimize gly- diabetes care providers. Pediatr Diabetes 2018; 49. Lawrence JM, Yi-Frazier JP, Black MH, et al.; cemic imbalances. PLoS One 2015;10:e0125220 19:534–543 SEARCH for Diabetes in Youth Study Group. 19. Adolfsson P, Mattsson S, Jendle J. Evaluation 34. Shapiro JB, Vesco AT, Weil LEG, Evans MA, Demographic and clinical correlates of diabe- of glucose control when a new strategy of in- Hood KK, Weissberg-Benchell J. Psychometric tes-related quality of life among youth with creased carbohydrate supply is implemented properties of the Problem Areas in Diabetes: type 1 diabetes. J Pediatr 2012;161:201–207.e2 during prolonged physical exercise in type 1 Teen and Parent of Teen versions. J Pediatr 50. Wisting L, Frøisland DH, Skrivarhaug T, Dahl- diabetes. Eur J Appl Physiol 2015;115:2599–2607 Psychol 2018;43:561–571 Jørgensen K, Rø O. Disturbed eating behavior and 20. Baker LB, Rollo I, Stein KW, Jeukendrup AE. 35. Young-Hyman D, de Groot M, Hill-Briggs F, omission of insulin in adolescents receiving in- Acute effects of carbohydrate supplementation Gonzalez JS, Hood K, Peyrot M. Psychosocial care tensified insulin treatment: a nationwide pop- on intermittent sports performance. Nutrients for people with diabetes: a position statement of ulation-based study. Diabetes Care 2013;36: 2015;7:5733–5763 the American Diabetes Association. Diabetes 3382–3387 21. Redondo MJ, Libman I, Cheng P, et al.; Care 2016;39:2126–2140 51. Maahs DM, Hermann JM, DuBose SN, et al.; Pediatric Diabetes Consortium. Racial/ethnic mi- 36. Katz ML, Volkening LK, Butler DA, Anderson DPV Initiative; T1D Exchange Clinic Network. nority youth with recent-onset type 1 diabetes BJ, Laffel LM. Family-based psychoeducation and Contrasting the clinical care and outcomes of have poor prognostic factors. Diabetes Care Care Ambassador intervention to improve glyce- 2,622 children with type 1 diabetes less than – 2018;41:1017 1024 mic control in youth with type 1 diabetes: a ran- 6 years of age in the United States T1D Exchange 22. Liu LL, Lawrence JM, Davis C, et al.; SEARCH domized trial. Pediatr Diabetes 2014;15:142–150 and German/Austrian DPV registries. Diabetolo- for Diabetes in Youth Study Group. Prevalence of 37. Laffel LMB, Vangsness L, Connell A, Goebel- gia 2014;57:1578–1585 overweight and obesity in youth with diabetes in Fabbri A, Butler D, Anderson BJ. Impact of 52. Haynes A, Hermann JM, Miller KM, et al.; USA: the SEARCH for Diabetes in Youth study. ambulatory, family-focused teamwork interven- T1D Exchange, WACDD and DPV registries. Se- – Pediatr Diabetes 2010;11:4 11 tion on glycemic control in youth with type 1 vere hypoglycemia rates are not associated with 23. DuBose SN, Hermann JM, Tamborlane WV, diabetes. J Pediatr 2003;142:409–416 HbA1c: a cross-sectional analysis of 3 contempo- et al.; Type 1 Diabetes Exchange Clinic Network 38. Anderson BJ, Vangsness L, Connell A, Butler rary pediatric diabetes registry databases. Pe- and Diabetes Prospective Follow-up Registry. D, Goebel-Fabbri A, Laffel LMB. Family conflict, diatr Diabetes 2017;18:643–650 Obesity in youth with type 1 diabetes in Ger- adherence, and glycaemic control in youth with 53. Ryan CM. Why is cognitive dysfunction many, Austria, and the United States. J Pediatr short duration type 1 diabetes. Diabet Med 2002; associated with the development of diabetes 2015;167:627–632.e4 19:635–642 early in life? The diathesis hypothesis. Pediatr 24. Corbin KD, Driscoll KA, Pratley RE, Smith SR, 39. Helgeson VS, Palladino DK. Implications of Diabetes 2006;7:289–297 Maahs DM, Mayer-Davis EJ; Advancing Care for psychosocial factors for diabetes outcomes 54. Cameron FJ. The impact of diabetes on brain Type 1 Diabetes and Obesity Network (ACT1ON). among children with type 1 diabetes: a review. function in childhood and adolescence. Pediatr Obesity in type 1 diabetes: pathophysiology, Soc Personal Psychol Compass 2012;6:228–242 Clin North Am 2015;62:911–927 clinical impact, and mechanisms. Endocr Rev 40. McCarthy AM, Lindgren S, Mengeling MA, 55. Campbell MS, Schatz DA, Chen V, et al.; T1D 2018;39:629–663 Tsalikian E, Engvall J. Factors associated with Exchange Clinic Network. A contrast between 25. Redondo MJ, Foster NC, Libman IM, et al. academic achievement in children with type 1 children and adolescents with excellent and poor Prevalence of cardiovascular risk factors in youth diabetes. Diabetes Care 2003;26:112–117 with type 1 diabetes and elevated body mass control: the T1D Exchange clinic registry expe- 41. Kuther TL. Medical decision-making and – index. Acta Diabetol 2016;53:271–277 rience. Pediatr Diabetes 2014;15:110 117 ’ 26. Jackson CC, Albanese-O’Neill A, Butler KL, minors: issues of consent and assent. Adoles- 56. Cooper MN, O Connell SM, Davis EA, Jones – et al. Diabetes care in the school setting: a posi- cence 2003;38:343 358 TW. A population-based study of risk factors for tion statement of the American Diabetes Asso- 42. Coleman DL, Rosoff PM. The legal authority severe hypoglycaemia in a contemporary cohort ciation. Diabetes Care 2015;38:1958–1963 of mature minors to consent to general medical of childhood-onset type 1 diabetes. Diabetologia – – 27. Siminerio LM, Albanese-O’Neill A, Chiang JL, treatment. Pediatrics 2013;131:786 793 2013;56:2164 2170 et al.; American Diabetes Association. Care of young 43. Charron-Prochownik D, Sereika SM, Becker 57. Bergenstal RM, Klonoff DC, Garg SK, et al.; children with diabetes in the child care setting: D, et al. Long-term effects of the booster-en- ASPIRE In-Home Study Group. Threshold-based a position statement of the American Diabetes hanced READY-Girls preconception counseling insulin-pump interruption for reduction of hy- Association. Diabetes Care 2014;37:2834–2842 program on intentions and behaviors for family poglycemia. N Engl J Med 2013;369:224–232 28. Corathers SD, Kichler J, Jones N-HY, et al. planning in teens with diabetes. Diabetes Care 58. Abraham MB, Davey R, O’Grady MJ, et al. Improving depression screening for adolescents 2013;36:3870–3874 Effectiveness of a predictive algorithm in the with type 1 diabetes. Pediatrics. 2013;132: 44. Charron-Prochownik D, Downs J. Diabetes prevention of exercise-induced hypoglycemia in e1395–e1402 and Reproductive Health for Girls. Alexandria, type 1 diabetes. Diabetes Technol Ther 2016;18: 29. Hood KK, Beavers DP, Yi-Frazier J, et al. VA, American Diabetes Association, 2016 543–550 Psychosocial burden and glycemic control dur- 45. Markowitz JT, Butler DA, Volkening LK, 59. Buckingham BA, Bailey TS, Christiansen M, ing the first 6 years of diabetes: results from Antisdel JE, Anderson BJ, Laffel LMB. Brief screen- et al. Evaluation of a predictive low-glucose the SEARCH for Diabetes in Youth study. J ing tool for disordered eating in diabetes: internal management system in-clinic. Diabetes Technol Adolesc Health 2014;55:498–504 consistency and external validity in a contempo- Ther 2017;19:288–292 30. Ducat L, Philipson LH, Anderson BJ. The rary sample of pediatric patients with type 1 60. Nimri R, Muller I, Atlas E, et al. MD-Logic mental health comorbidities of diabetes. diabetes. Diabetes Care 2010;33:495–500 overnight control for 6 weeks of home use in JAMA 2014;312:691–692 46. Goebel-Fabbri AE. Disturbed eating behav- patients with type 1 diabetes: randomized cross- 31. Hagger V, Hendrieckx C, Sturt J, Skinner TC, iors and eating disorders in type 1 diabetes: over trial. Diabetes Care 2014;37:3025–3032 Speight J. Diabetes distress among adolescents clinical significance and treatment recommen- 61. Thabit H, Tauschmann M, Allen JM, et al. with type 1 diabetes: a systematic review. Curr dations. Curr Diab Rep 2009;9:133–139 Home use of an artificial beta cell in type 1 Diab Rep 2016;16:9 47. Atik Altınok Y, Ozg¨ ur¨ S, Meseri R, Ozen¨ S, diabetes. N Engl J Med 2015;373:2129–2140 32. Anderson BJ, Laffel LM, Domenger C, et al. Darcan S¸,Goks¨ ¸en D. Reliability and validity of the 62. Bergenstal RM, Garg S, Weinzimer SA, et al. Factorsassociatedwithdiabetes-specific diabeteseating problemsurvey in Turkish children Safety of a hybrid closed-loop insulin delivery health-related qualityoflifeinyouthwith and adolescents with type 1 diabetes mellitus. J system in patients with type 1 diabetes. JAMA type 1 diabetes: the global TEENs study Clin Res Pediatr Endocrinol 2017;9:323–328 2016;316:1407–1408 S162 Children and Adolescents Diabetes Care Volume 42, Supplement 1, January 2019

63. Kovatchev B, Cheng P, Anderson SM, et al. 77. Dost A, Rohrer TR, Frohlich-Reiterer¨ E, et al.; adolescents with type 1 diabetes. N Engl J Med Feasibility of long-term closed-loopcontrol: a mul- DPV Initiative and the German Competence 2017;377:1733–1745 ticenter 6-month trial of 24/7 automated insulin Network Diabetes Mellitus. Hyperthyroidism 91. de Ferranti SD, de Boer IH, Fonseca V, et al. delivery. Diabetes Technol Ther 2017;19:18–24 in 276 children and adolescents with type 1 Type 1 diabetes mellitus and cardiovascular 64. El-Khatib FH, Balliro C, Hillard MA, et al. diabetes from Germany and Austria. Horm disease:ascientific statementfromthe American Homeuseof abihormonalbionicpancreasversus Res Paediatr 2015;84:190–198 Heart Association and American Diabetes Asso- insulin pump therapy in adults with type 1 di- 78. Jonsdottir B, Larsson C, Carlsson A, et al.; ciation. Circulation 2014;130:1110–1130 abetes: a multicentre randomised crossover Better Diabetes Diagnosis Study Group. Thyroid 92. Rodriguez BL, Fujimoto WY, Mayer-Davis EJ, trial. Lancet 2017;389:369–380 and islet autoantibodies predict autoimmune et al. Prevalence of cardiovascular disease risk 65. Levine BS, Anderson BJ, Butler DA, Antisdel thyroid disease at type 1 diabetes diagnosis. J factors in U.S. children and adolescents with JE, Brackett J, Laffel LM. Predictors of glycemic Clin Endocrinol Metab 2017;102:1277–1285 diabetes: the SEARCH for Diabetes in Youth control and short-term adverse outcomes in 79. Mohn A, Di Michele S, Di Luzio R, Tumini S, study. Diabetes Care 2006;29:1891–1896 youth with type 1 diabetes. J Pediatr 2001; Chiarelli F. The effect of subclinical hypothyroid- 93. Margeirsdottir HD, Larsen JR, Brunborg C, 139:197–203 ism on metabolic control in children and ado- Overby NC, Dahl-Jørgensen K; Norwegian Study 66. Miller KM, Beck RW, Bergenstal RM, et al.; lescents with type 1 diabetes mellitus. Diabet Group for Childhood Diabetes. High preva- T1D Exchange Clinic Network. Evidence of a Med 2002;19:70–73 lence of cardiovascular risk factors in chil- strong association between frequency of self- 80. Holmes GKT. Screening for coeliac disease dren and adolescents with type 1 diabetes: monitoring of blood glucose and hemoglobin in type 1 diabetes. Arch Dis Child 2002;87:495– a population-based study. Diabetologia 2008; 498 51:554–561 A1c levels in T1D Exchange clinic registry participants. Diabetes Care 2013;36:2009–2014 81. Rewers M, Liu E, Simmons J, Redondo MJ, 94. Schwab KO, Doerfer J, Hecker W, et al.; DPV 67. Rosenbauer J, Dost A, Karges B, et al.; DPV Hoffenberg EJ. Celiac disease associated with Initiative of the German Working Group for Initiative and the German BMBF Competence type 1 diabetes mellitus. Endocrinol Metab Clin Pediatric Diabetology. Spectrum and prevalence – Network Diabetes Mellitus. Improved metabolic North Am 2004;33:197 214 of atherogenic risk factors in 27,358 children, control in children and adolescents with type 1 82. Pham-Short A, Donaghue KC, Ambler G, adolescents, and young adults with type 1 di- diabetes: a trend analysis using prospective Phelan H, Twigg S, Craig ME. Screening for celiac abetes: cross-sectional data from the German multicenter data from Germany and Austria. disease in type 1 diabetes: a systematic review. diabetes documentation and quality manage- – – Diabetes Care 2012;35:80–86 Pediatrics 2015;136:e170 e176 ment system (DPV). Diabetes Care 2006;29:218 68. Cameron FJ, de Beaufort C, Aanstoot HJ, 83. Craig ME, Prinz N, Boyle CT, et al.; Austral- 225 et al.; Hvidoere International Study Group. Les- asian Diabetes Data Network (ADDN); T1D 95. Singh TP, Groehn H, Kazmers A. Vascular Exchange Clinic Network (T1DX); National Pae- function and carotid intimal-medial thickness in sons from the Hvidoere International Study diatric Diabetes Audit (NPDA) and the Royal children with insulin-dependent diabetes melli- Group on childhood diabetes: be dogmatic about College of Paediatrics and Child Health; Pro- tus. J Am Coll Cardiol 2003;41:661–665 outcome and flexible in approach. Pediatr Di- spective Diabetes Follow-up Registry (DPV) ini- 96. Haller MJ, Stein J, Shuster J, et al. Peripheral abetes 2013;14:473–480 tiative. Prevalence of celiac disease in 52,721 artery tonometry demonstrates altered endo- 69. Nimri R, Weintrob N, Benzaquen H, Ofan R, youth with type 1 diabetes: international com- thelial function in children with type 1 diabetes. Fayman G, Phillip M. Insulin pump therapy in parison across three continents. Diabetes Care Pediatr Diabetes 2007;8:193–198 youth with type 1 diabetes: a retrospective 2017;40:1034–1040 97. Urbina EM, Wadwa RP, Davis C, et al. Prev- paired study. Pediatrics 2006;117:2126–2131 84. Simmons JH, Foster NC, Riddlesworth TD, alence of increased arterial stiffness in children 70. Doyle EA, Weinzimer SA, Steffen AT, Ahern et al.; T1D ExchangeClinic Network. Sex- andage- with type 1 diabetes mellitus differs by mea- JAH, Vincent M, Tamborlane WVA. A random- dependent effects of celiac disease on growth surement site and sex: the SEARCH for Diabetes ized, prospective trial comparing the efficacy of and weight gain in children with type 1 diabetes: in Youth Study. J Pediatr 2010;156:731–737.e1 continuous subcutaneous insulin infusion with analysis of the Type 1 Diabetes Exchange Clinic 98. Expert Panel on Integrated Guidelines for multiple daily injections using insulin glargine. Registry. Pediatr Diabetes 2018;19:741–748 Cardiovascular Health and Risk Reduction in – Diabetes Care 2004;27:1554 1558 85. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood Children and Adolescents; National Heart, 71. Swift PGF, Skinner TC, de Beaufort CE, et al.; AH, Murray JA; American College of Gastroen- Lung, and Blood Institute. Expert Panel on In- Hvidoere Study Group on Childhood Diabetes. terology. ACG clinical guidelines: diagnosis and tegrated Guidelines for Cardiovascular Health Target setting in intensive insulin management is management of celiac disease. Am J Gastro- and Risk Reduction in Children and Adolescents: associated with metabolic control: the Hvidoere enterol 2013;108:656–676 summary report. Pediatrics 2011;128(Suppl. 5): childhood diabetes study group centre differ- 86. Paul SP, Sandhu BK, Spray CH, Basude D, S213–S256 ences study 2005. Pediatr Diabetes 2010;11: Ramani P. Evidence supporting serology-based 99. Daniels SR, Greer FR; Committee on Nutri- – 271 278 pathway for diagnosing celiac disease in asymp- tion. Lipid screening and cardiovascular health in 72. Hughes JW, Riddlesworth TD, DiMeglio LA, tomatic children from high-risk groups. J Pediatr childhood. Pediatrics 2008;122:198–208 Miller KM, Rickels MR, McGill JB. Autoimmune Gastroenterol Nutr 2018;66:641–644 100. Kavey R-EW, Allada V, Daniels SR, et al.; diseases in children and adults with type 1 di- 87. AbidN,McGloneO,CardwellC,McCallionW, American Heart Association Expert Panel on abetes from the T1D Exchange Clinic Registry. J Carson D. Clinical and metabolic effects of gluten Population and Prevention Science; American Clin Endocrinol Metab 2016;101:4931–4937 free diet in children with type 1 diabetes and coeliac Heart Association Council on Cardiovascular 73. Kahaly GJ, Hansen MP. Type 1 diabetes disease. Pediatr Diabetes 2011;12:322–325 Disease in the Young; American Heart Associa- associated autoimmunity. Autoimmun Rev 2016; 88. Husby S, Koletzko S, Korponay-Szabo´ IR, tion Council on Epidemiology and Prevention; 15:644–648 et al.; ESPGHAN Working Group on Coeliac American Heart Association Council on Nutri- 74. Roldan´ MB, Alonso M, Barrio R. Thyroid Disease Diagnosis; ESPGHAN Gastroenterology tion, Physical Activity and Metabolism; Ameri- autoimmunity in children and adolescents Committee; European Society for Pediatric Gas- can Heart Association Council on High Blood with type 1 diabetes mellitus. Diabetes Nutr troenterology, Hepatology, and Nutrition. Euro- Pressure Research; American Heart Association Metab 1999;12:27–31 pean Society for Pediatric Gastroenterology, Council on Cardiovascular Nursing; American 75. Triolo TM, Armstrong TK, McFann K, et al. Hepatology, and Nutrition guidelines for the Heart Association Council on the Kidney in Heart Additional autoimmune disease found in 33% of diagnosis of coeliac disease. J Pediatr Gastro- Disease; Interdisciplinary Working Group on patients at type 1 diabetes onset. Diabetes Care enterol Nutr 2012;54:136–160 Quality of Care and Outcomes Research. Cardio- 2011;34:1211–1213 89. Kurppa K, Paavola A, Collin P, et al. Benefits vascular risk reduction in high-risk pediatric 76. Kordonouri O, Deiss D, Danne T, Dorow A, of a gluten-free diet for asymptomatic patients patients: a scientific statement from the Amer- Bassir C, Gruters-Kieslich¨ A. Predictivity of thyroid with serologic markers of celiac disease. Gastro- ican Heart Association Expert Panel on Popula- autoantibodies for the development of thyroid enterology 2014;147:610–617.e1 tion and Prevention Science; the Councils on disorders in children and adolescents with type 1 90. Marcovecchio ML, Chiesa ST, Bond S, et al.; Cardiovascular Disease in the Young, Epidemi- diabetes. Diabet Med 2002;19:518–521 AdDIT Study Group. ACE inhibitors and statins in ology and Prevention, Nutrition, Physical Activity care.diabetesjournals.org Children and Adolescents S163

and Metabolism, High Blood Pressure Research, 112. Audrain-McGovern J, Stone MD, preschool through early adolescence. Psycho- Cardiovascular Nursing, and the Kidney in Heart Barrington-Trimis J, Unger JB, Leventhal AM. som Med 2016;78:1008–1018 Disease; and the Interdisciplinary Working Group Adolescent e-cigarette, hookah, and conven- 127. Dabelea D, Mayer-Davis EJ, Saydah S, et al.; on Quality of Care and Outcomes Research: tional cigarette use and subsequent marijuana SEARCH for Diabetes in Youth Study. Prevalence endorsed by the American Academy of Pediat- use. Pediatrics 2018;142:e20173616 of type 1 and type 2 diabetes among children and rics. Circulation 2006;114:2710–2738 113. Daniels M, DuBose SN, Maahs DM, et al.; adolescents from 2001 to 2009. JAMA 2014;311: 101. Cadario F, Prodam F, Pasqualicchio S, et al. T1D Exchange Clinic Network. Factors associated 1778–1786 Lipid profile and nutritional intake in children and with microalbuminuria in 7,549 children and 128. Buse JB, Kaufman FR, Linder B, Hirst K, El adolescents with type 1 diabetes improve after a adolescents with type 1 diabetes in the T1D Ghormli L, Willi S; HEALTHY Study Group. Di- structured dietician training to a Mediterranean- Exchange clinic registry. Diabetes Care 2013;36: abetes screening with hemoglobin A1c versus style diet. J Endocrinol Invest 2012;35:160–168 2639–2645 fasting plasma glucose in a multiethnic middle- 102. Salem MA, AboElAsrar MA, Elbarbary NS, 114. Schwartz GJ, Work DF. Measurement and school cohort. Diabetes Care 2013;36:429–435 ElHilaly RA, Refaat YM. Is exercise a therapeutic estimation of GFR in children and adolescents. 129. Klingensmith GJ, Pyle L, Arslanian S, et al.; tool for improvement of cardiovascular risk Clin J Am Soc Nephrol 2009;4:1832–1843 TODAY Study Group. The presence of GAD and factors in adolescents with type 1 diabetes 115. Inker LA, Schmid CH, Tighiouart H, et al.; IA-2 antibodies in youth with a type 2 diabetes mellitus? A randomised controlled trial. Diabetol CKD-EPI Investigators. Estimating glomerular phenotype: results from the TODAY study. Di- Metab Syndr 2010;2:47 filtration rate from serum creatinine and cystatin abetes Care 2010;33:1970–1975 103. McCrindle BW, Urbina EM, Dennison BA, C. N Engl J Med 2012;367:20–29 130. Hannon TS, Arslanian SA. The changing face et al.; American Heart Association Atheroscle- 116. Cho YH, Craig ME, Hing S, et al. Microvas- ofdiabetesinyouth:lessonslearnedfromstudies rosis, Hypertension, and Obesity in Youth Com- cular complications assessment in adolescents of type 2 diabetes. Ann N Y Acad Sci 2015;1353: mittee; American Heart Association Council of with 2- to 5-yr duration of type 1 diabetes from 113–137 – Cardiovascular Disease in the Young; American 1990 to 2006. Pediatr Diabetes 2011;12:682 131. Kapadia C, Zeitler P; Drugs and Therapeu- Heart Association Council on Cardiovascular 689 tics Committee of the Pediatric Endocrine Soci- Nursing. Drug therapy of high-risk lipid abnor- 117. Jaiswal M, Divers J, Dabelea D, et al. Prev- ety. Hemoglobin A1c measurement for the fi malities in children and adolescents: a scienti c alence of and risk factors for diabetic peripheral diagnosis of type 2 diabetes in children. Int J statement from the American Heart Association neuropathy in youth with type 1 and type 2 Pediatr Endocrinol 2012;2012:31 Atherosclerosis, Hypertension, and Obesity in diabetes: SEARCH for Diabetes in Youth Study. 132. Kester LM, Hey H, Hannon TS. Using he- – Youth Committee, Council of Cardiovascular Diabetes Care 2017;40:1226 1232 moglobin A1c for prediabetes and diabetes Disease in the Young, with the Council on Car- 118. Pop-Busui R, Boulton AJM, Feldman EL, diagnosis in adolescents: can adult recommen- et al. Diabetic neuropathy: a position statement diovascular Nursing. Circulation 2007;115: dations be upheld for pediatric use? J Adolesc 1948–1967 by the American Diabetes Association. Diabetes Health 2012;50:321–323 104. Salo P, Viikari J, Ham¨ al¨ ainen¨ M, et al. Serum Care 2017;40:136–154 133. Wu E-L, Kazzi NG, Lee JM. Cost-effective- cholesterol ester fatty acids in 7- and 13-month- 119. Lawrence JM, Imperatore G, Pettitt DJ, et al. ness of screening strategies for identifying pe- old children in a prospective randomized trial of a Incidence of diabetes in United States youth by diatric diabetes mellitus and dysglycemia. JAMA low-saturated fat, low-cholesterol diet: the STRIP diabetes type, race/ethnicity, and age, 2008– Pediatr 2013;167:32–39 baby project: Special Turku coronary Risk factor 2009 (Abstract). Diabetes 2014;63(Suppl. 1): 134. Dabelea D, Rewers A, Stafford JM, et al.; Intervention Project for children. Acta Paediatr A407 SEARCH for Diabetes in Youth Study Group. 1999;88:505–512 120. Imperatore G, Boyle JP, Thompson TJ, et al.; Trends in the prevalence of ketoacidosis at di- 105. Maahs DM, Dabelea D, D’Agostino RB Jr, SEARCH for Diabetes in Youth Study Group. abetes diagnosis: the SEARCH for Diabetes in et al.; SEARCH for Diabetes in Youth Study. Projections of type 1 and type 2 diabetes burden Youth Study. Pediatrics 2014;133:e938–e945 Glucose control predicts 2-year change in lipid in the U.S. population aged ,20 years through 135. Hutchins J, Barajas RA, Hale D, Escaname E, profile in youth with type 1 diabetes. J Pediatr 2050: dynamic modeling of incidence, mortality, 2013;162:101–107.e1 and population growth. Diabetes Care 2012;35: Lynch J. Type 2 diabetes in a 5-year-old and single 106. McCrindle BW, Ose L, Marais AD. Efficacy 2515–2520 center experience of type 2 diabetes in youth – and safety of atorvastatin in children and adoles- 121. Pettitt DJ, Talton J, Dabelea D, et al.; under 10. Pediatr Diabetes 2017;18:674 677 cents with familial hypercholesterolemia or severe SEARCH for Diabetes in Youth Study Group. 136. Ferrara CT, Geyer SM, Liu Y-F, et al.; Type hyperlipidemia: a multicenter, randomized, pla- Prevalence of diabetes in U.S. youth in 2009: 1 Diabetes TrialNet Study Group. Excess BMI in fi cebo-controlled trial. J Pediatr 2003;143:74–80 theSEARCHforDiabetesinYouthStudy.Diabetes childhood: a modi able risk factor for type 1 107. Wiegman A, Hutten BA, de Groot E, et al. Care 2014;37:402–408 diabetes development? Diabetes Care 2017;40: – Efficacy and safety of statin therapy in children 122. Copeland KC, Zeitler P, Geffner M, et al.; 698 701 with familial hypercholesterolemia: a random- TODAY Study Group. Characteristics of adoles- 137. Redondo MJ, Geyer S, Steck AK, et al.; Type ized controlled trial. JAMA 2004;292:331–337 cents and youth with recent-onset type 2 di- 1 Diabetes TrialNet Study Group. TCF7L2 genetic 108. Karter AJ, Stevens MR, Gregg EW, et al. abetes: the TODAY cohort at baseline. J Clin variants contribute to phenotypic heterogeneity Educational disparities in rates of smoking Endocrinol Metab 2011;96:159–167 of type 1 diabetes. Diabetes Care 2018;41:311– among diabetic adults: the Translating Research 123. Arslanian SA. Metabolic differences be- 317 Into Action for Diabetes study. Am J Public Health tween Caucasian and African-American children 138. Pinhas-Hamiel O, Dolan LM, Zeitler PS. 2008;98:365–370 and the relationship to type 2 diabetes mellitus. J Diabetic ketoacidosis among obese African- 109. Reynolds K, Liese AD, Anderson AM, et al. Pediatr Endocrinol Metab 2002;15(Suppl. 1): American adolescents with NIDDM. Diabetes Prevalence of tobacco use and association be- 509–517 Care 1997;20:484–486 tween cardiometabolic risk factors and cigarette 124. Naughton MJ, Ruggiero AM, Lawrence JM, 139. TODAY Study Group. Safety and tolerability smoking in youth with type 1 or type 2 diabetes et al.; SEARCH for Diabetes in Youth Study Group. of the treatment of youth-onset type 2 diabetes: mellitus. J Pediatr 2011;158:594–601.e1 Health-related quality of life of children and the TODAY experience. Diabetes Care 2013;36: 110. Scott LJ, Warram JH, Hanna LS, Laffel LM, adolescents with type 1 or type 2 diabetes 1765–1771 Ryan L, Krolewski AS. A nonlinear effect of mellitus: SEARCH for Diabetes in Youth Study. 140. TODAY Study Group. Retinopathy in youth hyperglycemia and current cigarette smoking Arch Pediatr Adolesc Med 2008;162:649–657 with type 2 diabetes participating in the TODAY are major determinants of the onset of micro- 125. Wadden TA, Webb VL, Moran CH, Bailer BA. clinical trial. Diabetes Care 2013;36:1772–1774 albuminuria in type 1 diabetes. Diabetes 2001; Lifestyle modification for obesity: new develop- 141. TODAY Study Group. Lipid and inflamma- 50:2842–2849 ments in diet, physical activity, and behavior tory cardiovascular risk worsens over 3 years in 111. Chaffee BW, Watkins SL, Glantz SA. Elec- therapy. Circulation 2012;125:1157–1170 youth with type 2 diabetes: the TODAY clinical tronic cigarette use and progression from ex- 126. WhalenDJ,BeldenAC, TillmanR, BarchDM, trial. Diabetes Care 2013;36:1758–1764 perimentation to establishedsmoking. Pediatrics Luby JL. Early adversity, psychopathology, and 142. TODAY Study Group. Rapid rise in hyper- 2018;141:e20173594 latent class profiles of global physical health from tension and nephropathy in youth with type 2 S164 Children and Adolescents Diabetes Care Volume 42, Supplement 1, January 2019

diabetes: the TODAY clinical trial. Diabetes Care 158. Michalsky MP, Inge TH, Simmons M, et al.; baseline data from the TODAY study. Diabetes 2013;36:1735–1741 Teen-LABS Consortium. Cardiovascular risk fac- Care 2011;34:858–860 143. Grey M, Schreiner B, Pyle L. Development tors in severely obese adolescents: the Teen 174. Shelton RC. Depression, antidepressants, of a diabetes education program for youth with Longitudinal Assessment of Bariatric Surgery and weight gain in children. Obesity (Silver type 2 diabetes. Diabetes Educ 2009;35:108–116 (Teen-LABS) study. JAMA Pediatr 2015;169: Spring) 2016;24:2450 144. American Diabetes Association. Be Healthy 438–444 175. Baeza I, Vigo L, de la Serna E, et al. The Today; Be Healthy For Life [Internet]. Available 159. Zeinoddini A, Heidari R, Talebpour M. effects of antipsychotics on weight gain, weight- from http://main.diabetes.org/dorg/PDFs/Type- Laparoscopic gastric plication in morbidly obese related hormones and homocysteine in children 2-Diabetes-in-Youth/Type-2-Diabetes-in-Youth adolescents:aprospectivestudy.SurgObesRelat and adolescents: a 1-year follow-up study. Eur .pdf. Accessed 16 October 2018 Dis 2014;10:1135–1139 Child Adolesc Psychiatry 2017;26:35–46 145. Atkinson A, Radjenovic D. Meeting quality 160. Gothberg¨ G, Gronowitz E, Flodmark C-E, 176. Klingensmith GJ, Pyle L, Nadeau KJ, et al. standards for self-management education in et al. Laparoscopic Roux-en-Y gastric bypass in Pregnancy outcomes in youth with type 2 di- pediatric type 2 diabetes. Diabetes Spectr adolescents with morbid obesitydsurgical as- abetes: the TODAY study experience. Diabetes 2007;20:40–46 pects and clinical outcome. Semin Pediatr Surg Care 2016;39:122–129 146. Copeland KC, Silverstein J, Moore KR, et al. 2014;23:11–16 177. Arnett JJ. Emerging adulthood: a theory of Management of newly diagnosed type 2 diabe- 161. Inge TH, Prigeon RL, Elder DA, et al. Insulin development from the late teens through the tes mellitus (T2DM) in children and adolescents. sensitivity and b-cell function improve after twenties. Am Psychol 2000;55:469–480 Pediatrics 2013;131:364–382 gastric bypass in severely obese adolescents. J 178. Weissberg-BenchellJ,WolpertH,Anderson 147. Levitt Katz LE, Bacha F, Gidding SS, et al.; Pediatr 2015;167:1042–1048.e1 BJ. Transitioning from pediatric to adult care: TODAY Study Group. Lipid profiles, inflammatory 162. Styne DM, Arslanian SA, Connor EL, et al. a new approach to the post-adolescent young markers, and insulin therapy in youth with type 2 Pediatric obesitydassessment, treatment, and person with type 1 diabetes. Diabetes Care 2007; – Diabetes. J Pediatr 2018;196:208–216.e2 prevention: an Endocrine Society clinical practice 30:2441 2446 148. Zeitler P, Hirst K, Pyle L, et al.; TODAY Study guideline. J Clin Endocrinol Metab 2017;102: 179. Peters A, Laffel L; American Diabetes As- Group. A clinical trial to maintain glycemic con- 709–757 sociation Transitions Working Group. Diabetes trol in youth with type 2 diabetes. N Engl J Med 163. Eppens MC, Craig ME, Cusumano J, et al. care for emerging adults: recommendations for 2012;366:2247–2256 Prevalence of diabetes complications in adoles- transition from pediatric to adult diabetes care 149. Inge TH, Courcoulas AP, Jenkins TM, et al.; cents with type 2 compared with type 1 diabetes. systems: a position statement of the Ameri- can Diabetes Association, with representation Teen-LABS Consortium. Weight loss and health Diabetes Care 2006;29:1300–1306 by the American College of Osteopathic Fam- status 3 years after bariatric surgery in adoles- 164. Song SH, Hardisty CA. Early onset type 2 ily Physicians, the American Academy of Pedi- cents. N Engl J Med 2016;374:113–123 diabetes mellitus: a harbinger for complications atrics, the American Association of Clinical 150. Rubino F, Nathan DM, Eckel RH, et al.; in later yearsdclinical observation from a sec- Endocrinologists, the American Osteopathic As- Delegates of the 2nd Diabetes Surgery Summit. ondary care cohort. QJM 2009;102:799–806 sociation, the Centers for Disease Control and Metabolic surgery in the treatment algorithm 165. Zeitler P, Fu J, Tandon N, et al.; International Prevention, Children with Diabetes, The Endo- for type 2 diabetes: a joint statement by Society for Pediatric and Adolescent Diabetes. crine Society, the International Society for Pe- international diabetes organizations. Diabetes ISPAD Clinical Practice Consensus Guidelines diatric and Adolescent Diabetes, Juvenile Care 2016;39:861–877 2014. Type 2 diabetes in the child and adolescent. Diabetes Research Foundation International, 151. Pratt JSA, Lenders CM, Dionne EA, et al. Pediatr Diabetes 2014;15(Suppl. 20):26–46 the National Diabetes Education Program, and Best practice updates for pediatric/adolescent 166. Song SH. Complication characteristics be- the Pediatric Endocrine Society (formerly Lawson weight loss surgery. Obesity (Silver Spring) 2009; tween young-onset type 2 versus type 1 diabetes Wilkins Pediatric Endocrine Society). Diabetes – 17:901 910 in a UK population. BMJ Open Diabetes Res Care Care 2011;34:2477–2485 152. Dolan K, Creighton L, Hopkins G, Fielding 2015;3:e000044 180. Bryden KS, Peveler RC, Stein A, Neil A, “ ” fl G. Laparoscopic gastric banding in morbidly 167. Cefalu WT. TODAY re ects on the chang- Mayou RA, Dunger DB. Clinical and psychological – “ ” obese adolescents. Obes Surg 2003;13:101 ing faces of type 2 diabetes. Diabetes Care course of diabetes from adolescence to young – 104 2013;36:1732 1734 adulthood: a longitudinal cohort study. Diabetes 153. Sugerman HJ, Sugerman EL, DeMaria EJ, 168. Lawrence JM, Standiford DA, Loots B, et al.; Care 2001;24:1536–1540 et al. Bariatric surgery for severely obese ado- SEARCH for Diabetes in Youth Study. Prevalence 181. Laing SP, Jones ME, Swerdlow AJ, Burden – lescents. J Gastrointest Surg 2003;7:102 108 and correlates of depressed mood among youth AC, Gatling W. Psychosocial and socioeconomic 154. Inge TH, Garcia V, Daniels S, et al. A with diabetes: the SEARCH for Diabetes in Youth risk factors for premature death in young people multidisciplinary approach to the adolescent study. Pediatrics 2006;117:1348–1358 with type 1 diabetes. Diabetes Care 2005;28: bariatric surgical patient. J Pediatr Surg 2004; 169. Levitt Katz LE, Swami S, Abraham M, et al. 1618–1623 39:442–447; discussion 446–447 Neuropsychiatric disorders at the presentation 182. Mays JA, Jackson KL, Derby TA, et al. An 155. Lawson ML, Kirk S, Mitchell T, et al.; Pe- of type 2 diabetes mellitus in children. Pediatr evaluation of recurrent diabetic ketoacidosis, diatricBariatricStudyGroup.One-yearoutcomes Diabetes 2005;6:84–89 fragmentation of care, and mortality across of Roux-en-Y gastric bypass for morbidly obese 170. Lewis-Fernandez´ R, Rotheram-Borus MJ, Chicago, Illinois. Diabetes Care 2016;39:1671– adolescents: a multicenter study from the Pe- Betts VT, et al. Rethinking funding priorities in 1676 diatric Bariatric Study Group. J Pediatr Surg mental health research. Br J Psychiatry 2016;208: 183. GarveyKC, Foster NC, AgarwalS, etal.Health 2006;41:137–143 507–509 care transition preparation and experiences in a 156. Inge TH, Zeller M, Harmon C, et al. Teen- 171. Reinehr T. Type 2 diabetes mellitus in U.S. national sample of young adults with type 1 Longitudinal Assessment of Bariatric Surgery: children and adolescents. World J Diabetes diabetes. Diabetes Care 2017;40:317–324 methodological features of the first prospective 2013;4:270–281 184. The Endocrine Society. Managing the tran- multicenter study of adolescent bariatric sur- 172. Pinhas-Hamiel O, Hamiel U, Levy-Shraga Y. sition of care for patients with type 1 diabe- gery. J Pediatr Surg 2007;42:1969–1971 Eating disorders in adolescents with type 1 di- tes [Internet]. Available from https://www 157. Ells LJ, Mead E, Atkinson G, et al. Surgery for abetes: challenges in diagnosis and treatment. .endocrine.org/guidelines-and-clinical-practice/ the treatment of obesity in children and ado- World J Diabetes 2015;6:517–526 quality-improvement-resources/clinical-practice- lescents. Cochrane Database Syst Rev 2015;6: 173. TODAY Study Group. Binge eating, mood, resources/transition-of-care. Accessed 16 Octo- CD011740 and quality of life in youth with type 2 diabetes: ber 2018 Diabetes Care Volume 42, Supplement 1, January 2019 S165

14. Management of Diabetes in American Diabetes Association Pregnancy: Standards of Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S165–S172 | https://doi.org/10.2337/dc19-S014 4 AAEETO IBTSI PREGNANCY IN DIABETES OF MANAGEMENT 14. The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

DIABETES IN PREGNANCY The prevalence of diabetes in pregnancy has been increasing in the U.S. The majority is gestational diabetes mellitus (GDM) with the remainder primarily preexisting type 1 diabetes and type 2 diabetes. The rise in GDM and type 2 diabetes in parallel with obesity both in the U.S. and worldwide is of particular concern. Both type 1 diabetes and type 2 diabetes in pregnancy confer signiﬁcantly greater maternal and fetal risk than GDM, with some differences according to type of diabetes. In general, speciﬁc risks of uncontrolled diabetes in pregnancy include spontaneous abortion, fetal anomalies, preeclampsia, fetal demise, macrosomia, neonatal hypoglycemia, and neonatal hyperbilirubinemia, among others. In addition, diabetes in pregnancy may increase the risk of obesity and type 2 diabetes in offspring later in life (1,2).

PRECONCEPTION COUNSELING

Recommendations 14.1 Starting at puberty and continuing in all women with reproductive potential, preconception counseling should be incorporated into routine diabetes care. A 14.2 Family planning should be discussed and effective contraception should be prescribed and used until a woman is prepared and ready to become pregnant. A 14.3 Preconception counseling should address the importance of glycemic Suggested citation: American Diabetes Associa- management as close to normal as is safely possible, ideally A1C ,6.5% tion. 14. Management of diabetes in pregnancy: (48 mmol/mol), to reduce the risk of congenital anomalies, preeclampsia, Standards of Medical Care in Diabetesd2019. macrosomia, and other complications. B Diabetes Care 2019;42(Suppl. 1):S165–S172 © 2018 by the American Diabetes Association. All women of childbearing age with diabetes should be counseled about the Readers may use this article as long as the work is properly cited, the use is educational and not importance of tight glycemic control prior to conception. Observational studies show for proﬁt, and the work is not altered. More infor- an increased risk of diabetic embryopathy, especially anencephaly, microcephaly, mation is available at http://www.diabetesjournals congenital heart disease, and caudal regression, directly proportional to elevations in .org/content/license. S166 Management of Diabetes in Pregnancy Diabetes Care Volume 42, Supplement 1, January 2019

A1C during the first 10 weeks of preg- 14.5 Women with preexisting diabe- diabetes should also test blood nancy (3). Although observational stud- tes should ideally be managed glucose preprandially. B ies are confounded by the association in a multidisciplinary clinic in- 14.7 Due to increased red blood cell between elevated periconceptional A1C cluding an endocrinologist, turnover, A1C is slightly lower in and other poor self-care behaviors, the maternal-fetal medicine special- normal pregnancy than in nor- quantity and consistency of data are ist, dietitian, and diabetes educa- mal nonpregnant women. Ide- convincing and support the recommen- tor, when available. B ally, the A1C target in pregnancy dation to optimize glycemic control prior is ,6% (42 mmol/mol) if this can to conception, with A1C ,6.5% (48 Preconception visits should include be achieved without significant mmol/mol) associated with the lowest rubella, syphilis, hepatitis B virus, and hypoglycemia, but the target risk of congenital anomalies (3–6). HIV testing, as well as Pap test, cervical may be relaxed to ,7% (53 There are opportunities to educate all cultures, blood typing, prescription of mmol/mol) if necessary to pre- women and adolescents of reproductive prenatal vitamins (with at least 400 vent hypoglycemia. B age with diabetes about the risks of mg of folic acid), and smoking cessation unplanned pregnancies and improved counseling if indicated. Diabetes-specific Pregnancy in women with normal glu- maternal and fetal outcomes with preg- testing should include A1C, thyroid- cose metabolism is characterized by fast- nancy planning (7). Effective preconcep- stimulating hormone, creatinine, and uri- ing levels of blood glucose that are lower tion counseling could avert substantial nary albumin-to-creatinine ratio; review than in the nonpregnant state due to health and associated cost burdens in of the medication list for potentially insulin-independent glucose uptake by offspring (8). Family planning should be teratogenic drugs, i.e., ACE inhibitors the fetus and placenta and by postpran- discussed, and effective contraception (10), angiotensin receptor blockers (10), dial hyperglycemia and carbohydrate in- should be prescribed and used until a and statins (11,12); and referral for a tolerance as a result of diabetogenic woman is prepared and ready to become comprehensive eye exam. Women with placental hormones. In patients with pregnant. preexisting diabetic retinopathy will preexisting diabetes, glycemic targets To minimize the occurrence of com- need close monitoring during pregnancy are usually achieved through a combi- plications, beginning at the onset of to ensure that retinopathy does not nationof insulinadministration and med- puberty or at diagnosis, all girls and progress (13). Preconception counseling ical nutrition therapy. Because glycemic women with diabetes of childbearing po- should include an explanation of the risks targets in pregnancy are stricter than in tential should receive education about to mother and fetus related to pregnancy nonpregnant individuals, it is important 1) the risks of malformations associated and the ways to reduce risk and include that women with diabetes eat consistent with unplanned pregnancies and poor glycemic goal setting, lifestyle manage- amounts of carbohydrates to match with metabolic control and 2) the use of ef- ment, and medical nutrition therapy. insulin dosage and to avoid hyperglyce- fective contraception at all times when Several studies have shown improved mia or hypoglycemia. Referral to a reg- preventing a pregnancy. Preconcep- diabetes and pregnancy outcomes when istered dietitian is important in order to tion counseling using developmentally care has been delivered from precon- establish a food plan and insulin-to- appropriate educational tools enables ception through pregnancy by a multi- carbohydrate ratio and to determine adolescent girls to make well-informed disciplinary group focused on improved weight gain goals. decisions (7). Preconception counseling glycemic control (14–16). One study resources tailored for adolescents are showed that care of preexisting diabe- available at no cost through the Amer- tes in clinics that included diabetes Insulin Physiology ican Diabetes Association (ADA) (9). Early pregnancy is a time of enhanced and obstetric specialists improved care insulin sensitivity, lower glucose levels, (17). However, there is no consensus on and lower insulin requirements in Preconception Care the structure of multidisciplinary team women with type 1 diabetes. The situ- Recommendations care for diabetes and pregnancy, and ation rapidly reverses as insulin resis- 14.4 Women with preexisting type 1 there is a lack of evidence on the impact tance increases exponentially during the or type 2 diabetes who are plan- on outcomes of various methods of second and early third trimesters and ning pregnancy or who have health care delivery (18). levels off toward the end of the third become pregnant should be trimester. In women with normal pan- counseled on the risk of devel- creatic function, insulin production is opment and/or progression of GLYCEMIC TARGETS IN PREGNANCY sufficient to meet the challenge of this diabetic retinopathy. Dilated eye physiological insulin resistance and to examinations should occur ide- Recommendations maintain normal glucose levels. How- ally before pregnancy or in the 14.6 Fasting and postprandial self- ever, in women with GDM or preexisting first trimester, and then patients monitoring of blood glucose are diabetes, hyperglycemia occurs if treat- should be monitored every tri- recommended in both gesta- ment is not adjusted appropriately. mester and for 1-year postpar- tional diabetes mellitus and pre- tum as indicated by the degree of existing diabetes in pregnancy retinopathy and as recommended to achieve glycemic control. Glucose Monitoring Reflecting this physiology, fasting and by the eye care provider. B Some women with preexisting postprandial monitoring of blood glucose care.diabetesjournals.org Management of Diabetes in Pregnancy S167

is recommended to achieve metabolic maternal hypoglycemia in setting an GDM is characterized by increased risk of control in pregnant women with diabe- individualized target of ,6% (42 macrosomia and birth complications tes. Preprandial testing is also recom- mmol/mol) to ,7% (53 mmol/mol). Due and an increased risk of maternal type 2 mended for women with preexisting to physiological increases in red blood diabetes after pregnancy. The associa- diabetes using insulin pumps or basal- cell turnover, A1C levels fall during tion of macrosomia and birth complica- bolus therapy, so that premeal rapid- normal pregnancy (26,27). Additionally, tions with oral glucose tolerance test acting insulin dosage can be adjusted. as A1C represents an integrated mea- (OGTT) results is continuous with no clear Postprandial monitoring is associated sure of glucose, it may not fully cap- inflection points (24). In other words, with better glycemic control and lower ture postprandial hyperglycemia, which risks increase with progressive hypergly- risk of preeclampsia (19–21). There are drives macrosomia. Thus, although A1C cemia. Therefore, all women should no adequately powered randomized tri- may be useful, it should be used as a sec- be tested as outlined in Section 2 als comparing different fasting and post- ondary measure of glycemic control in “Classification and Diagnosis of Diabe- meal glycemic targets in diabetes in pregnancy, after self-monitoring of blood tes.” Although there is some heteroge- pregnancy. glucose. neity, many randomized controlled trials Similar to the targets recommended In the second and third trimesters, (RCTs) suggest that the risk of GDM may by the American College of Obstetri- A1C ,6% (42 mmol/mol) has the lowest be reduced by diet, exercise, and life- cians and Gynecologists (the same as risk of large-for-gestational-age infants style counseling, particularly when inter- for GDM; described below) (22), the (25,28,29), preterm delivery (30), and ventions are started during the first or ADA-recommended targets for women preeclampsia (1,31). Taking all of this early in the second trimester (33–35). with type 1 or type 2 diabetes are as into account, a target of ,6% (42 follows: mmol/mol) is optimal during pregnancy Lifestyle Management fi if it can be achieved without signi - After diagnosis, treatment starts with ○ , Fasting 95 mg/dL (5.3 mmol/L) and cant hypoglycemia. The A1C target in medical nutrition therapy, physical ac- either a given patient should be achieved tivity, and weight management depend- ○ , One-hour postprandial 140 mg/dL without hypoglycemia, which, in addi- ing on pregestational weight, as outlined (7.8 mmol/L) or tion to the usual adverse sequelae, may in the section below on preexisting type 2 ○ , Two-hour postprandial 120 mg/dL increase the risk of low birth weight (32). diabetes, and glucose monitoring aiming (6.7 mmol/L) Given the alteration in red blood cell for the targets recommended by the Fifth kinetics during pregnancy and physiolog- International Workshop-Conference on These values represent optimal control if ical changes in glycemic parameters, A1C Gestational Diabetes Mellitus (36): they can be achieved safely. In practice, levels may need to be monitored more it may be challenging for women frequently than usual (e.g., monthly). ○ Fasting ,95 mg/dL (5.3 mmol/L) and with type 1 diabetes to achieve these either targets without hypoglycemia, particu- ○ One-hour postprandial ,140 mg/dL larly women with a history of recur- MANAGEMENT OF GESTATIONAL (7.8 mmol/L) or rent hypoglycemia or hypoglycemia DIABETES MELLITUS ○ Two-hour postprandial ,120 mg/dL unawareness. (6.7 mmol/L) If women cannot achieve these tar- Recommendations 14.8 Lifestyle change is an essential gets without significant hypoglycemia, component of management of Depending on the population, studies the ADA suggests less stringent targets gestational diabetes mellitus suggest that 70–85% of women di- based on clinical experience and indi- and may suffice for the treat- agnosed with GDM under Carpenter- vidualization of care. ment of many women. Medica- Coustan or National Diabetes Data Group tions should be added if needed (NDDG) criteria can control GDM with A1C in Pregnancy to achieve glycemic targets. A lifestyle modification alone; it is antici- In studies of women without preexist- 14.9 Insulin is the preferred medica- pated that this proportion will be even ing diabetes, increasing A1C levels within tion for treating hyperglycemia higher if the lower International Associ- the normal range is associated with ad- in gestational diabetes mellitus ation of Diabetes and Pregnancy Study verse outcomes (23). In the Hyperglyce- as it does not cross the placenta Groups (IADPSG) (37) diagnostic thresh- mia and Adverse Pregnancy Outcome to a measurable extent. Metfor- olds are used. (HAPO) study, increasing levels of glyce- min and glyburide should not be mia were associated with worsening used as first-line agents, as both Medical Nutrition Therapy outcomes (24). Observational studies Medical nutrition therapy for GDM is an cross the placenta to the fetus. in preexisting diabetes and pregnancy individualized nutrition plan developed All oral agents lack long-term show the lowest rates of adverse fetal between the woman and a registered safety data. A outcomes in association with A1C ,6– dietitian familiar with the management 14.10 Metformin, when used to treat 6.5% (42–48 mmol/mol) early in gesta- of GDM (38,39). The food plan should polycystic ovary syndrome and tion (4–6,25). Clinical trials have not provide adequate calorie intake to induce ovulation, should be dis- evaluated the risks and benefits of promote fetal/neonatal and maternal continued once pregnancy has achieving these targets, and treatment health, achieve glycemic goals, and pro- been confirmed. A goals should account for the risk of mote appropriate gestational weight S168 Management of Diabetes in Pregnancy Diabetes Care Volume 42, Supplement 1, January 2019

gain. There is no definitive research that systematic reviews (46,49,50); however, and frequent self-monitoring of blood identifies a specific optimal calorie in- metformin may slightly increase the risk glucose. Early in the first trimester, take for women with GDM or suggests of prematurity. Like glyburide, metfor- there is an increase in insulin require- that their calorie needs are different min crosses the placenta, and umbili- ments, followed by a decrease in weeks from those of pregnant women without cal cord blood levels of metformin are 9 through 16 (60). Women, particularly GDM. The food plan should be based higher than simultaneous maternal levels those with type 1 diabetes, may experi- on a nutrition assessment with guidance (51,52). In the Metformin in Gestational ence increased hypoglycemia. After from the Dietary Reference Intakes Diabetes: The Offspring Follow-Up (MiG 16 weeks, rapidly increasing insulin re- (DRI). The DRI for all pregnant women TOFU) study’sanalysesof7-to9-year-old sistance requires weekly increases in recommends a minimum of 175 g of offspring, 9-year-old offspring exposed insulin dose of about 5% per week to carbohydrate, a minimum of 71 g of to metformin for the treatment of GDM achieve glycemic targets. There is protein, and 28 g of fiber. As is true were larger (based on a number of roughly a doubling of insulin require- for all nutrition therapy in patients with measurements) than those exposed to ments by the late third trimester. In diabetes, the amount and type of car- insulin(53).In two RCTs of metformin use general, a smaller proportion of the total bohydrate will impact glucose levels, in pregnancy for polycystic ovary syn- daily dose should be given as basal in- especially postmeal excursions. drome, follow-up of 4-year-old offspring sulin (,50%) and a greater proportion demonstrated higher BMI and increased (.50%) as prandial insulin. Late in the Pharmacologic Therapy obesity in the offspring exposed to met- third trimester, there is often a leveling Treatment of GDM with lifestyle and formin (53,54). Further study of long- off or small decrease in insulin require- insulin has been demonstrated to im- term outcomes in the offspring is needed ments. Due to the complexity of insu- prove perinatal outcomes in two large (53,54). lin management in pregnancy, referral randomized studies as summarized in a Randomized, double-blind, controlled to a specialized center offering team- U.S. Preventive Services Task Force re- trials comparing metformin with other based care (with team members includ- view (40). Insulin is the first-line agent therapies for ovulation induction in ing maternal-fetal medicine specialist, recommended for treatment of GDM in women with polycystic ovary syndrome endocrinologist, or other provider ex- the U.S. While individual RCTs support have not demonstrated benefit in pre- perienced in managing pregnancy in limited efficacy of metformin (41,42) venting spontaneous abortion or GDM women with preexisting diabetes, di- and glyburide (43) in reducing glucose (55), and there is no evidence-based etitian, nurse, and social worker, as levels for the treatment of GDM, these need to continue metformin in such needed) is recommended if this re- agents are not recommended as first- patients once pregnancy has been con- source is available. line treatment for GDM because they firmed (56–58). None of the currently available hu- are known to cross the placenta and Insulin man insulin preparations have been data on safety for offspring is lacking Insulin use should follow the guidelines demonstrated to cross the placenta – (22).Furthermore,intwoRCTs,glyburide below. Both multiple daily insulin injec- (61 66). and metformin failed to provide ade- tions and continuous subcutaneous insu- A recent Cochrane systematic review fi quate glycemic control in 23% and 25– lin infusion are reasonable delivery was not able to recommend any speci c 28%, respectively (44,45), of women with strategies, and neither has been shown insulin regimen over another for the GDM. to be superior during pregnancy (59). treatment of diabetes in pregnancy (67). Sulfonylureas Sulfonylureas are known to cross the MANAGEMENT OF PREEXISTING Preeclampsia and Aspirin placenta and have been associated TYPE 1 DIABETES AND TYPE Recommendation with increased neonatal hypoglycemia. 2 DIABETES IN PREGNANCY 14.12 Women with type 1 or type 2 Concentrations of glyburide in umbilical Insulin Use diabetes should be prescribed cord plasma are approximately 70% of Recommendation low-dose aspirin 60–150 mg/day maternal levels (44,45). Glyburide was 14.11 Insulin is the preferred agent (usual dose 81 mg/day) from associated with a higher rate of neona- for management of both type 1 the end of the first trimester tal hypoglycemia and macrosomia than diabetes and type 2 diabetes in until the baby is born in order insulin or metformin in a 2015 meta- pregnancy because it does not to lower the risk of preeclamp- analysis and systematic review (46). cross the placenta and be- sia. A More recently, glyburide failed to be cause oral agents are generally found noninferior to insulin based on insufficient to overcome the Diabetes in pregnancy is associated a composite outcome of neonatal hypo- insulin resistance in type 2 di- with an increased risk of preeclampsia glycemia, macrosomia, and hyperbiliru- abetes and are ineffective in (68). Based upon the results of clinical binemia. Long-term safety data for type 1 diabetes. E trials, the U.S. Preventive Services Task offspring are not available (47,48). Force recommends the use of low-dose Metformin The physiology of pregnancy necessi- aspirin (81 mg/day) as a preventive med- Metformin was associated with a lower tates frequent titration of insulin to ication after 12 weeks of gestation in risk of neonatal hypoglycemia and less match changing requirements and women who are at high risk for pre- maternal weight gain than insulin in underscores the importance of daily eclampsia (69). A cost-benefit analysis care.diabetesjournals.org Management of Diabetes in Pregnancy S169

has concluded that this approach would may be as high or higher with type 2 is not recommended as it has been reduce morbidity, save lives, and lower diabetes as with type 1 diabetes, even if associated with restricted maternal health care costs (70). diabetes is better controlled and of plasma volume, which may reduce utero- shorter apparent duration, with preg- placental perfusion (77). On the basis Type 1 Diabetes nancy loss appearing to be more prev- of available evidence, statins should also Women with type 1 diabetes have an alent in the third trimester in women be avoided in pregnancy (78). increased risk of hypoglycemia in the first with type 2 diabetes compared with the Please see PREGNANCY AND ANTIHYPERTENSIVE trimester and, like all women, have al- first trimester in women with type 1 MEDICATIONS in Section 10 “Cardiovascular tered counterregulatory response in diabetes (73,74). Disease and Risk Management” for more pregnancy that may decrease hypogly- information on managing blood pressure in pregnancy. cemia awareness. Education for patients PREGNANCY AND DRUG and family members about the preven- CONSIDERATIONS tion, recognition, and treatment of hy- POSTPARTUM CARE poglycemia is important before, during, Recommendations 14.13 and after pregnancy to help to prevent In pregnant patients with di- Postpartum care should include psy- and manage the risks of hypoglycemia. abetes and chronic hyperten- chosocial assessment and support for Insulin resistance drops rapidly with de- sion, blood pressure targets self-care. – – livery of the placenta. Women become of 120 160/80 105 mmHg are Lactation very insulin sensitive immediately follow- suggested in the interest of In light of the immediate nutritional and ing delivery and may initially require optimizing long-term mater- immunological benefits of breastfeeding much less insulin than in the prepartum nal health and minimizing im- E for the baby, all women including those period. paired fetal growth. 14.14 with diabetes should be supported in Pregnancy is a ketogenic state, and Potentially teratogenic medica- attempts to breastfeed. Breastfeeding women with type 1 diabetes, and to a tions (i.e., ACE inhibitors, an- may also confer longer-term metabolic lesser extent those with type 2 diabetes, giotensin receptor blockers, benefits to both mother (79) and off- are at risk for diabetic ketoacidosis at statins) should be avoided in spring (80). lower blood glucose levels than in the sexually active women of child- nonpregnant state. Women with pre- bearing age who are not using B Gestational Diabetes Mellitus existing diabetes, especially type 1 di- reliable contraception. Initial Testing abetes, need ketone strips at home and Because GDM may represent preexisting education on diabetic ketoacidosis pre- undiagnosed type 2 or even type 1 di- vention and detection. In addition, rapid In normal pregnancy, blood pressure abetes, women with GDM should be implementation of tight glycemic control is lower than in the nonpregnant state. tested for persistent diabetes or predi- in the setting of retinopathy is associated In a pregnancy complicated by diabe- abetes at 4–12 weeks postpartum with a with worsening of retinopathy (13). tes and chronic hypertension, target 75-g OGTT using nonpregnancy criteria The role of continuous glucose mon- goals for systolic blood pressure 120– as outlined in Section 2 “Classification itoring in pregnancies impacted by di- 160 mmHg and diastolic blood pressure and Diagnosis of Diabetes.” abetes is still being studied. In one RCT, 80–105 mmHg are reasonable (75). continuous glucose monitoring use in Lower blood pressure levels may be Postpartum Follow-up pregnancies complicated by type 1 di- associated with impaired fetal growth. The OGTT is recommended over A1C at abetes showed improved neonatal out- In a 2015 study targeting diastolic blood the time of the 4- to 12-week postpartum comes and a slight reduction in A1C, but pressure of 100 mmHg versus 85 mmHg visit because A1C may be persistently interestingly no difference in severe hy- in pregnant women, only 6% of whom impacted (lowered) by the increased red poglycemic events compared with con- had GDM at enrollment, there was no blood cell turnover related to pregnancy trol subjects (71). difference in pregnancy loss, neonatal or blood loss at delivery and because care, or other neonatal outcomes, al- the OGTT is more sensitive at detecting Type 2 Diabetes though women in the less intensive glucose intolerance, including both pre- Type 2 diabetes is often associated with treatment group had a higher rate of diabetes and diabetes. Reproductive- obesity. Recommended weight gain dur- uncontrolled hypertension (76). aged women with prediabetes may ing pregnancy for overweight women is During pregnancy, treatment with develop type 2 diabetes by the time 15–25 lb and for obese women is 10–20 lb ACE inhibitors and angiotensin receptor of their next pregnancy and will need (72). Glycemic control is often easier to blockers is contraindicated because they preconception evaluation. Because GDM achieve in women with type 2 diabetes may cause fetal renal dysplasia, oligo- is associated with an increased life- than in those with type 1diabetes but can hydramnios, and intrauterine growth time maternal risk for diabetes estimated require much higher doses of insulin, restriction (10). Antihypertensive drugs at 50–70% after 15–25 years (81,82), sometimes necessitating concentrated known to be effective and safe in preg- women should also be tested every 1– insulin formulations. As in type 1 diabe- nancy include methyldopa, nifedipine, 3 years thereafter if the 4- to 12-week tes, insulin requirements drop dramati- labetalol, diltiazem, clonidine, and postpartum 75-g OGTT is normal, with cally after delivery. The risk for associated prazosin. Atenolol is not recommended. frequency of testing depending on other hypertension and other comorbidities Chronic diuretic use during pregnancy risk factors including family history, S170 Management of Diabetes in Pregnancy Diabetes Care Volume 42, Supplement 1, January 2019

prepregnancy BMI, and need for insulin or pregnancy is critical in women with pre- inhibitors: effects on fetal and neonatal out- oral glucose-lowering medication dur- existing diabetes due to the need for comes. Reprod Toxicol 2008;26:175–177 ing pregnancy. Ongoing evaluation may preconception glycemic control to pre- 12. Bateman BT, Hernandez-Diaz S, Fischer MA, et al. Statins and congenital malformations: co- be performed with any recommended vent congenital malformations and re- hort study. BMJ 2015;350:h1035 glycemic test (e.g., A1C, fasting plasma duce the risk of other complications. 13. Chew EY, Mills JL, Metzger BE, et al.; National glucose, or 75-g OGTT using nonpregnant Therefore, all women with diabetes of Institute of Child Health and Human Develop- thresholds). childbearing potential should have fam- ment Diabetes in Early Pregnancy Study. Met- ily planning options reviewed at regular abolic control and progression of retinopathy: Gestational Diabetes Mellitus and Type 2 the Diabetes in Early Pregnancy Study. Diabetes Diabetes intervals. This applies to women in the Care 1995;18:631–637 Women with a history of GDM have a immediate postpartum period. Women 14. McElvy SS, Miodovnik M, Rosenn B, et al. A greatly increased risk of conversion to with diabetes have the same contracep- focused preconceptional and early pregnancy program in women with type 1 diabetes reduces type 2 diabetes over time (81). In the tion options and recommendations as those without diabetes. The risk of an perinatal mortality and malformation rates to prospective Nurses’ Health Study II (NHS general population levels. J Matern Fetal Med II), subsequent diabetes risk after a his- unplanned pregnancy outweighs the risk 2000;9:14–20 tory of GDM was significantly lower in of any given contraception option. 15. Murphy HR, Roland JM, Skinner TC, et al. women who followed healthy eating Effectiveness of a regional prepregnancy care References program in women with type 1 and type 2 patterns (83). Adjusting for BMI mod- fi 1. Holmes VA, Young IS, Patterson CC, et al.; diabetes: bene ts beyond glycemic control. Di- erately, but not completely, attenu- Diabetes and Pre-eclampsia Intervention Trial abetes Care 2010;33:2514–2520 ated this association. Interpregnancy or Study Group. Optimal glycemic control, pre- 16. Elixhauser A, WeschlerJM, Kitzmiller JL, et al. postpartum weight gain is associated eclampsia, and gestational hypertension in Cost-benefit analysis of preconception care for with increased risk of adverse pregnancy women with type 1 diabetes in the Diabetes women with established diabetes mellitus. Di- abetes Care 1993;16:1146–1157 outcomes in subsequent pregnancies and Pre-eclampsia Intervention Trial. Diabetes Care 2011;34:1683–1688 17. Owens LA, Avalos G, Kirwan B, Carmody L, (84) and earlier progression to type 2 2. Dabelea D, Hanson RL, Lindsay RS, et al. Dunne F. ATLANTIC DIP: closing the loop: diabetes. Intrauterine exposure to diabetes conveys risks a change in clinical practice can improve out- Both metformin and intensive lifestyle for type 2 diabetes and obesity: a study of comes for women with pregestational diabetes. – intervention prevent or delay progres- discordant sibships. Diabetes 2000;49:2208– Diabetes Care 2012;35:1669 1671 18. Taylor C, McCance DR, Chappell L, Nelson- sion to diabetes in women with predia- 2211 3. Guerin A, Nisenbaum R, Ray JG. Use of Piercy C, Thorne SA, Ismail KMK, et al. Imple- betes and a history of GDM. Of women maternal GHb concentration to estimate the mentation of guidelines for multidisciplinary with a history of GDM and prediabetes, risk of congenital anomalies in the offspring team management of pregnancy in women only 5–6 women need to be treated with of women with prepregnancy diabetes. Diabe- with pre-existing diabetes or cardiac conditions: either intervention to prevent one case tes Care 2007;30:1920–1925 results from a UK national survey. BMC Preg- nancy Childbirth 2017;17:434 of diabetes over 3 years (85). In these 4. Jensen DM, Korsholm L, Ovesen P, et al. Peri- conceptional A1C and risk of serious adverse 19. Manderson JG, Patterson CC, Hadden DR, women, lifestyle intervention and met- pregnancy outcome in 933 women with type 1 Traub AI, Ennis C, McCance DR. Preprandial formin reduced progression to diabe- diabetes. Diabetes Care 2009;32:1046–1048 versus postprandial blood glucose monitoring tes by 35% and 40%, respectively, over 5. Nielsen GL, Møller M, Sørensen HT. HbA1c in in type 1 diabetic pregnancy: a randomized 10 years compared with placebo (86). If early diabetic pregnancy and pregnancy out- controlled clinical trial. Am J Obstet Gynecol 2003;189:507–512 the pregnancy has motivated the adop- comes: a Danish population-based cohort study of 573 pregnancies in women with type 1 di- 20. de Veciana M, Major CA, Morgan MA, et al. tion of a healthier diet, building on these abetes. Diabetes Care 2006;29:2612–2616 Postprandial versus preprandial blood glucose gains to support weight loss is recom- 6. Suhonen L, Hiilesmaa V, Teramo K. Glycaemic monitoring in women with gestational diabetes mended in the postpartum period. control during early pregnancy and fetal mal- mellitus requiring insulin therapy. N Engl J Med formations in women with type I diabetes mel- 1995;333:1237–1241 litus. Diabetologia 2000;43:79–82 21. Jovanovic-Peterson L, Peterson CM, Reed GF, et al. Maternal postprandial glucose levels Preexisting Type 1 and Type 2 Diabetes 7. Charron-Prochownik D, Sereika SM, Becker D, and infant birth weight: the Diabetes in Early Insulin sensitivity increases dramatically et al. Long-term effects of the booster-enhanced READY-Girls preconception counseling program Pregnancy Study. The National Institute of Child with delivery of the placenta. Thus, in- on intentions and behaviors for family planning Health and Human Development–Diabetes in sulin requirements in the immediate in teens with diabetes. Diabetes Care 2013;36: Early Pregnancy Study. Am J Obstet Gynecol postpartum period are roughly 34% 3870–3874 1991;164:103–111 lower than prepregnancy insulin require- 8. Peterson C, Grosse SD, Li R, et al. Preventable 22. Committee on Practice BulletinsdObstetrics. ACOG Practice Bulletin No. 190: Gestational ments (87). Insulin sensitivity then re- health and cost burden of adverse birth outcomes associated with pregestational diabetes Diabetes Mellitus. Obstet Gynecol 2018;131: turns to prepregnancy levels over the in the United States. Am J Obstet Gynecol 2015; e49–e64 following 1–2 weeks. In women taking 212:74.e1–74.e9 23. Ho Y-R, Wang P, Lu M-C, Tseng S-T, Yang C-P, insulin, particular attention should be 9. Charron-Prochownik D, Downs J. Diabetes Yan Y-H. Associations of mid-pregnancy HbA1c directed to hypoglycemia prevention and Reproductive Health for Girls. Alexandria, with gestational diabetes and risk of adverse VA, American Diabetes Association, 2016 pregnancy outcomes in high-risk Taiwanese in the setting of breastfeeding and er- 10. Bullo M, Tschumi S, Bucher BS, Bianchetti women. PLoS One 2017;12:e0177563 ratic sleep and eating schedules (88). MG, Simonetti GD. Pregnancy outcome following 24. Metzger BE, Lowe LP, Dyer AR, et al.; HAPO exposure to angiotensin-converting enzyme in- Study Cooperative Research Group. Hyperglyce- mia and adverse pregnancy outcomes. N Engl J Contraception hibitors or angiotensin receptor antagonists: a systematic review. Hypertension 2012;60: Med 2008;358:1991–2002 A major barrier to effective preconcep- 444–450 25. Maresh MJA, Holmes VA, Patterson CC, et al.; tion care is the fact that the majority of 11. Taguchi N, Rubin ET, Hosokawa A, et al. Diabetes and Pre-eclampsia Intervention Trial pregnancies are unplanned. Planning Prenatal exposure to HMG-CoA reductase Study Group. Glycemic targets in the second and care.diabetesjournals.org Management of Diabetes in Pregnancy S171

third trimester of pregnancy for women with Preventive Services Task Force and the National 56. Legro RS, Barnhart HX, Schlaff WD, et al.; type 1 diabetes. Diabetes Care 2015;38:34–42 Institutes of Health Office of Medical Applica- Cooperative Multicenter Reproductive Medicine 26. Nielsen LR, Ekbom P, Damm P, et al. HbA1c tions of Research. Ann Intern Med 2013;159: Network. Clomiphene, metformin, or both for levels are significantly lower in early and late 123–129 infertility in the polycystic ovary syndrome. N pregnancy. Diabetes Care 2004;27:1200–1201 41. Rowan JA, Hague WM, Gao W, Battin MR, Engl J Med 2007;356:551–566 27. Mosca A, Paleari R, Dalfra` MG, et al. Ref- Moore MP; MiG Trial Investigators. Metformin 57. Palomba S, Orio F Jr, Falbo A, et al. Prospec- erence intervals for hemoglobin A1c in pregnant versus insulin for the treatment of gestational tive parallel randomized, double-blind, double- women: data from an Italian multicenter study. diabetes. N Engl J Med 2008;358:2003–2015 dummy controlled clinical trial comparing Clin Chem 2006;52:1138–1143 42. Gui J, Liu Q, Feng L. Metformin vs insulin in clomiphene citrate and metformin as the first- 28. Hummel M, Marienfeld S, Huppmann M, the management of gestational diabetes: a line treatment for ovulation induction in non- et al. Fetal growth is increased by maternal type 1 meta-analysis. PLoS One 2013;8:e64585 obese anovulatory women with polycystic diabetes and HLA DR4-related gene interactions. 43. Langer O, Conway DL, Berkus MD, Xenakis ovary syndrome. J Clin Endocrinol Metab 2005; Diabetologia 2007;50:850–858 EM-J, Gonzales O. A comparison of glyburide 90:4068–4074 29. Cyganek K, Skupien J, Katra B, et al. Risk of and insulin in women with gestational diabetes 58. Palomba S, Orio F Jr, Nardo LG, et al. Met- macrosomia remains glucose-dependent in a mellitus. N Engl J Med 2000;343:1134–1138 formin administration versus laparoscopic ovar- cohort of women with pregestational type 1 44. Hebert MF, Ma X, Naraharisetti SB, et al.; ian diathermy in clomiphene citrate-resistant diabetes and good glycemic control. Endocrine Obstetric-Fetal Pharmacology Research Unit Net- women with polycystic ovary syndrome: a prospec- – 2017;55:447 455 work. Are we optimizing gestational diabetes tive parallel randomized double-blind placebo- 30. Abell SK, Boyle JA, de Courten B, et al. Impact treatment with glyburide? The pharmacologic controlled trial. J Clin Endocrinol Metab 2004; of type 2 diabetes, obesity and glycaemic control basis for better clinical practice. Clin Pharmacol 89:4801–4809 – on pregnancy outcomes. Aust N Z J Obstet Ther 2009;85:607 614 59. Farrar D, Tuffnell DJ, West J, West HM. – fi Gynaecol 2017;57:308 314 45. Malek R, Davis SN. Pharmacokinetics, ef - Continuous subcutaneous insulin infusion versus 31. Temple RC, Aldridge V, Stanley K, Murphy cacy and safety of glyburide for treatment of multiple daily injections of insulin for pregnant HR. Glycaemic control throughout pregnancy gestational diabetes mellitus. Expert Opin Drug women with diabetes. Cochrane Database Syst – and risk of pre-eclampsia in women with Metab Toxicol 2016;12:691 699 Rev 2016;6:CD005542 – ı type I diabetes. BJOG 2006;113:1329 1332 46. Balsells M, Garcá-Patterson A, Sola` I, Roque´ 60. Garc´ıa-Patterson A, Gich I, Amini SB, 32. Combs CA, Gunderson E, Kitzmiller JL, Gavin M, Gich I, Corcoy R. Glibenclamide, metformin, Catalano PM, de Leiva A, Corcoy R. Insulin re- LA, Main EK. Relationship of fetal macrosomia and insulin for the treatment of gestational quirements throughout pregnancy in women to maternal postprandial glucose control dur- diabetes: a systematic review and meta-analysis. with type 1 diabetes mellitus: three changes ing pregnancy. Diabetes Care 1992;15:1251– BMJ 2015;350:h102 of direction. Diabetologia 2010;53:446–451 1257 47. Coustan DR. Pharmacological management 61. Menon RK, Cohen RM, Sperling MA, Cutfield 33. Bain E, Crane M, Tieu J, Han S, Crowther CA, of gestational diabetes: an overview. Diabetes WS, Mimouni F, Khoury JC. Transplacental pas- Middleton P. Diet and exercise interventions for Care 2007;30(Suppl. 2):S206–S208 sage of insulin in pregnant women with insulin- preventing gestational diabetes mellitus. Co- 48. Senat´ M-V, Affres H, Letourneau A, et al.; dependent diabetes mellitus. Its role in fetal chrane Database Syst Rev 2015;4:CD010443 Groupe de Recherche en Obstetrique´ et macrosomia. N Engl J Med 1990;323:309–315 34. Koivusalo SB, Ron¨ o¨ K, Klemetti MM, et al. Gynecologie´ (GROG). Effect of glyburide vs sub- 62. Pollex EK, Feig DS, Lubetsky A, Yip PM, Koren Gestational diabetes mellitus can be prevented cutaneous insulin on perinatal complications G. Insulin glargine safety in pregnancy: a trans- by lifestyle intervention: the Finnish Gestational among women with gestational diabetes: a ran- placental transfer study. Diabetes Care 2010;33: Diabetes Prevention Study (RADIEL): a random- domized clinical trial. JAMA 2018;319:1773– 29–33 ized controlled trial. Diabetes Care 2016;39:24– 1780 63. Holcberg G, Tsadkin-Tamir M, Sapir O, et al. 30 49. Jiang Y-F, Chen X-Y, Ding T, Wang X-F, Zhu 35. Wang C, Wei Y, Zhang X, et al. A randomized Z-N, Su S-W. Comparative efficacy and safety Transfer of insulin lispro across the human clinical trial of exercise during pregnancy to of OADs in management of GDM: network placenta. Eur J Obstet Gynecol Reprod Biol – prevent gestational diabetes mellitus and im- meta-analysis of randomized controlled trials. 2004;115:117 118 prove pregnancy outcome in overweight and J Clin Endocrinol Metab 2015;100:2071–2080 64. Boskovic R, Feig DS, Derewlany L, Knie B, obese pregnant women. Am J Obstet Gynecol 50. Camelo Castillo W, Boggess K, Sturmer¨ T, Portnoi G, Koren G. Transfer of insulin lispro 2017;216:340–351 Brookhart MA, Benjamin DK Jr, Jonsson Funk M. across the human placenta: in vitro perfusion – 36. Metzger BE, Buchanan TA, Coustan DR, et al. Association of adverse pregnancy outcomes with studies. Diabetes Care 2003;26:1390 1394 Summary and recommendations of the Fifth glyburide vs insulin in women with gestational 65. McCance DR, Damm P, Mathiesen ER, et al. International Workshop-Conference on Gesta- diabetes. JAMA Pediatr 2015;169:452–458 Evaluation of insulin antibodies and placental tional Diabetes Mellitus. Diabetes Care;2007;30 51. Vanky E, Zahlsen K, Spigset O, Carlsen SM. transfer of insulin aspart in pregnant women (Suppl. 2):S251–S260 Placental passage of metformin in women with with type 1 diabetes mellitus. Diabetologia 2008; 37. Mayo K, Melamed N, Vandenberghe H, polycystic ovary syndrome. Fertil Steril 2005; 51:2141–2143 Berger H. The impact of adoption of the In- 83:1575–1578 66. Suffecool K, Rosenn B, Niederkofler EE, et al. ternational Association of Diabetes in Pregnancy 52. Charles B, Norris R, Xiao X, Hague W. Pop- Insulin detemir does not cross the human pla- Study Group criteria for the screening and di- ulation pharmacokinetics of metformin in late centa. Diabetes Care 2015;38:e20–e21 agnosis of gestational diabetes. Am J Obstet pregnancy. Ther Drug Monit 2006;28:67–72 67. O’Neill SM, Kenny LC, Khashan AS, West HM, Gynecol 2015;212:224.e1–224.e9 53. Rowan JA, Rush EC, Plank LD, et al. Metfor- Smyth RM, Kearney PM. Different insulin types 38. Han S, Crowther CA, Middleton P, Heatley E. min in Gestational Diabetes: The Offspring and regimens for pregnant women with pre- Different types of dietary advice for women with Follow-Up (MiG TOFU): body composition and existing diabetes. Cochrane Database Syst Rev gestational diabetes mellitus. Cochrane Data- metabolic outcomes at 7-9 years of age. BMJ 2017;2:CD011880 base Syst Rev 2013;3:CD009275 Open Diabetes Res Care 2018;6:e000456 68. Duckitt K, Harrington D. Risk factors for pre- 39. Viana LV, Gross JL, Azevedo MJ. Dietary 54. Hanem LGE, Stridsklev S, Jul´ ´ıusson PB, et al. eclampsia at antenatal booking: systematic reintervention in patients with gestational diabe- Metformin use in PCOS pregnancies increases view of controlled studies. BMJ 2005;330:565 tes mellitus: a systematic review and meta- the risk of offspring overweight at 4 years of age: 69. Henderson JT, Whitlock EP, O’Conner E, analysis of randomized clinical trials on maternal follow-up of two RCTs. J Clin Endocrinol Metab Senger CA, Thompson JH, Rowland MG. Low- and newborn outcomes. Diabetes Care 2014;37: 2018;103:1612–1621 dose aspirin for the prevention of morbidity and 3345–3355 55. Vanky E, Stridsklev S, Heimstad R, et al. mortality from preeclampsia: a systematic evi- 40. Hartling L, Dryden DM, Guthrie A, Muise M, Metformin versus placebo from first trimester dence review for the U.S. Preventive Services Vandermeer B, Donovan L. Benefits and harms of to delivery in polycystic ovary syndrome: a ran- Task Force, 2014. Rockville, MD, Agency for treating gestational diabetes mellitus: a system- domized, controlled multicenter study. J Clin Healthcare Research and Quality (Report No. atic review and meta-analysis for the U.S. Endocrinol Metab 2010;95:E448–E455 14-05207-EF-1) S172 Management of Diabetes in Pregnancy Diabetes Care Volume 42, Supplement 1, January 2019

70. Werner EF, Hauspurg AK, Rouse DJ. A cost- 76. Magee LA, von Dadelszen P, Rey E, et al. women with a history of gestational diabetes beneﬁt analysis of low-dose aspirin prophylaxis Less-tight versus tight control of hypertension mellitus. Arch Intern Med 2012;172:1566–1572 for the prevention of preeclampsia in the United in pregnancy. N Engl J Med 2015;372:407–417 84. Villamor E, Cnattingius S. Interpregnancy States. Obstet Gynecol 2015;126:1242–1250 77. Sibai BM. Treatment of hypertension in weight change and risk of adverse pregnancy 71. Feig DS, Donovan LE, Corcoy R, et al.; pregnant women. N Engl J Med 1996;335: outcomes: a population-based study. Lancet – CONCEPTT Collaborative Group. Continuous 257 265 2006;368:1164–1170 78. Kazmin A, Garcia-Bournissen F, Koren G. glucose monitoring in pregnant women with 85. Ratner RE, Christophi CA, Metzger BE, et al.; Risks of statin use during pregnancy: a systematic type 1 diabetes (CONCEPTT): a multicentre in- Diabetes Prevention Program Research Group. review. J Obstet Gynaecol Can 2007;29:906–908 ternational randomised controlled trial. Lancet Prevention of diabetes in women with a history 79. Stuebe AM, Rich-Edwards JW, Willett WC, of gestational diabetes: effects of metformin and 2017;390:2347–2359 Manson JE, Michels KB. Duration of lactation 72. Institute of Medicine and National Research lifestyle interventions. J Clin Endocrinol Metab and incidence of type 2 diabetes. JAMA 2005; 2008;93:4774–4779 Council. Weight Gain During Pregnancy: Re- – 294:2601 2610 86. Aroda VR, Christophi CA, Edelstein SL, et al.; examining the Guidelines. Washington, DC, 80. Pereira PF, Alfenas Rde CG, Araujo´ RMA. Diabetes Prevention Program Research Group. National Academies Press, 2009 Does breastfeeding inﬂuence the risk of de- The effect of lifestyle intervention and metfor- 73. Clausen TD, Mathiesen E, Ekbom P, Hellmuth veloping diabetes mellitus in children? A re- min on preventing or delaying diabetes among E, Mandrup-Poulsen T, Damm P. Poor pregnancy view of current evidence. J Pediatr (Rio J) 2014; 90:7–15 women with and without gestational diabetes: outcome in women with type 2 diabetes. Di- the Diabetes Prevention Program Outcomes abetes Care 2005;28:323–328 81. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: Study 10-year follow-up. J Clin Endocrinol Metab 74. Cundy T, Gamble G, Neale L, et al. Differing – a systematic review. Diabetes Care 2002;25: 2015;100:1646 1653 causes of pregnancy loss in type 1 and type 2 1862–1868 87. Roeder HA, Moore TR, Ramos GA. Changes diabetes. Diabetes Care 2007;30:2603–2607 82. Drury MI. Carbohydrate metabolism in in postpartum insulin requirements for patients 75. American College of Obstetricians and Gy- pregnancy and the newborn. Sutherland HW, with well-controlled type 1 diabetes. Am J Peri- necologists; Task Force on Hypertension in Preg- Stowers JM, Eds. Edinburgh, Churchill Living- natol 2016;33:683–687 nancy. Hypertension in pregnancy. Report of the stone, 1984 88. Riviello C, Mello G, Jovanovic LG. Breastfeed- American College of Obstetricians and Gynecol- 83. Tobias DK, Hu FB, Chavarro J, Rosner B, ing and the basal insulin requirement in type 1 ogists’ Task Force on Hypertension in Pregnancy. Mozaffarian D, Zhang C. Healthful dietary pat- diabetic women. Endocr Pract 2009;15:187– Obstet Gynecol 2013;122:1122–1131 terns and type 2 diabetes mellitus risk among 193 Diabetes Care Volume 42, Supplement 1, January 2019 S173

15. Diabetes Care in the Hospital: American Diabetes Association Standards of Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S173–S181 | https://doi.org/10.2337/dc19-S015

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” 5 IBTSCR NTEHOSPITAL THE IN CARE DIABETES 15. includes ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

In the hospital, both hyperglycemia and hypoglycemia are associated with adverse outcomes, including death (1,2). Therefore, inpatient goals should include the prevention of both hyperglycemia and hypoglycemia. Hospitals should promote the shortest safe hospital stay and provide an effective transition out of the hospital that prevents acute complications and readmission. For in-depth review of inpatient hospital practice, consult recent reviews that focus on hospital care for diabetes (3,4).

HOSPITAL CARE DELIVERY STANDARDS

Recommendation 15.1 Perform an A1C on all patients with diabetes or hyperglycemia (blood glucose .140 mg/dL [7.8 mmol/L]) admitted to the hospital if not performed in the prior 3 months. B

High-quality hospital care for diabetes requires both hospital care delivery standards, often assured by structured order sets, and quality assurance standards for process improvement. “Best practice” protocols, reviews, and guidelines (2) are inconsistently implemented within hospitals. To correct this, hospitals have established protocols for structured patient care and structured order sets, which include computerized physician order entry (CPOE). Suggested citation: American Diabetes Associa- tion. 15. Diabetes care in the hospital: Standards Considerations on Admission of Medical Care in Diabetesd2019. Diabetes Initial orders should state the type of diabetes (i.e., type 1 or type 2 diabetes) or no Care 2019;42(Suppl. 1):S173–S181 previous history of diabetes. Because inpatient insulin use (5) and discharge orders © 2018 by the American Diabetes Association. (6) can be more effective if based on an A1C level on admission (7), perform an A1C Readers may use this article as long as the work is properly cited, the use is educational and not test on all patients with diabetes or hyperglycemia admitted to the hospital if the for proﬁt, and the work is not altered. More infor- test has not been performed in the prior 3 months (8). In addition, diabetes mation is available at http://www.diabetesjournals self-management knowledge and behaviors should be assessed on admission and .org/content/license. S174 Diabetes Care in the Hospital Diabetes Care Volume 42, Supplement 1, January 2019

diabetes self-management education Early evidence suggests that virtual glu- at which neuroglycopenic symptoms should be provided, if appropriate. cose management services may be used to begin to occur and requires immediate Diabetes self-management education improve glycemic outcomes in hospital- action to resolve the hypoglycemic event. should include appropriate skills needed ized patients and facilitate transition of Lastly, level 3 hypoglycemia is defined as after discharge, such as taking antihyper- care after discharge (17). Details of team a severe event characterized by altered glycemic medications, monitoring glu- formation are available from the Joint mental and/or physical functioning that cose, and recognizing and treating Commission standards for programs and requires assistance from another person hypoglycemia (2). the Society of Hospital Medicine (18,19). for recovery. See Table 15.1 for levels of hypoglycemia (21). Hypoglycemia is dis- Physician Order Entry Quality Assurance Standards cussed more fully below. Recommendation Even the best orders may not be carried 15.2 Insulin should be administered out in a way that improves quality, nor Moderate Versus Tight Glycemic using validated written or com- are they automatically updated when Control A meta-analysis of over 26 studies, includ- puterized protocols that allow new evidence arises. To this end, the ing the Normoglycemia in Intensive Care for predefined adjustments in Joint Commission has an accreditation – the insulin dosage based on program for the hospital care of dia- Evaluation Survival Using Glucose Algo- rithm Regulation (NICE-SUGAR) study, glycemic fluctuations. E betes (18), and the Society of Hospital “ Medicine has a workbook for program showed increased rates of severe hy- ” fi The National Academy of Medicine rec- development (19). poglycemia (de ned in the analysis as , ommends CPOE to prevent medication- blood glucose 40 mg/dL [2.2 mmol/L]) and mortality in cohorts with tight versus related errors and to increase efficiency GLYCEMIC TARGETS IN moderate glycemic control (22). Recent in medication administration (9). A Co- HOSPITALIZED PATIENTS chrane review of randomized controlled randomized controlled studies and meta- Recommendations trials using computerized advice to im- analyses in surgical patients have also 15.4 Insulin therapy should be initiated prove glucose control in the hospital reported that targeting perioperative for treatment of persistent hyper- , found significant improvement in the blood glucose levels to 180 mg/dL (10- glycemia starting at a threshold percentage of time patients spent in mmol/L) is associated with lower rates of $180 mg/dL (10.0 mmol/L). the target glucose range, lower mean mortality and stroke compared with a tar- Once insulin therapy is started, , blood glucose levels, and no increase in get glucose 200 mg/dL (11.1 mmol/L), a target glucose range of 140– fi fi hypoglycemia (10). Thus, where feasible, whereas no signi cant additional bene t 180 mg/dL (7.8–10.0 mmol/L) is there should be structured order sets was found with more strict glycemic recommended for the majority , that provide computerized advice for control ( 140 mg/dL [7.8 mmol/L]) of critically ill patients and non- glucose control. Electronic insulin order (23,24). Insulin therapy should be initiated critically ill patients. A templates also improve mean glucose for treatment of persistent hyperglyce- 15.5 More stringent goals, such as $ levels without increasing hypoglycemia mia starting at a threshold 180 mg/dL 110–140 mg/dL (6.1–7.8 mmol/L), in patients with type 2 diabetes, so (10.0 mmol/L). Once insulin therapy is may be appropriate for se- – structured insulin order sets should be started, a target glucose range of 140 lected patients, if this can be – incorporated into the CPOE (11). 180 mg/dL (7.8 10.0 mmol/L) is recom- achieved without significant mended for the majority of critically ill hypoglycemia. C and noncritically ill patients (2). More Diabetes Care Providers in the Hospital stringent goals, such as ,140 mg/dL Recommendation Standard Definition of Glucose (7.8 mmol/L), may be appropriate for 15.3 When caring for hospitalized Abnormalities selected patients, as long as this can be patients with diabetes, consider Hyperglycemia in hospitalized patients achieved without significant hypoglyce- consulting with a specialized di- is defined as blood glucose levels .140 mia. Conversely, higher glucose ranges abetes or glucose management mg/dL (7.8 mmol/L) (2,20). Blood glu- may be acceptable in terminally ill patients, team where possible. E cose levels that are persistently above this level may require alterations in diet — Appropriately trained specialists or spe- or a change in medications that cause Table 15.1 Levels of hypoglycemia (21) cialty teams may reduce length of stay, hyperglycemia. An admission A1C value Glycemic improve glycemic control, and improve $6.5% (48 mmol/mol) suggests that Level criteria/description outcomes, but studies are few (12,13). A diabetes preceded hospitalization (see , call to action outlined the studies needed Section 2 “Classification and Diagnosis Level 1 Glucose 70 mg/dL (3.9 mmol/L) and glucose $54 mg/dL to evaluate these outcomes (14). People of Diabetes”) (2,20). Level 1 hypoglyce- (3.0 mmol/L) with diabetes are known to have a higher mia in hospitalized patients is defined Level 2 Glucose ,54 mg/dL (3.0 mmol/L) risk of 30-day readmission following hos- as a measurable glucose concentration , $ Level 3 A severe event characterized pitalization. Specialized diabetes teams 70 mg/dL (3.9 mmol/L) but 54 mg/dL by altered mental and/or caring for patients with diabetes during (3.0 mmol/L). Level 2 hypoglycemia physical status requiring their hospital stay can improve readmis- (defined as a blood glucose concentration assistance sion rates and lower cost of care (15,16). ,54 mg/dL [3.0 mmol/L]) is the threshold care.diabetesjournals.org Diabetes Care in the Hospital S175

in patients with severe comorbidities, and well as direction and magnitude of glucose shown to be the best method for achieving in inpatient care settings where frequent trends, which may have an advantage glycemic targets. Intravenous insulin infu- glucose monitoring or close nursing su- over POC glucose testing in detecting and sions should be administered based on pervision is not feasible. reducing the incidence of hypoglycemia validated written or computerized proto- Clinical judgment combined with on- in the hospital setting (28,29). Several in- cols that allow for predefined adjustments going assessment of the patient’s clinical patient studies have shown that CGM use in the infusion rate, accounting for glyce- status, including changes in the trajec- did not improve glucose control but mic fluctuations and insulin dose (2). tory of glucose measures, illness severity, detected a greater number of hypogly- Noncritical Care Setting nutritional status, or concomitant med- cemic events than POC testing (30,31). Outside of critical care units, scheduled ications that might affect glucose levels However, a recent review has recom- insulin regimens are recommended to (e.g., glucocorticoids), should be incor- mended against using CGM in adults in manage hyperglycemia in patients with porated into the day-to-day decisions a hospital setting until more safety and diabetes. Regimens using insulin analogs fi regarding insulin dosing (2). ef cacy data become available (30). For and human insulin result in similar gly- more information on CGM, see Section 7 cemic control in the hospital setting (37). BEDSIDE BLOOD GLUCOSE “Diabetes Technology.” MONITORING The use of subcutaneous rapid- or short- acting insulin before meals or every 4–6h Indications ANTIHYPERGLYCEMIC AGENTS IN if no meals are given or if the patient is In the patient who is eating meals, glu- HOSPITALIZED PATIENTS cose monitoring should be performed receiving continuous enteral/parenteral before meals. In the patient who is not Recommendations nutrition is indicated to correct hyper- 15.6 eating, glucose monitoring is advised Basal insulin or a basal plus bolus glycemia (2). Basal insulin or a basal plus every 4–6 h (2). More frequent blood correction insulin regimen is the bolus correction insulin regimen is the glucose testing ranging from every preferred treatment for noncriti- preferred treatment for noncritically ill 30mintoevery2hisrequiredfor cally ill hospitalized patients with hospitalized patients with poor oral in- poor oral intake or those who are patients receiving intravenous insulin. take or those who are taking nothing by taking nothing by mouth. An in- Observational studies have shown that mouth (NPO). An insulin regimen with safety standards should be established sulin regimen with basal, prandial, and correction components basal, prandial, and correction compo- for blood glucose monitoring that pro- nents is the preferred treatment for hibit the sharing of fingerstick lancing is the preferred treatment for noncritically ill hospitalized patients with devices, lancets, and needles (25). noncritically ill hospitalized patients with good nutritional in- good nutritional intake. Point-of-Care Meters take. A If the patient is eating, insulin injec- Point-of-care (POC) meters have limi- 15.7 Sole use of sliding scale insulin in tions should align with meals. In such tations for measuring blood glucose. the inpatient hospital setting is instances, POC glucose testing should Although the U.S. Food and Drug Ad- strongly discouraged. A be performed immediately before meals. ministration (FDA) has standards for If oral intake is poor, a safer procedure is blood glucose meters used by lay per- In most instances in the hospital setting, to administer the rapid-acting insulin sons, there have been questions about insulin is the preferred treatment for immediately after the patient eats or the appropriateness of these criteria, hyperglycemia (2). However, in certain to count the carbohydrates and cover especially in the hospital and for lower circumstances, it may be appropriate to the amount ingested (37). blood glucose readings (26). Significant continue home regimens including oral A randomized controlled trial has discrepancies between capillary, venous, antihyperglycemic medications (32). If shown that basal-bolus treatment im- and arterial plasma samples have been oral medications are held in the hospital, proved glycemic control and reduced observed in patients with low or high there should be a protocol for resuming hospital complications compared with hemoglobin concentrations and with hy- them 1–2 days before discharge. Insulin sliding scale insulin in general surgery poperfusion. Any glucose result that does pens are the subject of an FDA warning not correlate with the patient’s clinical because of potential blood-borne dis- patients with type 2 diabetes (38). Pro- status should be confirmed through con- eases, and care should be taken to follow longed sole use of sliding scale insulin in ventional laboratory glucose tests. The the label insert “For single patient use the inpatient hospital setting is strongly FDA established a separate category for only” (33). Recent reports, however, discouraged (2,14). POC glucose meters for use in health care have indicated that the inpatient use While there is evidence for using pre- settings and has released guidance on of insulin pens appears to be safe and mixed insulin formulations in the out- in-hospital use with stricter standards may be associated with improved nurse patient setting (39), a recent inpatient (27). Before choosing a device for in- satisfaction compared with the use of study of 70/30 NPH/regular insulin ver- hospital use, consider the device’sap- insulin vials and syringes (34–36). sus basal-bolus therapy showed compa- proval status and accuracy. rable glycemic control but significantly Continuous Glucose Monitoring Insulin Therapy increased hypoglycemia in the group re- Real-time continuous glucose monitor- Critical Care Setting ceiving premixed insulin (40). Therefore, ing (CGM) provides frequent measure- In the critical care setting, continuous premixed insulin regimens are not rou- ments of interstitial glucose levels, as intravenous insulin infusion has been tinely recommended for in-hospital use. S176 Diabetes Care in the Hospital Diabetes Care Volume 42, Supplement 1, January 2019

Type 1 Diabetes Moreover, the gastrointestinal symp- and treating hypoglycemia for each pa- For patients with type 1 diabetes, dosing toms associated with the glucagon-like tient. An American Diabetes Association insulin based solely on premeal glucose peptide 1 receptor agonists may be (ADA) consensus report suggested that levels does not account for basal insulin problematic in the inpatient setting. apatient’s overall treatment regimen requirements or caloric intake, increas- Regarding the sodium–glucose trans- be reviewed when a blood glucose value ing both hypoglycemia and hyperglyce- porter 2 (SGLT2) inhibitors, the FDA of ,70 mg/dL (3.9 mmol/L) is identified mia risks. Typically, basal insulin dosing includes warnings about diabetic keto- because such readings often predict im- schemes are based on body weight, with acidosis (DKA) and urosepsis (52), urinary minent level 3 hypoglycemia (2). some evidence that patients with renal tract infections, and kidney injury (53) on Episodes of hypoglycemia in the hos- insufficiency should be treated with lower the drug labels. A recent review suggested pital should be documented in the med- doses (41). An insulin regimen with basal SGLT2 inhibitors be avoided in severe ical record and tracked (2). andcorrectioncomponentsisnecessary illness, when ketone bodies are present, for all hospitalized patients with type 1 and during prolonged fasting and surgical Triggering Events diabetes, with the addition of prandial procedures (3). Until safety and effec- Iatrogenic hypoglycemia triggers may in- insulin if the patient is eating. tiveness are established, SGLT2 inhibitors clude sudden reduction of corticosteroid Transitioning Intravenous to cannot be recommended for routine dose, reduced oral intake, emesis, new Subcutaneous Insulin in-hospital use. NPO status, inappropriate timing of short- When discontinuing intravenous insu- or rapid-acting insulin in relation to meals, lin, a transition protocol is associated HYPOGLYCEMIA reduced infusion rate of intravenous with less morbidity and lower costs of dextrose, unexpected interruption of oral, care (42) and is therefore recommended. Recommendations enteral, or parenteral feedings, and al- 15.8 A patient with type 1 or type 2 diabetes A hypoglycemia management tered ability of the patient to report being transitioned to outpatient subcu- protocol should be adopted and symptoms (3). taneous insulin should receive subcuta- implemented by each hospital or neous basal insulin 2–4 h before the hospital system. A plan for pre- Predictors of Hypoglycemia intravenous insulin is discontinued. Con- venting and treating hypoglyce- In one study, 84% of patients with an verting to basal insulin at 60–80% of the mia should be established for episode of “severe hypoglycemia” (de- daily infusion dose has been shown to be each patient. Episodes of hypo- fined as ,40 mg/dL [2.2 mmol/L]) had a effective (2,42,43). For patients continu- glycemia in the hospital should prior episode of hypoglycemia (,70 ing regimens with concentrated insulin be documented in the medical mg/dL [3.9 mmol/L]) during the same ad- (U-200, U-300, or U-500) in the inpatient record and tracked. E mission (55). In another study of hypo- setting, it is important to ensure the 15.9 The treatment regimen should glycemic episodes (defined as ,50 mg/dL correct dosing by utilizing an individual be reviewed and changed as nec- [2.8 mmol/L]), 78% of patients were pen and cartridge for each patient, me- essary to prevent further hypogly- using basal insulin, with the incidence ticulous pharmacist supervision of the cemia when a blood glucose value of hypoglycemia peaking between mid- dose administered, or other means of ,70 mg/dL (3.9 mmol/L) is night and 6 A.M. Despite recognition of (44,45). documented. C hypoglycemia, 75% of patients did not have their dose of basal insulin changed Noninsulin Therapies Patients with or without diabetes may ex- before the next insulin administration The safety and efficacy of noninsulin perience hypoglycemia in the hospital set- (56). antihyperglycemic therapies in the hos- ting. While hypoglycemia is associated pital setting is an area of active research. with increased mortality (54), hypoglycemia Prevention A few recent randomized pilot trials in may be a marker of underlying disease Common preventable sources of iatro- general medicine and surgery patients rather than the cause of increased mor- genic hypoglycemia are improper pre- reported that a dipeptidyl peptidase 4 tality. However, until it is proven not to be scribing of hypoglycemic medications, inhibitor alone or in combination with causal, it is prudent to avoid hypoglycemia. inappropriate management of the first basal insulin was well tolerated and Despite the preventable nature of many episode of hypoglycemia, and nutrition– resulted in similar glucose control and inpatient episodes of hypoglycemia, insti- insulin mismatch, often related to an frequency of hypoglycemia compared tutions are more likely to have nursing pro- unexpected interruption of nutrition. with a basal-bolus regimen (46–48). tocols for hypoglycemia treatment than Studies of “bundled” preventative ther- However, an FDA bulletin states that for its prevention when both are needed. apies including proactive surveillance of providers should consider discontinu- A hypoglycemia prevention and man- glycemic outliers and an interdisciplinary ing saxagliptin and alogliptin in people agement protocol should be adopted data-driven approach to glycemic man- who develop heart failure (49). A review and implemented by each hospital or agement showed that hypoglycemic epi- of antihyperglycemic medications con- hospital system. There should be a stan- sodes in the hospital could be prevented. cluded that glucagon-like peptide 1 re- dardized hospital-wide, nurse-initiated Compared with baseline, two such stud- ceptor agonists show promise in the hypoglycemia treatment protocol to ies found that hypoglycemic events fell inpatient setting (50); however, proof immediately address blood glucose lev- by 56% to 80% (57,58). The Joint Com- of safety and efficacy awaits the results els of ,70 mg/dL (3.9 mmol/L), as well mission recommends that all hypogly- of randomized controlled trials (51). as individualized plans for preventing cemic episodes be evaluated for a root care.diabetesjournals.org Diabetes Care in the Hospital S177

cause and the episodes be aggregated patient, nursing staff, and physician agree is encouraged to consult review articles and reviewed to address systemic issues. that patient self-management is appro- detailing this topic (2,66). priate. If CSII is to be used, hospital policy MEDICAL NUTRITION THERAPY IN and procedures delineating guidelines Glucocorticoid Therapy Glucocorticoid type and duration of ac- THE HOSPITAL for CSII therapy, including the changing tion must be considered in determining The goals of medical nutrition therapy in of infusion sites, are advised (63). insulin treatment regimens. Once-a-day, the hospital are to provide adequate short-acting glucocorticoids such as calories to meet metabolic demands, STANDARDS FOR SPECIAL prednisone peak in about 4–8 h (67), optimize glycemic control, address per- SITUATIONS so coverage with intermediate-acting sonal food preferences, and facilitate Enteral/Parenteral Feedings (NPH)insulinmaybesufficient. For creation of a discharge plan. The ADA For patients receiving enteral or paren- long-acting glucocorticoids such as dexa- does not endorse any single meal plan or teral feedings who require insulin, insulin methasone or multidose or continuous specified percentages of macronutrients. should be divided into basal, prandial, glucocorticoid use, long-acting insulin Current nutrition recommendations ad- and correctional components. This is may be used (32,66). For higher doses vise individualization based on treatment particularly important for people with of glucocorticoids, increasing doses of goals, physiological parameters, and med- type 1 diabetes to ensure that they prandial and correctional insulin may be ication use. Consistent carbohydrate meal continue to receive basal insulin even if needed in addition to basal insulin (68). plans are preferred by many hospitals as the feedings are discontinued. One may Whatever orders are started, adjust- they facilitate matching the prandial in- use the patient’s preadmission basal in- ments based on anticipated changes in sulin dose to the amount of carbohydrate sulin dose or a percentage of the total glucocorticoid dosing and POC glucose consumed (59). Regarding enteral nutri- daily dose of insulin when the patient is fi test results are critical. tional therapy, diabetes-speci c formu- being fed (usually 30–50% of the total las appear to be superior to standard daily dose of insulin) to estimate basal Perioperative Care formulas in controlling postprandial glu- insulin requirements. However, if no Many standards for perioperative care cose, A1C, and the insulin response (60). basal insulin was used, consider using lack a robust evidence base. However, When the nutritional issues in the 5 units of NPH/detemir insulin subcuta- the following approach (69) may be hospital are complex, a registered di- neously every 12 h or 10 units of insulin considered: etitian, knowledgeable and skilled in glargine every 24 h (64). For patients medical nutrition therapy, can serve as 1. Target glucose range for the perioper- receiving continuous tube feedings, the an individual inpatient team member. ative period should be 80–180 mg/dL total daily nutritional component may be That person should be responsible for (4.4–10.0 mmol/L). calculated as 1 unit of insulin for every integrating information about the pa- 2. Perform a preoperative risk assess- 10–15 g carbohydrate per day or as a tient’s clinical condition, meal planning, ment for patients at high risk for percentage of the total daily dose of and lifestyle habits and for establishing ischemic heart disease and those insulin when the patient is being fed realistic treatment goals after discharge. with autonomic neuropathy or renal (usually 50–70% of the total daily dose Orders should also indicate that the meal failure. of insulin). Correctional insulin should delivery and nutritional insulin coverage 3. Withhold metformin the day of sur- should be coordinated, as their variability also be administered subcutaneously gery. often creates the possibility of hypergly- every 6 h using human regular insulin 4. Withhold any other oral hypoglycemic cemic and hypoglycemic events. or every 4 h using a rapid-acting insulin agents the morning of surgery or pro- such as lispro, aspart, or glulisine. For cedure and give half of NPH dose or SELF-MANAGEMENT IN THE patients receiving enteral bolus feedings, 60–80% doses of long-acting analog HOSPITAL approximately 1 unit of regular human or pump basal insulin. – Diabetes self-management in the hospi- insulin or rapid-acting insulin per 10 15 g 5. Monitor blood glucose at least tal may be appropriate for select youth carbohydrate should be given subcuta- every 4–6 h while NPO and dose and adult patients (61,62). Candidates neously before each feeding. with short- or rapid-acting insulin as include patients who successfully conduct Correctional insulin coverage should needed. self-management of diabetes at home, be added as needed before each feeding. have the cognitive and physical skills For patients receiving continuous periph- A review found that perioperative needed to successfully self-administer eral or central parenteral nutrition, hu- glycemic control tighter than 80– insulin, and perform self-monitoring of man regular insulin may be added to 180 mg/dL (4.4–10.0 mmol/L) did not blood glucose. In addition, they should the solution, particularly if .20 units of improve outcomes and was associated have adequate oral intake, be proficient correctional insulin have been required with more hypoglycemia (70); therefore, in carbohydrate estimation, use multi- in the past 24 h. A starting dose of 1 unit in general, tighter glycemic targets are ple daily insulin injections or continuous of human regular insulin for every 10 g not advised. A recent study reported subcutaneous insulin infusion (CSII), dextrose has been recommended (65), that, compared with the usual insulin have stable insulin requirements, and to be adjusted daily in the solution. dose, on average an approximate 25% understand sick-day management. If Correctional insulin should be admin- reduction in the insulin dose given the self-management is to be used, a protocol istered subcutaneously. For full enteral/ evening before surgery was more likely should include a requirement that the parenteral feeding guidance, the reader to achieve perioperative blood glucose S178 Diabetes Care in the Hospital Diabetes Care Volume 42, Supplement 1, January 2019

levels in the target range with decreased discharge, and its use is generally not transitions to outpatient care. Providing risk for hypoglycemia (71). recommended (80). For further informa- information regarding the cause of hy- In noncardiac general surgery patients, tion regarding treatment, refer to recent perglycemia (or the plan for determining basal insulin plus premeal short- or rapid- in-depth reviews (3). the cause), related complications and acting insulin (basal-bolus) coverage has comorbidities, and recommended treat- been associated with improved glycemic ments can assist outpatient providers as control and lower rates of perioperative TRANSITION FROM THE ACUTE they assume ongoing care. complications compared with the tradi- CARE SETTING The Agency for Healthcare Research tional sliding scale regimen (short- or Recommendation and Quality (AHRQ) recommends that, rapid-acting insulin coverage only with 15.10 There should be a structured at a minimum, discharge plans include no basal insulin dosing) (38,72). discharge plan tailored to the in- the following (82): dividual patient with diabetes. B Diabetic Ketoacidosis and Medication Reconciliation Hyperosmolar Hyperglycemic State A structured discharge plan tailored to ○ The patient’s medications must be There is considerable variability in the pre- the individual patient may reduce length cross-checked to ensure that no sentation of DKA and hyperosmolar hyper- of hospital stay and readmission rates chronic medications were stopped glycemic state, ranging from euglycemia and increase patient satisfaction (81). and to ensure the safety of new or mild hyperglycemia and acidosis to Therefore, there should be a structured prescriptions. severe hyperglycemia, dehydration, and discharge plan tailored to each patient. ○ Prescriptions for newor changed med- coma; therefore, treatment individualiza- Discharge planning should begin at ad- ication should be filled and reviewed tion based on a careful clinical and lab- mission and be updated as patient needs with the patient and family at or oratory assessment is needed (73–76). change. before discharge. Management goals include restora- Transition from the acute care setting tion of circulatory volume and tissue is a risky time for all patients. Inpatients Structured Discharge Communication perfusion, resolution of hyperglycemia, may be discharged to varied settings, ○ Information on medication changes, and correction of electrolyte imbalance including home (with or without visiting pending tests and studies, and follow- and ketosis. It is also important to treat nurse services), assisted living, rehabili- up needs must be accurately and any correctable underlying cause of DKA tation, or skilled nursing facilities. For the promptly communicated to outpa- such as sepsis. patient who is discharged to home or to tient physicians. In critically ill and mentally obtunded assisted living, the optimal program will ○ Discharge summaries should be patients with DKA or hyperosmolar hy- need to consider diabetes type and se- transmitted to the primary care pro- perglycemic state, continuous intrave- verity, effects of the patient’s illness on vider as soon as possible after dis- nous insulin is the standard of care. blood glucose levels, and the patient’s charge. Successful transition of patients from capacities and preferences. See Section ○ Appointment-keeping behavior is en- intravenous to subcutaneous insulin re- 12 “Older Adults” for more information. hanced when the inpatient team quires administration of basal insulin 2– An outpatient follow-up visit with the schedules outpatient medical follow- 4 h prior to the intravenous insulin being primary care provider, endocrinologist, up prior to discharge. stopped to prevent recurrence of keto- or diabetes educator within 1 month of acidosis and rebound hyperglycemia (76). discharge is advised for all patients hav- It is recommended that the following There is no significant difference in out- ing hyperglycemia in the hospital. If areas of knowledge be reviewed and comes for intravenous human regular glycemic medications are changed or addressed prior to hospital discharge: insulin versus subcutaneous rapid-acting glucose control is not optimal at dis- analogs when combined with aggressive charge, an earlier appointment (in 1–2 ○ Identification of the health care pro- fluid management for treating mild or weeks) is preferred, and frequent con- vider who will provide diabetes care moderate DKA (77). Patients with un- tact may be needed to avoid hypergly- after discharge. complicated DKA may sometimes be cemia and hypoglycemia. A recently ○ Level of understanding related to the treated with subcutaneous insulin in described discharge algorithm for glyce- diabetes diagnosis, self-monitoring of the emergency department or step- mic medication adjustment based on blood glucose, home blood glucose down units (78), an approach that may admission A1C found that use of the goals, and when to call the provider. be safer and more cost-effective than algorithm to guide treatment decisions ○ Definition, recognition, treatment, and treatment with intravenous insulin (79). resulted in significant improvements in prevention of hyperglycemia and hy- If subcutaneous administration is used, the average A1C after discharge (6). poglycemia. it is important to provide adequate fluid Therefore, if an A1C from the prior 3 ○ Information on making healthy food replacement, nurse training, frequent months is unavailable, measuring the A1C choices at home and referral to an bedside testing, infection treatment if in all patients with diabetes or hyper- outpatient registered dietitian nutri- warranted, and appropriate follow-up glycemia admitted to the hospital is tionist to guide individualization of to avoid recurrent DKA. Several studies recommended. meal plan, if needed. have shown that the use of bicarbonate Clear communication with outpatient ○ If relevant, when and how to take in patients with DKA made no difference providers either directly or via hospital blood glucose–lowering medications, in resolution of acidosis or time to discharge summaries facilitates safe including insulin administration. care.diabetesjournals.org Diabetes Care in the Hospital S179

○ Sick-day management. with admission A1C .9% (75 mmol/mol) management of hyperglycemia and diabetes: ○ Proper use and disposal of needles and (89), and a transitional care model (90). a call to action. Diabetes Care 2013;36:1807–1814 syringes. For people with diabetic kidney dis- 15. Bansal V, Mottalib A, Pawar TK, et al. In- patient diabetes management by specialized ease, patient-centered medical home It is important that patients be pro- diabetes team versus primary service team in collaboratives may decrease risk-adjusted non-critical care units: impact on 30-day read- vided with appropriate durable medical readmission rates (91). mission rate and hospital cost. BMJ Open Di- equipment, medications, supplies (e.g., abetes Res Care 2018;6:e000460 blood glucose test strips), and prescrip- References 16. Ostling S, Wyckoff J, Ciarkowski SL, et al. The tions along with appropriate education 1. Clement S, Braithwaite SS, Magee MF, et al.; relationship between diabetes mellitus and at the time of discharge in order to Diabetes in Hospitals Writing Committee. Man- 30-day readmission rates. Clin Diabetes Endo- agement of diabetes and hyperglycemia in hos- crinol 2017;3:3 avoid a potentially dangerous hiatus 17. Rushakoff RJ, Sullivan MM, MacMaster HW, in care. pitals [published corrections appear in Diabetes Care 2004;27:856 and Diabetes Care 2004;27: et al. Association between a virtual glucose 1255]. Diabetes Care 2004;27:553–591 management service and glycemic control in PREVENTING ADMISSIONS AND 2. Moghissi ES, Korytkowski MT, DiNardo M, hospitalized adult patients: an observational READMISSIONS et al.; American Association of Clinical Endocri- study. Ann Intern Med 2017;166:621–627 Preventing Hypoglycemic Admissions nologists; American Diabetes Association. Amer- 18. Arnold P, Scheurer D, Dake AW, et al. Hos- pital guidelines for diabetes management and in Older Adults ican Association of Clinical Endocrinologists and the Joint Commission-American Diabetes Asso- Insulin-treated patients 80 years of age American Diabetes Association consensus statement on inpatient glycemic control. Diabetes ciation Inpatient Diabetes Certification. Am J or older are more than twice as likely to visit Care 2009;32:1119–1131 Med Sci 2016;351:333–341 the emergency department and nearly 3. Umpierrez G, Korytkowski M. Diabetic 19. Society of Hospital Medicine. Glycemic five times as likely to be admitted for emergenciesdketoacidosis, hyperglycaemic Control for Hospitalists [Internet]. Available insulin-related hypoglycemia than those hyperosmolar state and hypoglycaemia. Nat from http://www.hospitalmedicine.org/Web/ Rev Endocrinol 2016;12:222–232 Quality_Innovation/Implementation_Toolkits/ 45–64 years of age (83). However, older 4. Bogun M, Inzucchi SE. Inpatient management Glycemic_Control/Web/Quality___Innovation/ adults with type 2 diabetes in long-term of diabetes and hyperglycemia. Clin Ther 2013; Implementation_Toolkit/Glycemic/Clinical_ care facilities taking either oral antihy- 35:724–733 Tools/Clinical_Tools.aspx. Accessed 24 Sep- perglycemic agents or basal insulin have 5. Pasquel FJ, Gomez-Huelgas R, Anzola I, et al. tember 2018 similar glycemic control (84), suggesting Predictive value of admission hemoglobin A1c 20. Umpierrez GE, Hellman R, Korytkowski MT, on inpatient glycemic control and response to that oral therapy may be used in place of et al.; Endocrine Society. Management of insulin therapy in medicine and surgery patients hyperglycemia in hospitalized patients in noninsulin to lower the risk of hypoglycemia with type 2 diabetes. Diabetes Care 2015;38: critical care setting: an Endocrine Society clini- for some patients. In addition, many e202–e203 cal practice guideline. J Clin Endocrinol Metab older adults with diabetes are over- 6. Umpierrez GE, Reyes D, Smiley D, et al. 2012;97:16–38 treated (85), with half of those maintain- Hospital discharge algorithm based on admission 21. Agiostratidou G, Anhalt H, Ball D, et al. , HbA1c for the management of patients with type 2 Standardizing clinically meaningful outcome ing an A1C 7% (53 mmol/mol) being diabetes. Diabetes Care 2014;37:2934–2939 measures beyond HbA1c for type 1 diabetes: treated with insulin or a sulfonylurea, 7. Carpenter DL, Gregg SR, Xu K, Buchman TG, a consensus report of the American Association which are associated with hypoglycemia. Coopersmith CM. Prevalence and impact of un- of Clinical Endocrinologists, the American Asso- To further lower the risk of hypoglyce- known diabetes in the ICU. Crit Care Med 2015; ciation of Diabetes Educators, the American – mia-related admissions in older adults, 43:e541 e550 Diabetes Association, the Endocrine Society, 8. Rhee MK, Safo SE, Jackson SL, et al. Inpatient JDRF International, The Leona M. and Harry B. providers may, on an individual basis, glucose values: determining the nondiabetic Helmsley Charitable Trust, the Pediatric Endo- relax A1C targets to 8% (64 mmol/mol) range and use in identifying patients at high crine Society, and the T1D Exchange. Diabetes risk for diabetes. Am J Med 2018;131:443.e11– or 8.5% (69 mmol/mol) in patients with Care 2017;40:1622–1630 443.e24 shortened life expectancies and signifi- 22. NICE-SUGAR Study Investigators, Finfer S, 9. Institute of Medicine. Preventing Medication Chittock DR, et al. Intensive versus conventional cant comorbidities (refer to Section 12 Errors. Aspden P, Wolcott J, Bootman JL, glucose control in critically ill patients. N Engl J “Older Adults” for detailed criteria). Cronenwett LR, Eds. Washington, DC, The Na- Med 2009;360:1283–1297 tional Academies Press, 2007 Preventing Readmissions 10. Gillaizeau F, Chan E, Trinquart L, et al. Com- 23. Sathya B, Davis R, Taveira T, Whitlatch H, Wu In patients with diabetes, the hospital re- puterized advice on drug dosage to improve W-C. Intensity of peri-operative glycemic con- admission rate is between 14 and 20% (86). prescribing practice. Cochrane Database Syst trol and postoperative outcomes in patients Rev 2013;11:CD002894 with diabetes: a meta-analysis. Diabetes Res Risk factors for readmission include Clin Pract 2013;102:8–15 lower socioeconomic status, certain ra- 11. Wexler DJ, Shrader P, Burns SM, Cagliero E. Effectiveness of a computerized insulin order 24. Umpierrez G, Cardona S, Pasquel F, et al. cial/ethnic minority groups, comorbid- template in general medical inpatients with Randomized controlled trial of intensive versus ities, urgent admission, and recent prior type 2 diabetes: a cluster randomized trial. Di- conservative glucose control in patients under- hospitalization (86). Of interest, 30% of abetes Care 2010;33:2181–2183 going coronary artery bypass graft surgery: patients with two or more hospital stays 12. Wang YJ, Seggelke S, Hawkins RM, et al. GLUCO-CABG trial. Diabetes Care 2015;38: 1665–1672 account for over 50% of hospitalizations Impact of glucose management team on outcomes of hospitalizaron in patients with type 2 25. Cobaugh DJ, Maynard G, Cooper L, et al. and their accompanying hospital costs diabetes admitted to the medical service. Enhancing insulin-use safety in hospitals: prac- (87). While there is no standard to pre- Endocr Pract 2016;22:1401–1405 tical recommendations from an ASHP Founda- vent readmissions, several successful 13. Garg R, Schuman B, Bader A, et al. Effect of tion expert consensus panel. Am J Health Syst – strategies have been reported, including preoperative diabetes management on glyce- Pharm 2013;70:1404 1413 mic control and clinical outcomes after elective 26. Boyd JC, Bruns DE. Quality specifications for an intervention program targeting ketosis- surgery. Ann Surg 2018;267:858–862 glucose meters: assessment by simulation mod- prone patients with type 1 diabetes (88), 14. Draznin B, Gilden J, Golden SH, et al.; PRIDE eling of errors in insulin dose. Clin Chem 2001;47: initiating insulin treatment in patients investigators. Pathways to quality inpatient 209–214 S180 Diabetes Care in the Hospital Diabetes Care Volume 42, Supplement 1, January 2019

27. U.S. Food and Drug Administration. Blood 41. Baldwin D, Zander J, Munoz C, et al. A 54. Akirov A, Grossman A, Shochat T, Shimon I. Glucose Monitoring Test Systems for Prescription randomized trial of two weight-based doses Mortality among hospitalized patients with hy- Point-of-Care Use: Guidance for Industry and Food of insulin glargine and glulisine in hospitalized poglycemia: insulin related and noninsulin re- and Drug Administration Staff [Internet], 2016. subjects with type 2 diabetes and renal insuffi- lated. J Clin Endocrinol Metab 2017;102:416–424 Available from https://www.fda.gov/downloads/ ciency. Diabetes Care 2012;35:1970–1974 55. Dendy JA, Chockalingam V, Tirumalasetty medicaldevices/deviceregulationandguidance/ 42. Schmeltz LR, DeSantis AJ, Thiyagarajan V, NN, et al. Identifying risk factors for severe guidancedocuments/ucm380325.pdf. Accessed et al. Reduction of surgical mortality and mor- hypoglycemia in hospitalized patients with di- 23 October 2018 bidity in diabetic patients undergoing cardiac abetes. Endocr Pract 2014;20:1051–1056 28. Wallia A, Umpierrez GE, Rushakoff RJ, et al.; surgery with a combined intravenous and sub- 56. Ulmer BJ, Kara A, Mariash CN. Temporal DTS Continuous Glucose Monitoring in the Hos- cutaneous insulin glucose management strategy. occurrences and recurrence patterns of hypo- pital Panel. Consensus statement on inpatient Diabetes Care 2007;30:823–828 glycemia during hospitalization. Endocr Pract use of continuous glucose monitoring. J Diabetes 43. Shomali ME, Herr DL, Hill PC, Pehlivanova M, 2015;21:501–507 Sci Technol 2017;11:1036–1044 Sharretts JM, Magee MF. Conversion from in- 57. Maynard G, Kulasa K, Ramos P, et al. Impact 29. Umpierrez GE, Klonoff DC. Diabetes tech- travenous insulin to subcutaneous insulin after of a hypoglycemia reduction bundle and a sys- nology update: use of insulin pumps and con- cardiovascularsurgery:transitiontotargetstudy. tems approach to inpatient glycemic manage- tinuous glucose monitoring in the hospital. Diabetes Technol Ther 2011;13:121–126 ment. Endocr Pract 2015;21:355–367 Diabetes Care 2018;41:1579–1589 44. Tripathy PR, Lansang MC. U-500 regular 58. Milligan PE, Bocox MC, Pratt E, Hoehner CM, 30. Gomez AM, Umpierrez GE. Continuous glu- insulin use in hospitalized patients. Endocr Pract Krettek JE, Dunagan WC. Multifaceted approach cose monitoring in insulin-treated patients in 2015;21:54–58 to reducing occurrence of severe hypoglycemia non-ICU settings. J Diabetes Sci Technol 2014;8: 45. Lansang MC, Umpierrez GE. Inpatient hy- in a large healthcare system. Am J Health Syst – 930 936 perglycemia management: a practical review for Pharm 2015;72:1631–1641 31.KrinsleyJS,ChaseJG,GunstJ,etal. primary medical and surgical teams. Cleve Clin J 59. Curll M, Dinardo M, Noschese M, – Continuous glucose monitoring in the ICU: clin- Med 2016;83(Suppl. 1):S34 S43 Korytkowski MT. Menu selection, glycaemic ical considerations and consensus. Crit Care 46. Umpierrez GE, Gianchandani R, Smiley D, control and satisfaction with standard and fi 2017;21:197 et al. Safety and ef cacy of sitagliptin therapy for patient-controlled consistent carbohydrate meal ’ 32. Maynard G, Wesorick DH, O Malley C, the inpatient management of general medicine plans in hospitalised patients with diabetes. Inzucchi SE; Society of Hospital Medicine Glyce- and surgery patients with type 2 diabetes: a pilot, Qual Saf Health Care 2010;19:355–359 mic Control Task Force. Subcutaneous insulin randomized, controlled study. Diabetes Care 60. Ojo O, Brooke J. Evaluation of the role of – order sets and protocols: effective design and 2013;36:3430 3435 enteral nutrition in managing patients with di- implementation strategies. J Hosp Med 2008;3 47. Pasquel FJ, Gianchandani R, Rubin DJ, et al. abetes: a systematic review. Nutrients 2014;6: (Suppl.):29–41 Efficacy of sitagliptin for the hospital manage- 5142–5152 33. U.S. Food and Drug Administration. FDA ment of general medicine and surgery patients 61. Mabrey ME, Setji TL. Patient self-management Drug Safety Communication: FDA requires label with type 2 diabetes (Sita-Hospital): a multi- of diabetes care in the inpatient setting: pro. J warnings to prohibit sharing of multi-dose di- centre, prospective, open-label, non-inferiority Diabetes Sci Technol 2015;9:1152–1154 abetes pen devices among patients [Internet], randomised trial. Lancet Diabetes Endocrinol 62. Shah AD, Rushakoff RJ. Patient self- 2015. Available from https://www.fda.gov/ 2017;5:125–133 management of diabetes care in the inpatient Drugs/DrugSafety/ucm435271.htm. Accessed 24 48. Garg R, Schuman B, Hurwitz S, Metzger C, setting: con. J Diabetes Sci Technol 2015;9:1155– September 2018 Bhandari S. Safety and efficacy of saxagliptin for 1157 34. Brown KE, Hertig JB. Determining current glycemic control in non-critically ill hospitalized 63. Houlden RL, Moore S. In-hospital manage- insulin pen use practices and errors in the inpatients. BMJ Open Diabetes Res Care 2017;5: ment of adults using insulin pump therapy. Can J patient setting. Jt Comm J Qual Patient Saf e000394 Diabetes 2014;38:126–133 2016;42:568–575 49. U.S. Food and Drug Administration. FDA 64. Umpierrez GE. Basal versus sliding-scale 35. HorneJ,BondR,SarangarmP.Comparisonof Drug Safety Communication: FDA adds warnings inpatient glycemic control with insulin vials about heart failure risk to labels of type 2 di- regular insulin in hospitalized patients with hy- versus insulin pens in general medicine patients. abetes medicines containing saxagliptin and perglycemia during enteral nutrition therapy. – Hosp Pharm 2015;50:514–521 alogliptin [Internet], 2016. Available from http:// Diabetes Care 2009;32:751 753 36. Veronesi G, Poerio CS, Braus A, et al. Deter- www.fda.gov/drugs/drugsafety/ucm486096.htm. 65. Pichardo-Lowden AR, Fan CY, Gabbay RA. minants of nurse satisfaction using insulin pen Accessed 24 September 2018 Management of hyperglycemia in the non- devices with safety needles: an exploratory 50. Mendez CE, Umpierrez GE. Pharmacother- intensive care patient: featuring subcutaneous – factor analysis. Clin Diabetes Endocrinol 2015; apy for hyperglycemia in noncritically ill hospi- insulin protocols. Endocr Pract 2011;17:249 260 1:15 talized patients. Diabetes Spectr 2014;27: 66. Corsino L, Dhatariya K, Umpierrez G. Man- 37. Bueno E, Benitez A, Rufinelli JV, et al. Basal- 180–188 agement of diabetes and hyperglycemia in bolus regimen with insulin analogues versus 51. Umpierrez GE, Korytkowski M. Is incretin- hospitalized patients. In Endotext [Internet]. human insulin in medical patients with type 2 based therapy ready for the care of hospitalized Available from http://www.ncbi.nlm.nih.gov/ diabetes: a randomized controlled trial in Latin patientswithtype2diabetes?Insulintherapyhas books/NBK279093/. Accessed 24 September 2018 America. Endocr Pract 2015;21:807–813 proven itself and is considered the mainstay of 67. Kwon S, Hermayer KL, Hermayer K. 38. Umpierrez GE, Smiley D, Jacobs S, et al. treatment. Diabetes Care 2013;36:2112–2117 Glucocorticoid-induced hyperglycemia. Am J Randomized study of basal-bolus insulin therapy 52. U.S. Food and Drug Administration. FDA Med Sci 2013;345:274–277 in the inpatient management of patients with Drug Safety Communication: FDA revises labels 68. BradyV, ThosaniS,Zhou S,BassettR, Busaidy type 2 diabetes undergoing general surgery of SGLT2 inhibitors for diabetes to include warn- NL, Lavis V. Safe and effective dosing of basal- (RABBIT 2 surgery). Diabetes Care 2011;34: ings about too much acid in the blood and bolus insulin in patients receiving high-dose 256–261 serious urinary tract infections [Internet], 2015. steroids for hyper-cyclophosphamide, doxorubi- 39. Giugliano D, Chiodini P, Maiorino MI, Available from http://www.fda.gov/Drugs/ cin, vincristine, and dexamethasone chemother- Bellastella G, Esposito K. Intensification of insulin DrugSafety/ucm475463.htm. Accessed 24 Sep- apy. Diabetes Technol Ther 2014;16:874–879 therapy with basal-bolus or premixed insulin tember 2018 69. Smiley DD, Umpierrez GE. Perioperative regimens in type 2 diabetes: a systematic review 53. U.S. Food and Drug Administration. FDA glucose control in the diabetic or nondiabetic and meta-analysis of randomized controlled strengthens kidney warnings for diabetes medi- patient. South Med J 2006;99:580–589 trials. Endocrine 2016;51:417–428 cines canagliflozin (Invokana, Invokamet) and da- 70. Buchleitner AM, Mart´ınez-Alonso M, 40. Bellido V, Suarez L, Rodriguez MG, et al. pagliflozin (Farxiga, Xigduo XR) [Internet], 2016. Hernandez´ M, Sola` I, Mauricio D. Perioperative Comparison of basal-bolus and premixed insulin Available from http://www.fda.gov/drugs/ glycaemic control for diabetic patients under- regimens in hospitalized patients with type 2 drugsafety/drugsafetypodcasts/ucm507785.htm. going surgery. Cochrane Database Syst Rev 2012; diabetes. Diabetes Care 2015;38:2211–2216 Accessed 24 September 2018 9:CD007315 care.diabetesjournals.org Diabetes Care in the Hospital S181

71. Demma LJ, Carlson KT, Duggan EW, Morrow diabetic ketoacidosis. Cochrane Database Syst patients with type 2 diabetes in long-term care JG 3rd, Umpierrez G. Effect of basal insulin Rev 2016;1:CD011281 facilities. BMJ Open Diabetes Res Care 2015;3: dosage on blood glucose concentration in am- 78. Kitabchi AE, Umpierrez GE, Fisher JN, e000104 bulatory surgery patients with type 2 diabetes. Murphy MB, Stentz FB. Thirty years of personal 85. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, – J Clin Anesth 2017;36:184 188 experience in hyperglycemic crises: diabetic ke- Steinman MA. Potential overtreatment of dia- 72. Umpierrez GE, Smiley D, Hermayer K, et al. toacidosis and hyperglycemic hyperosmolar state. betes mellitus in older adults with tight glycemic Randomized study comparing a basal-bolus J Clin Endocrinol Metab 2008;93:1541–1552 control. JAMA Intern Med 2015;175:356–362 with a basal plus correction insulin regimen 79. UmpierrezGE,LatifK,StoeverJ,etal.Efﬁcacy 86. Rubin DJ. Hospital readmission of patients for the hospital management of medical and of subcutaneous insulin lispro versus continuous with diabetes. Curr Diab Rep 2015;15:17 surgical patients with type 2 diabetes: Basal Plus intravenous regular insulin for the treatment of 87. Jiang HJ, Stryer D, Friedman B, Andrews R. Trial. Diabetes Care 2013;36:2169–2174 patients with diabetic ketoacidosis. Am J Med 73. Kitabchi AE, Umpierrez GE, Miles JM, Fisher 2004;117:291–296 Multiple hospitalizations for patients with di- – JN. Hyperglycemic crises in adult patients with 80. Duhon B, Attridge RL, Franco-Martinez AC, abetes. Diabetes Care 2003;26:1421 1426 ’ diabetes. Diabetes Care 2009;32:1335–1343 Maxwell PR, Hughes DW. Intravenous sodium 88. Maldonado MR, D Amico S, Rodriguez L, Iyer 74. Vellanki P, Umpierrez GE. Diabetic ketoaci- bicarbonate therapy in severely acidotic diabetic D, Balasubramanyam A. Improved outcomes in dosis: a common debut of diabetes among ketoacidosis. Ann Pharmacother 2013;47:970– indigent patients with ketosis-prone diabetes: african americans with type 2 diabetes. Endocr 975 effect of a dedicated diabetes treatment unit. Pract 2017;23:971–978 81. Shepperd S, Lannin NA, Clemson LM, Endocr Pract 2003;9:26–32 75. Harrison VS, Rustico S, Palladino AA, Ferrara McCluskey A, Cameron ID, Barras SL. Discharge 89. Wu EQ, Zhou S, Yu A, et al. Outcomes C, Hawkes CP. Glargine co-administration with planning from hospital to home. Cochrane Da- associated with post-discharge insulin continuity intravenous insulin in pediatric diabetic keto- tabase Syst Rev 1996;1:CD000313 in US patients with type 2 diabetes mellitus acidosis is safe and facilitates transition to a 82. Agency for Healthcare Research and Quality. initiating insulin in the hospital. Hosp Pract subcutaneous regimen. Pediatr Diabetes 2017; Readmission and adverse events after hospital (1995) 2012;40:40–48 18:742–748 discharge [Internet], 2018. Available from http:// 90. Hirschman KB, Bixby MB. Transitions in 76. Hsia E, Seggelke S, Gibbs J, et al. Subcuta- psnet.ahrq.gov/primer.aspx?primerID511. Ac- care from the hospital to home for patients neous administration of glargine to diabetic cessed 24 September 2018 – patients receiving insulin infusion prevents re- 83. Bansal N, Dhaliwal R, Weinstock RS. Man- with diabetes. Diabetes Spectr 2014;27:192 bound hyperglycemia. J Clin Endocrinol Metab agement of diabetes in the elderly. Med Clin 195 2012;97:3132–3137 North Am 2015;99:351–377 91. TuttleKR,BakrisGL,BilousRW,etal.Diabetic 77. Andrade-CastellanosCA,Colunga-LozanoLE, 84. Pasquel FJ, Powell W, Peng L, et al. A kidney disease: a report from an ADA Consen- Delgado-Figueroa N, Gonzalez-Padilla DA. Sub- randomized controlled trial comparing treatment sus Conference. Diabetes Care 2014;37:2864– cutaneous rapid-acting insulin analogues for with oral agents and basal insulin in elderly 2883 S182 Diabetes Care Volume 42, Supplement 1, January 2019

16. Diabetes Advocacy: Standards American Diabetes Association of Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S182–S183 | https://doi.org/10.2337/dc19-S016

The American Diabetes Association (ADA) “Standards of Medical Care in Di- abetes” includes ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction. Readers whowishtocommentontheStandardsofCareareinvitedtodosoat professional.diabetes.org/SOC. 16. DIABETES ADVOCACY Managing the daily health demands of diabetes can be challenging. People living with diabetes should not have to face additional discrimination due to diabetes. By advocating for the rights of those with diabetes at all levels, the American Diabetes Association (ADA) 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. The ADA is also focused on making sure cost is not a barrier to successful diabetes management. One tactic for achieving these goals has been to implement the ADA’s Standards of Care through advocacy-oriented position statements. The ADA publishes evidence-based, peer-reviewed statements on topics such as diabetes and employment, diabetes and driving, insulin access and affordability, and diabetes management in certain settings such as schools, child care programs, and correctional institutions. In addition to the ADA’s clinical documents, these advocacy statements are important tools in educating schools, employers, licensing agencies, policy makers, and others about the intersection of diabetes medicine and the law and for providing scientiﬁcally supported policy recommendations.

ADVOCACY STATEMENTS Partial list, with the most recent publications appearing first Insulin Access and Affordability Working Group: Conclusions and Suggested citation: American Diabetes Associa- Recommendations (1) tion. 16. Diabetes advocacy: Standards of Med- (first publication 2018) ical Care in Diabetesd2019. Diabetes Care The ADA’s Insulin Access and Affordability Working Group compiled public 2019;42(Suppl. 1):S182–S183 information and convened a series of meetings with stakeholders throughout © 2018 by the American Diabetes Association. the insulin supply chain to learn how each entity affects the cost of insulin Readers may use this article as long as the work for the consumer. Their conclusions and recommendations are published in is properly cited, the use is educational and not for profit, and the work is not altered. More infor- the ADA statement “Insulin Access and Affordability Working Group: Conclusions mation is available at http://www.diabetesjournals and Recommendations” (https://doi.org/10.2337/dci18-0019). .org/content/license. care.diabetesjournals.org S183

Diabetes Care in the School Setting (2) with diabetes should be individually as- that meets national standards. Because (first publication 1998; latest revision 2015) sessed by a health care professional it is estimated that nearly 80,000 A sizable portion of a child’s day is knowledgeable in diabetes if license inmates have diabetes, correctional in- spent in school, so close communication restrictions are being considered, and stitutions should have written policies with and cooperation of school per- patients should be counseled about and procedures for the management of sonnel are essential to optimize dia- detecting and avoiding hypoglycemia diabetes and for the training of medical betes management, safety, and academic while driving. See the ADA position and correctional staff in diabetes care opportunities. See the ADA position state- statement “Diabetes and Driving” (https:// practices. See the ADA position statement “Diabetes Care in the School Setting” doi.org/10.2337/dc14-S097). ment “Diabetes Management in Correc- (https://doi.org/10.2337/dc15-1418). Editor’s note: Federal commercial tional Institutions” (https://doi.org/ Care of Young Children With Diabetes in driving rules for individuals with insulin- 10.2337/dc14-S104). the Child Care Setting (3) treated diabetes changed on 19 Novem- ber 2018. These changes will be reflected (first publication 2014) References in an updated ADA statement. Very young children (aged ,6 years) 1.CefaluWT,DawesDE,GavlakG,etal.; with diabetes have legal protections and Diabetes and Employment (5) Insulin Access and Affordability Working Group. Insulin Access and Affordability Work- can be safely cared for by child care (first publication 1984; latest revision 2009) ing Group: conclusions and recommendations providers with appropriate training, ac- Any person with diabetes, whether [published correction appears in Diabetes Care cess to resources, and a system of com- insulin treated or noninsulin treated, 2018;41:1831]. Diabetes Care 2018;41:1299– munication with parents and the child’s should be eligible for any employment 1311 diabetes provider. See the ADA position for which he or she is otherwise qualified. 2. Jackson CC, Albanese-O’Neill A, Butler KL, statement “Care of Young Children With Employment decisions should never be et al. Diabetes care in the school setting: ” a position statement of the American Diabe- Diabetes in the Child Care Setting (https:// based on generalizations or stereotypes tes Association. Diabetes Care 2015;38:1958– doi.org/10.2337/dc14-1676). regarding the effects of diabetes. When 1963 fi 3. Siminerio LM, Albanese-O’Neill A, Chiang JL, Diabetes and Driving (4) questions arise about the medical tness of a person with diabetes for a particular et al. Care of young children with diabetes in the (first publication 2012) job, a health care professional with exper- child care setting: a position statement of the People with diabetes who wish to oper- American Diabetes Association. Diabetes Care tise in treating diabetes should perform an ate motor vehicles are subject to a great 2014;37:2834–2842 individualized assessment. See the ADA variety of licensing requirements applied by 4. American Diabetes Association. Diabetes and position statement “Diabetes and Employ- driving. Diabetes Care 2014;37(Suppl. 1):S97– both state and federal jurisdictions, which ment”(https://doi.org/10.2337/dc14-S112). S103 mayleadtolossofemploymentorsignif- 5. American Diabetes Association. Diabetes and icant restrictions on a person’slicense. Diabetes Management in Correctional employment. Diabetes Care 2014;37(Suppl. 1): Presence of a medical condition that can Institutions (6) S112–S117 6. American Diabetes Association. Diabe- fi fi lead to signi cantly impaired consciousness ( rst publication 1989; latest revision 2008) tes management in correctional institutions. or cognition may lead to drivers being People with diabetes in correc- Diabetes Care 2014;37(Suppl. 1):S104– evaluated for their fitness to drive. People tional facilities should receive care S111 S184 Diabetes Care Volume 42, Supplement 1, January 2019

Disclosures: Standards of Medical Care in Diabetesd2019

Diabetes Care 2019;42(Suppl. 1):S184–S186 | https://doi.org/10.2337/dc19-SDIS01

Committee members disclosed the following ﬁnancial or other conﬂicts of interest covering the period 12 months before December 2018 Other research Speakers’ bureau/ Ownership Consultant/ Member Employment Research grant support honoraria interest advisory board Other Professional Practice Committee

Joshua J. Washington State None None Diabetes Spectrum None None None Neumiller, University (Editorial) PharmD, CDE, FASCP, Chair

DISCLOSURES Christopher P. Brigham and Amgen*, Boehringer None None None Alnylam, Amarin, None Cannon, MD Women’s Hospital Ingelheim*, Bristol- Amgen, Myers Squibb*, Daiichi Boehringer Sankyo*, Janssen*, Ingelheim*, Merck* Bristol-Myers Squibb, Eisai, Janssen, Kowa, Merck, Pﬁzer, Regeneron, Sanoﬁ* Jill Crandall, MD Albert Einstein None None Data and Safety None None None College of Monitoring Board Medicine for National Institutes of Health–sponsored studies David D’Alessio, Duke University, Merck, Eli Lilly, vTv None Diabetes Care, None Eli Lilly Endocrine MD Division of Therapeutics Diabetes Society Endocrinology (Editorial) Ian H. de Boer, University of None Medtronic, None None Ironwood None MD, MS Washington Abbott Mary de Groot, Indiana University None None Diabetes Care None Johnson & Johnson None PhD School of Medicine (Editorial) Diabetes Institute, Diabetes Eli Lilly Translational Research Center Judith Fradkin, National Institute None None None None None None MD of Diabetes and Digestive and Kidney Diseases (NIDDK) Kathryn Evans Duke University None None None None Amgen None Kreider, DNP, Medical Center APRN, FNP- BC, BC-ADM care.diabetesjournals.org Disclosures S185

Other research Speakers’ bureau/ Ownership Consultant/ Member Employment Research grant support honoraria interest advisory board Other David Maahs, Stanford National Institutes of None None None Abbott, Eli Lilly, Secretary- MD, PhD University, School Health, JDRF, National Helmsley General of the of Medicine Science Foundation, Charitable Trust, International Helmsley Charitable Insulet, Sanofi Society for Trust, Medtronic#, Pediatric and Dexcom#, Insulet#, Adolescent Bigfoot Biomedical#, Diabetes Tandem#, Roche# Nisa Maruthur, Johns Hopkins None None None None None None MD, MHS University Medha N. Beth Israel Sanofi, Dexcom None None None Sanofi, Eli Lilly None Munshi, MD Deaconess Medical Center, Harvard Medical School Maria Jose Texas Children’s Medtronic, Caladrius None None None None None Redondo, Hospital–Baylor MD, PhD, College of MPH Medicine Guillermo E. Emory University Merck#, Sanofi#, Novo None None None Sanofi, Janssen BMJ Open Umpierrez, Nordisk#, Insulcloud# Diabetes MD, CDE, Research & FACE, FACP Care Editor in Chief Jennifer University of None None None None Epic Endocrine None Wyckoff, Michigan Steering MD Committee ADA Nutrition Consensus Report Writing GroupdLiaison

Melinda Maryniuk & None None None None None None Maryniuk, Associates MEd, RDN, Diabetes and CDE Nutrition Consultants American College of CardiologydDesignated Representative (Section 10)

Sandeep Das, University of Texas None None Circulation None None None MD, MPH, Southwestern (Associate Editor) FACC Medical Center Mikhail University of AstraZeneca*, None None None AstraZeneca*, None Kosiborod, Missouri-Kansas Boehringer Sanoﬁ*, MD, FACC City School of Ingelheim* GlaxoSmithKline, Medicine Amgen*, Boehringer Ingelheim*, Novo Nordisk*, Merck (Diabetes)*, Eisai*, Glytec, Janssen*, Intarcia, Novartis, Bayer American Diabetes Association Staff

William T. American Diabetes None None None None None None Cefalu, MD Association Erika Gebel American Diabetes None None None None None None Berg, PhD Association Mindy Saraco, American Diabetes None None None None None None MHA Association S186 Disclosures Diabetes Care Volume 42, Supplement 1, January 2019

Other research Speakers’ bureau/ Ownership Consultant/ Member Employment Research grant support honoraria interest advisory board Other Matthew P. American Diabetes None None None None None None Petersen Association Sacha Uelmen, American Diabetes None None None None None None RDN, CDE Association Shamera American Diabetes None None None None None None Robinson, Association MPH, RDN *$$10,000 per year from company to individual; #grant or contract is to university or other employer. Diabetes Care Volume 42, Supplement 1, January 2019 S187

Index

A1C, S14–S15, S61–S63. see alsoglycemic targets amylin mimetics, S83, S96 basal insulin analogs, S97–S99 advantages of, S15 angiotensin receptor blockers (ARBs) bedside blood glucose monitoring, S175 age and, S15 children and adolescents, S153, behavioral therapy, S82–S83 cardiovascular disease and, S64, S65 S154 b-blockers, S114 in children and adolescents, S20, chronic kidney disease, S128–S129 beverage consumption, S5 S62, S151, S156 hypertension, S106–S108 biguanides, S96 continuous glucose monitoring pregnancy, S169 bile acid sequestrants, S96 reduction of, S76 retinopathy, S131 blood glucose meter accuracy, S74 discharge planning, S178–S179 anorexia nervosa, S144, S145 blood pressure control. see hypertension ethnic variability in, S15, S62 anticholinergics, S83 blood pressure targets, S104 glucose assessment, S62–S63 anticonvulsants, S83 BMI, ethnicity and, S17, S20 goals, S63–S64 antidepressants, S83 board certified-advanced diabetes management goals, setting/modifying, S64–S66 antihistamines, S83 (BC-ADM), S47 hemoglobinopathies, S14, S15 antihyperglycemics bromocriptine, S96 HIV and, S41 cardiovascular disease, S115–S119 limitations of, S62 heart failure, S118 microvascular complications and, hospital care, S175–S176 canagliflozin, S96, S98, S115–S116, S128 S63–S65 obesity management, S83 cancer evaluation, S39 in older adults, S141, S142 type 2 diabetes, S92, S93 CANVAS-Renal (CANVAS-R) trial, S115–S118 other conditions affecting, S15 antihypertensives CANVAS trial, S115–S119, S127, S128 performance of, S14–S15 cardiovascular disease, S104, S106– carbohydrates, S49, S50 physical activity benefits, S52 S108 cardiovascular disease, S103–S119 prediabetes, S17 chronic kidney disease, S128 A1C and, S64, S65 pregnancy values, S14, S15, S166, S167 pregnancy, S169 antihyperglycemics, S115–S119 race/ethnicity, S15 antioxidant supplementation, S51 antiplatelet agents, S113–S114 recommendations, S14, S61, S63 antiplatelet agents, S113–S114 atherosclerotic, defined, S103 testing frequency, S61–S62 antipsychotics, S83 atherosclerotic, pharmacology in acarbose, S96 antiretroviral (ARV) therapies, S41 type 2, S92, S98 ACCORD BP trial, S104–S106 anti-VEGF, S129–S131 cardiac testing, S114–S115 ACCORD MIND trial, S140 anxiety disorders evaluation, S42, S55 children and adolescents, S153– ACCORD study, S40, S64, S65, S67, S127 ARRIVE trial, S113 S155, S159 ACE inhibitors ASCEND trial, S113, S114 chronic kidney disease and, S128– children and adolescents, S153, Asians Americans S129 S154 BMI cut point, S17, S20 fats (dietary) and, S51 – chronic kidney disease, S128 S129 idiopathic type 1 diabetes in, S16 heart failure, S103, S114, S118–S119 – hypertension, S106 S108 metabolic surgery, S85, S86 hypertension, S104–S113 pregnancy, S169 prediabetes/type 2 criteria, S18 lifestyle interventions, S115 retinopathy, S131 risk-based screening, S18, S19 obesity management and, S82 acute kidney injury, S126 Aspart, S97 pharmacology, S115–S119 ADA evidence-grading system, S2 Aspart 70/30, S97 pharmacology outcomes, S98 ADAG study, S62, S66 ASPIRE study, S76 physical activity benefits, S52 ADA statements, S1 aspirin prevention of, S31 adolescents. see children and adolescents cardiovascular disease and, S113– primary prevention/aspirin, S113– ADVANCE BP trial, S105 S114 S114 ADVANCE study, S64, S65, S67 preeclampsia, S167–S169 primary prevention/statins, S110 advocacy position statements, S6, S182–S183 resistance, S114 recommendations, S114 aerobic exercise, S52 retinopathy and, S129 revisions summary, S5 Affordable Care Act, S9, S160 ASPREE trial, S113 risk assessment, S36, S103–S104 African Americans assisted living facilities, S144, S145 risk factors, S17, S20, S66 A1C as predictive in, S17 atorvastatin, S111 screening, S114, S115 A1C variability in, S15, S52, S62 autoimmune diseases, S39, S152 secondary prevention/statins, S111 BMI cut point, S20 automated insulin delivery, S77 statins, S109–S113 exercise targets in, S52 autonomic neuropathy stroke. see stroke food insecurity in, S10 cardiac, S131, S132 treatment, S114 hemoglobinopathies in, S15 diagnosis, S132 care delivery systems hypoglycemia in, S67 genitourinary, S132 Affordable Care Act, S9, S160 idiopathic type 1 diabetes in, S16 glycemic control, S132 background, S8 risk-based screening, S18 physical activity and, S53 care team, S8 agave syrup, S51 pre-exercise evaluation, S52–S53 chronic care model, S8–S9, S34 age, S15, S20 prevention, S131 social context in, S9–S10 INDEX a-glucosidase inhibitors, S31, S96 screening, S131 system-level improvement strategies, AIM-HIGH trial, S112 treatment, S131, S132 S8 albiglutide, S116 telemedicine, S4, S5, S8–S9, S31, alcohol, S49, S51 S129 alogliptin, S96, S117, S118, S176 bariatric surgery referrals, S55 carotene, S51 American Indians, S18 BARI 2D trial, S132 Caucasians S188 Index Diabetes Care Volume 42, Supplement 1, January 2019

A1C/mean glucose levels in, S52 children and adolescents, S154, Da Qing Diabetes Prevention Study, S30 BMI cut points in, S20 S158–S159 DASH diet, S48, S109 exercise levels in, S52 complications of, S126 degludec, S97 hemoglobinopathies in, S15 diagnosis of, S125 dental care, S20, S41 celiac disease, S152–S153 eGFR assessment, S125 depression evaluation, S42, S55 certified diabetes educator (CDE), S47 epidemiology, S125 detemir, S97 CGM. see continuous glucose monitoring (CGM) glucose-lowering medications, renal effects, Diabetes Control and Complications Trial (DCCT) Charcot foot, S134 S127 trial, S65, S66, S67, S72, S91, S127, S140, S152 child care/school, S150 glycemic targets, S127 diabetes distress, S54–S55 children and adolescents, S148–S160 hypertension and, S124, S128–S129 Diabetes Prevention Program (DPP), S17, S29, A1C targets in, S151, S156 nutrition therapy, S50, S53, S124, S30, S31 A1C validity in, S20, S62 S127 Diabetes Prevention Program Outcomes Study autoimmune conditions in, S152 pharmacology, S92, S97, S125, (DPPOS), S30, S51, S96 cardiac function testing, S159 S127–S128 Diabetes Prevention Recognition Program cardiovascular risk factor manage- recommendations, S124–S125 (DPRP), S31 ment, S153–S155 referrals, S129 diabetes self-management education and support celiac disease, S152–S153 renal replacement treatment, S125, (DSMES), S9, S10 complications prevention/management, S129 benefits of, S47 S158–S160 screening, S124 children and adolescents, S149 continuous glucose monitoring in, staging of, S125–S126 older adults, S141 S149, S151 surveillance, S126–S127 principles of, S46–S47 diabetic ketoacidosis in, S149, S156, treatment, S124–S129 psychosocial issues and, S54 S157 CKD. see chronic kidney disease recommendations, S32 DSMES, S149 classification, S4, S13–S14 reimbursement, S47 dyslipidemia, S153–S154, S159 clopidogrel, S113, S114 social determinants of health and, eating disorders in, S151 closed-loop pump system, S91 S9, S10 glycemic control/type 1, S151– clozapine, S83 diabetic ketoacidosis S152 cognitive impairment/dementia in children and adolescents, S149, glycemic control/type 2, S156–S157 evaluation, S39–S40 S156, S157 hypertension, S153 older adults, S140 epidemiology, S13–S14 hypoglycemia in, S67 risk factors, S67 glycemic targets and, S68 immune-mediated diabetes, S16 statins and, S113 hospital care, S178 immunizations, S36 colesevelam, S96 nutrition therapy, S48, S50 insulin pumps, S72–S73 community health workers, S10 pregnancy, S169 lifestyle management, S156 community screening, S20 as pump complication, S72, S73 metabolic surgery, S158 community support, S10 referrals, S55 monogenic diabetes in, S25 comorbidities, S4, S36, S39–S43 risk factors, S16 nephropathy, S154 concentrated human regular insulin, S97, S99 in type 2 diabetes, S18 neuropathy, S155, S158 consensus reports, S1–S2 diabetic kidney disease. see chronic kidney disease new-onset management algorithm, contact dermatitis, S77 diabetic macular edema, S129, S131 S157 continuous glucose monitoring (CGM), S74–S77 diabetic retinopathy. see retinopathy nutrition therapy, S149, S156 accuracy, S74, S75 Diabetic Retinopathy Study (DRS), S130–S131 obesity management, S150, S155, A1C measurement with, S15 diagnosis S156 A1C reduction, S76 A1C. see A1C pediatric to adult care transition, A1C testing and, S62 CFRD, S23 S160 basal insulin/oral agents, S73–S74 community screening, S20 pharmacology, S156–S158 children and adolescents, S149, confirming, S15–S16 physical activity/exercise, S51, S52, S149– S151 criteria, S15 S150, S156 as complementary method, S73 fasting plasma glucose (FPG), S14, preconception counseling, S150, flash, S76–S77 S15, S20, S23 S151 function, applications of, S75 IFG, S17 psychosocial issues, S150–S151, glucose assessment, S62–S63 MODY, S13, S25 S159–S160 glycemic control impacts, S75 monogenic diabetes syndromes, real-time CGM in, S75 hospital care, S175 S13, S24–S25 retinopathy, S154–S155, S158–S159 hypoglycemia impacts, S67, S75, S76 neonatal diabetes, S24, S25 revisions summary, S6 intensive insulin regimens, S73 one-step strategy, GDM, S21–S22 school/child care, S150 optimization, S73 oral glucose tolerance test (OGTT), shared decision making, S150–S151 pregnancy, S169 S14, S20, S22 smoking, S154 real-time, S75–S76 posttransplantation diabetes thyroid disease, S152 recommendations, S74–S76 mellitus, S23–S24 type 2 diabetes in, S17, S18, S155– continuous subcutaneous insulin injection (CSII), revisions summary, S4 S160 S72–S73 testing interval, S20 type 1 diabetes in, S13–S14, S148– contraception, S170 2-h plasma glucose (2-h PG), S14, S155 counterfeit strips, S74 S15 chronic care model, S8–S9, S34 CREDENCE trial, S128 two-step strategy, GDM, S21, chronic kidney disease, S124–S129 CVD. see cardiovascular disease S22 acute kidney injury, S126 cystic fibrosis, S13 type 1 diabetes, S15, S16–S17 albuminuria screening, S125 cystic fibrosis–related diabetes, S23 type 2 diabetes, S17–S20 albuminuria treatment, S128 DIAMOND study, S76 antihypertensives, S128 Dietary Reference Intakes (DRI), cardiovascular disease and, S128– DAMOCLES trial, S135 S168 S129 dapagliflozin, S96, S128 discharge planning, S178–S179 care.diabetesjournals.org Index S189

disordered eating behavior evaluation, gabapentin, S5, S83 continuous glucose monitoring, S42–S43 gastrointestinal neuropathy, S132 S175 DKA. see diabetic ketoacidosis gastroparesis, S133 delivery standards, S173–S174 dopamine-2 agonists, S96 genitourinary autonomic neuropathy, S132 diabetes care providers in, S174 DPP-4 inhibitors German study, S16 diabetic ketoacidosis, S178 in combination therapy, S93–S94, gestational diabetes mellitus, S6, S13, S20–S23, discharge planning, S178–S179 S97–S98 S76, S167–S170 enteral/parenteral feedings, S177 costs, S96 GI surgery. see metabolic surgery glucocorticoid therapy, S177 heart failure, S118 glargine, glargine biosimilar, S97 glucose abnormalities definitions, hospital care, S176 glimepiride, S96 S174 indications, considerations, S93 glipizide, S96 glycemic targets, S174–S175 older patients, S143–S145 GLP-1 receptor agonists hyperglycemia management, S24 in renal transplant recipients, S24 cardiovascular disease outcomes, hyperosmolar hyperglycemic state, dulaglutide, S96 S65, S98, S114, S116 S178 duloxetine, S132 in CKD, S127, S128 hypoglycemia, S176–S177 dumping syndrome, S86 in combination therapy, S93–S94, insulin, IV to subcutaneous S97–S99 transition, S176 costs, S95, S97 insulin therapy, S174–S176 e-cigarettes, S5, S6, S53–S54, S154 heart failure, S118–S119 medical nutrition therapy, S177 economic costs of diabetes, S8 hospital care, S176 noninsulin therapies, S176 EDIC study, S64–S67, S127 indications, considerations, S93 perioperative care, S177–S178 – ELIXA trial, S116 S118 obesity management, S85 physician order entry, S174 fl empagli ozin, S96, S98, S115, S116, S119, older patients, S143–S145 quality assurance standards in, S128 stroke and, S116 S174 – EMPA-REG OUTCOME trial, S115, S117 S119, type 1 diabetes, S92 revisions summary, S6 S127, S128 type 2 diabetes prevention/delay, self-monitoring of blood glucose, S146 end-of-life/palliative care, S141, S144, S31 S177 enteral/parenteral feedings, S177 glucagon, S66–S68 stroke, S174 eplerenone, S129 glucocorticoids, S83, S177 type 1 diabetes, S176 erectile dysfunction, S133 glucose oxidase systems, S74 HOT trial, S105 fl ertugli ozin, S96 glulisine, S97 HPS2-THRIVE trial, S112 erythropoietin therapy, S15 gluten-free diets, S152, S153 Human NPH, S97 – ETDRS, S130 S131 glyburide, S96, S167 human regular insulin, S97 fi ethnicity, S15, S20, S62. see also speci c glycemic index/glycemic load, S50 hydralzine, S106 ethnicities glycemic targets, S61–S68. see also A1C hyperbaric oxygen therapy, S134–S135 evolocumab, S111 cardiovascular disease and, S64, S65 hyperglycemia EXAMINE trial, S117, S118 continuous glucose monitoring ARV-associated, S41 Exenatide, Exenatide ER, S96 impacts, S75 defined, S174 exercise. see physical activity evaluation of, S36, S39, S61–S63 evaluation of, S40 – EXSCEL trial, S116 S118 glucose assessment, S62–S63 exercise-induced, S149–S150 eye disease. see diabetic retinopathy hospital care, S174–S175 maternal, S22 ezetimibe, S111, S113 intercurrent illness and, S68 postprandial as predictive, S66 management algorithm, S35 posttransplant, S23 fasting plasma glucose (FPG), S14, S15, S20, S23 moderate vs. tight control, S174– risk factors, S10 fats (dietary), S49–S51 S175 hyperosmolar hyperglycemic state, S178 fenofibrate, S112 nonpregnant adults, S66 hypertension, S104–S113 fibrates, S112 physical activity and, S52 antihypertensives, S104, S106–S108 finerenone, S129 in pregnancy, S166–S167, S169 bedtime dosing, S107 Finland study, S16 preprandial, S67 blood pressure targets, S104 Finnish Diabetes Prevention Study, S30 revisions summary, S5 children and adolescents, S153 flash CGM, S76–S77 G6PD deficiency, S4, S14, S15 chronic kidney disease and, S124, food insecurity, S10 S128–S129 foot care defined, S104 hyperbaric oxygen therapy, S134– HAPO study, S21, S167 hyperkalemia/acute kidney injury, S135 Harmony Outcomes trial, S116 S107–S108 infections, S134 hearing impairment evaluation, S41 lipid management, S109–S113 loss of protective sensation, S131, hemodialysis, S15 meta-analyses of trials, S106 S134 hemoglobinopathies, S14, S15 multiple-drug therapy, S107, S108 neuropathy, S133–S135 hepatitis B vaccine, S36, S38–S39, S127 in older adults, S141 patient education, S134 herbal supplements, S49, S51 pharmacologic interventions, S107– peripheral arterial disease, S133, Hispanics. see Latinos S113 S134 HIV evaluation, S41 in pregnancy, S104, S106 recommendations, S133 homelessness, S10 randomized clinical trials, S104– revisions summary, S5 honey, S51 S106 treatment, S134 hospital care, S173–S179 resistant, S108, S109 ulcers/amputations risk, S133– admission considerations, S173– screening/diagnosis, S104 S134 S174 treatment algorithm, S108 footwear, S134 admission/readmission prevention, treatment goals, S104 FOURIER trial, S111 S179 treatment strategies, S107–S113 fractures, S40–S41 antihyperglycemics, S175–S176 treatment targets individualization, frailty, S141–S142 bedside blood glucose monitoring, S106 FRAX score, S41 S175 hypertriglyceridemia, S112 S190 Index Diabetes Care Volume 42, Supplement 1, January 2019

hypoglycemia, S66–S68 Internet-based DSMES, S47 children and adolescents, S149, S156 A1C testing and, S62 islet transplantation, S92 eating patterns, S48–S50 anxiety disorders and, S42 fats (dietary), S49–S51 – cardiovascular disease and, S65 JDRF CGM trial, S75, S76 gestational diabetes mellitus, S167 continuous glucose monitoring impacts, S168 S75, S76 goals of, S48 definitions, S67 ketoacidosis. see diabetic ketoacidosis herbal supplements, S49, S51 exercise-induced, S53, S149–S150 kidney disease. see chronic kidney disease hospital care, S177 hospital care, S176–S177 Kumamoto Study, S64 macronutrient distribution, S48–S50 insulin therapy and, S91 meal planning, S5, S48, S49 moderate vs. tight glycemic control, S174– labetalol, S106 micronutrients, S49, S51 S175 language, S10, S35–S36 nonnutritive sweeteners, S5, S49, S51 in older adults, S67, S140, S145 laropiprant, S112 protein, S49, S50 postprandial, post-RYGB, S86 Latinos recommendations, S49 predictors of, S176 A1C variability in, S62 sodium, S49, S51 prevention, S68, S176–S177 exercise targets in, S52 weight management, S48–S51 pumps and, S73 food insecurity in, S10 Medicare, S47, S77 recommendations, S66–S67 risk-based screening, S17, S18 medication adherence, S9 risk, evaluation of, S39, S40 LEADER trial, S116–S118, S127, S128 medication reconciliation, S178 risk factors, S10, S64 legacy effect, S66 Mediterranean diet, S30, S40, S48, S50, S51, S109 symptoms of, S67 lifestyle management, S46–S55 meglitinides, S96 treatment of, S67–S68 cardiovascular disease, S115 mental health triggering events, S176 children and adolescents, S156 children and adolescents, S150– hypoglycemia unawareness, S42, S66–S68 cost effectiveness, S31 S151, S159–S160 DSMES, S9, S10, S31–S32, S46–S47, diabetes distress, S54–S55 evaluation of, S41–S42, S54–S55 IADPSG criteria, S22–S23 S54 homelessness, S10 idiopathic type 1 diabetes, S16 gestational diabetes mellitus, S167 illness, serious, S43, S55 IFG, S17 hypertension, S107 issues, post-surgery, S86–S87 immune-mediated diabetes, S16 medical nutrition therapy. see medical referrals, S40, S55 immunizations, S36–S39 nutrition therapy S141–S142 metabolic memory, S66 IMPROVE-IT trial, S111 older adults, – metabolic surgery improvement. see quality of care revisions summary, S4 S5 adverse effects, S86 incretin-based therapies, S143. see also DPP-4 technology-assisted interventions, S31 S29– benefits of, S86 inhibitors; GLP-1 receptor agonists type 2 diabetes prevention/delay, S31 children and adolescents, S158 Indian Diabetes Prevention Programme (IDPP-1), – indications, S86 S31 weight loss, S48 S51 obesity management, S85–S87 influenza vaccine, S36, S38 linagliptin, S96 S109–S113 outcomes, S86 inhaled insulin, S91, S97, S99 lipid management, – recommendations, S85–S86 injection-related anxiety, S42 children and adolescents, S153 S154, S159 – referrals, S55 insulin pumps, S72–S73, S76, S91 combination treatment, S110 S112 metformin insulin resistance, S18 HDL cholesterol, S109, S112, S159 cardiovascular disease, S114, S116– insulin secretagogues, S143. see also sulfonyl- LDL cholesterol, S109, S113, S159 fi S118 ureas lifestyle modi cation, S109 fi children and adolescents, S156–S158 insulin syringes/pens, S71–S72 lipid pro le/panel, S109 – in chronic kidney disease, S127 insulin therapy statins, S109 S113 costs, S96 automated delivery, S77 triglycerides, S109, S112, S159 gestational diabetes mellitus, S167, S168 basal insulin, S98–S99 lipohypertrophy, S91 indications, considerations, S93 carbohydrates and, S49, S50 liraglutide, S85, S95, S97, S98, S116, S128 initial therapy, S92–S97 children and adolescents, S156, S157 Lispro 50/50, S97 older patients, S143 concentrated products, S97, S99 Lispro 75/25, S97 type 1 diabetes, S92 costs, S97–S99 Lispro, Lispro biosimilar, S97 type 2 diabetes, S92 critical care setting, S175 lixisenatide, S97, S116 type 2 diabetes prevention/delay, S31 delivery technology, S71–S73 long-term care facilities, S144, S145 – vitamin B12 deficiency and, S51, S92 gestational diabetes mellitus, S167, Look AHEAD trial, S41, S82 S83 methyldopa, S106 S168 Lorcaserin, Lorcaserin XR, S84 metoclopramide, S133 hospital care, S174–S176 loss of protective sensation (LOPS), S131, micronutrients, S49, S51 hypoglycemia and, S91 S134 microvascular complications, S5, S63–S65, S124– indications, considerations, S93, low-carbohydrate diets, S30, S48, S50 S135. see also specific conditions S96–S97 miglitol, S95 inhaled insulin, S91, S97, S99 macular edema, S129, S131 MiG TOFU study, S168 injection technique, S91 MAO inhibitors, S83 mineralocorticoid receptor antagonists, S109, intravenous to subcutaneous transition, S176 mature minor rule, S150–S151 S129 noncritical care setting, S175–S176 meal planning, S5, S48, S49 MODY, S13, S25 older adults, S142–S143, S145 medical evaluation, S36–S39 monogenic diabetes syndromes, S13, S24–S25 prandial insulin, S99 components of, S36–S38 multiple daily injections (MDI), S72–S73, S76, premixed insulin, S97, S99 immunizations, S36–S39 S91 type 1 diabetes, S90–S92 recommendations, S36 type 2 diabetes, S96, S98–S99 referrals, S40, S55 insurance, S47, S77 medical nutrition therapy, S47–S51. see also naltrexone/bupropion ER, S84 intermediate-acting insulin analogs, nutrition nateglinide, S96 S97 alcohol, S49, S51 neonatal diabetes, S24, S25 intermittently scanned CGM, S76–S77 carbohydrates, S49, S50 nephropathy. see chronic kidney disease care.diabetesjournals.org Index S191

neuropathy, S131–S133. see also autonomic lifestyle management, S141–S142 children and adolescents, S51, S52, neuropathy; peripheral neuropathy long-term care facilities, S144, S145 S149–S150, S156 characterization, S131 neurocognitive function, S140 DPP goals, S30 children and adolescents, S155, S158 frequency/type of, S52 diagnosis, S131–S132 glycemic control and, S52 palliative/end-of-life care, S141, S144, S146 distal symmetric polyneuropathy, pharmacology, S94, S96–S97, S142–S145 hypoglycemia and, S53 S131 physical activity recommendations, S51 kidney disease, S50, S53 erectile dysfunction, S133 S82–S83 recommendations, S139 obesity management, foot care, S133–S135 revisions summary, S6 peripheral neuropathy and (see gastrointestinal, S132 screening, S139–S140 peripheral neuropathy) gastroparesis, S133 – skilled nursing facilities, S144, S145 pre-exercise evaluation, S52 S53 neuropathic pain, S132, S133 stroke in, S139, S142 recommendations, S51 orthostatic hypotension, S133 treatment goals, S140–S142 retinopathy and, S53 pharmacology, S132–S133 treatment simplification/deintensification/ revisions summary, S5 recommendations, S131 S30–S31 deprescribing, S144 type 2 diabetes prevention/delay, screening, S131 one-step strategy, GDM, S21–S22 physician order entry, S174 treatment, S131, S132 oral glucose tolerance test (OGTT), S14, S20, S22 pioglitazone, S96 niacin, S112 orlistat, S84 pneumococcal pneumonia vaccine, S36, S38 NICE-SUGAR study, S174 orthostatic hypotension, S133 point-of-care meters, S175 nifedipine, S106 oxygen in meter accuracy, S74 polycystic ovary syndrome, S159, S167, S168 NODAT, S23 palliative/end-of-life care, S141, S144, S146 population health nonalcoholic fatty liver disease (NAFDL), S4, S6, S8 pancreas transplantation, S92 care delivery systems, S40, S158–S159 pancreatitis, S13, S40, S112, S116 community screening, S20 non-Hispanic whites. see Caucasians fi parenteral/enteral feedings, S177 de ned, S7 nonnutritive sweeteners, S5, S49, S51 – patient-centered care patient-centered care, S7 S8 nonproliferative diabetic retinopathy, S53 collaborative model of, S34–S36 recommendations, S7 NPH/Regular 70/30, S97, S99, S175 S23–S24 pharmacology, S92, S93 posttransplantation diabetes mellitus, nucleoside reverse transcriptase inhibitors population health, S7–S8 pramlintide, S92, S96 (NRTIs), S41 PCSK9 inhibitors, S111, S113 preconception counseling nutrition. see also medical nutrition therapy pediatrics. see children and adolescents children and adolescents, S150, S151 medical evaluation of, S40 periodontal disease screening, S41 contraception, S170 S165–S166 micronutrients, S49 peripheral arterial disease, S133, S134 pregnancy, obesity management, S82–S83 peripheral neuropathy prediabetes S17–S20 revisions summary, S4 characterization, S131 diagnosis, type 2 diabetes prevention/delay, S30 diagnosis, S131–S132 gestational diabetes mellitus, S170 micronutrients/supplements, S51 HIV and, S41 obesity management, S81–S87 pharmacology, S31 physical activity recommendations, S51 antihyperglycemics, S83 physical activity and, S53 serious mental illness and, S43 approved medications, S83–S85 pre-exercise evaluation, S52–S53 type 2 diabetes prevention/delay, S30–S32 assessment, S81–S82 treatment, S131 behavioral therapy, S82–S83 pharmacology, S90–S99. see also specific med- pregabalin, S132 benefits of, S81 ications, medication classes pregnancy, S165–S170 cardiovascular disease and, S82 cardiovascular disease, S115–S119 A1C values in, S14, S15, S166, S167 children and adolescents, S150, S155, S156 cardiovascular disease outcomes, S98 antihypertensives and, S106 concomitant medications, S83 children and adolescents, S156–S158 contraception, S170 hypertension, S107 combination injectable, S99 diabetes, preexisting, S168–S169 lipohypertrophy, S91 combination therapy, S93–S94, diabetes risks in, S165 medical devices, S85 S97–S98 diabetic ketoacidosis, S169 medical nutrition therapy, S48–S51 costs, S96, S98 drugs contraindicated, S106, S169 metabolic surgery, S85–S87 dual therapy, S92 gestational diabetes mellitus, S6, S13, S20– nutrition, S82–S83 gestational diabetes mellitus, S168 S23, S76, S167–S170 pharmacolotherapy, S83–S84 hypertension, S107–S113 glucose monitoring in, S166–S167 physical activity, S82–S83 initial therapy, S92–S97 glycemic targets in, S166–S167, S169 pregnancy, S169 injectables, S5, S97–S98 hypertension in, S104, S106 revisions summary, S5 medication adherence, S9 insulin physiology in, S166 treatment options, S82 medications as risk factor, S20 low-carbohydrate diets, S30, S48, type 2 diabetes, S82–S83 obesity management, S83–S84 S50 weight loss, S48–S51 older adults, S94, S96–S97, S142–S145 medical nutrition therapy, S48, S51 obstructive sleep apnea, S41, S158, S159 patient-centered care, S92, S93 obesity management, S169 olanzapine, S83 patient factors, S5 OGTT values in, S22, S169 older adults, S139–S146 revisions summary, S5 postpartum care, S169–S170 A1C in, S141, S142 type 1 diabetes, S90–S92 preconception care, S166 aspirin and, S113–S114 type 2 diabetes, S92–S98 preconception counseling, S165–S166 complications, reduced functionality, S64, type 2 diabetes prevention/delay, preeclampsia, S106, S167–S169 S141 S31 real-time CGM in, S76 DSMES, S141 phentermine, S84 retinopathy and, S129, S130 frailty in, S141–S142 phentermine/topiramate ER, S84 revisions summary, S6 healthy, good functional status, S141, S142 photocoagulation therapy, S129–S131 premixed insulin products, S97, S99, S175 hypertension in, S141 physical activity, S51–S53 progestins, S83 hypoglycemia in, S67, S140, S145 autonomic neuropathy and (see proliferative diabetic retinopathy, S53 hypoglycemic admissions prevention, S179 autonomic neuropathy) protease inhibitors (PIs), S41 insulin therapy, S142–S143, S145 benefits, S52 protein, S49, S50 S192 Index Diabetes Care Volume 42, Supplement 1, January 2019

psychosocial/emotional disorders evaluation, heart failure, S119 in diabetes prevention, S29, S31 S41–S42, S54–S55 hospital care, S176 insulin pumps, S72–S73, S76, S91 P2Y12 inhibitors, S113, S114 indications, considerations, S93 point-of-care meters, S175 pump. see insulin pump low-carbohydrate eating plans and, S50 TECOS trial, S117, S118 older patients, S145 telemedicine, S4, S5, S8–S9, S31, S129 stroke and, S115–S116 temperature in meter accuracy, S74 quality of care type 1 diabetes, S92 testosterone level evaluation, S41 evaluation of, S9 S173– shoes, S134 thiazolidinediones hospital care delivery standards, – – S174 short-acting insulin analogs, S97 in combination therapy, S93 S94, S97 S98 sickle cell disease, S14 costs, S96 quality assurance standards in, S174 simvastatin, S111 heart failure, S118 scientific evidence-grading system, S2 sitagliptin, S96 indications, considerations, S93 system-level improvement skilled nursing facilities, S144, S145 older patients, S143 strategies, S8 sleep in renal transplant recipients, S24 hypoglycemia prevention, S68, S170 type 2 diabetes prevention/delay, S31 ranibizumab, S129, S130 obstructive sleep apnea, S41, S158, S159 thought disorders, S43 rapid-acting insulin analogs, S97 pattern/duration assessment, S36 thyroid disease, S152 real-time CGM, S75–S76 pregnancy and, S170 tobacco use, S31, S53–S54, S154 referrals, S40, S55, S129 quality effects, S36 TODAY study, S157–S158, S160 repaglinide, S96 smoking, S31, S53–S54, S154 2-h plasma glucose (2-h PG), S14, S15 resistance exercise, S52 social determinants of health, S9–S10 two-step strategy, GDM, S21, S22 retinal photography, S130 sodium, S49, S51 type 1 diabetes retinal screening, S5 sodium consumption, S5 albuminuria in, S127 retinopathy, S129–S131 sotagliflozin, S92 autoimmune conditions in, S152 adjunctive therapy, S131 spironolactone, S106, S129 autoimmune diseases evaluation, S39 anti-VEGF, S129–S131 SPRINT trial, S105–S106 cardiovascular disease and, S65 children and adolescents, S154– SSRIs, S83, S84 celiac disease, S152–S153 S155, S158–S159 statins CGM in, S76 epidemiology, S129–S130 cognition, effects on, S40 in children and adolescents, S13–S14, macular edema, S129, S131 cognitive function and, S113 S148–S155 photocoagulation therapy, S129–S131 in combination treatment, S111, S112 classification, S13–S14 physical activity and, S53 diabetes with, S112–S113 diagnosis, S15, S16–S17 pregnancy and, S129, S130, S166 dosing strategies, S111 eating patterns, S48 proliferative, S130 patients ,40 years, S111–S112 hospital care, S176 recommendations, S129 primary prevention, S110 idiopathic, S16 screening, S129, S130 randomized trials, S110–S113 noninsulin treatments, S91–S92 treatment, S129–S131 recommendations, S109–S110 pathophysiology, S14 type 1 diabetes, S129, S130 risk-based therapy, S110 pharmacology, S90–S92 type 2 diabetes, S129, S130 secondary prevention, S111 physical activity benefits, S52 Risk Estimator Plus, S104 type 1 diabetes, S111–S112 preconception care, S166 risperidone, S83 type 2 diabetes, S110 pregnancy, S168–S169 rosiglitazone, S96 stroke recommendations, S16 rosuvastatin, S111 in children and adolescents, S158 retinopathy, S129, S130 Roux-en-Y gastric bypass, S86 combination therapy and, S112 risk screening, S16–S17 CVD outcomes trials, S115–S117 staging, S14 GLP-1 receptor agonists and, S116 statins, S111–S112 SAVOR-TIMI trial, S117, S118 hospital care, S174 surgical treatment, S92 saxagliptin, S96 hypertension treatment and, S105–S106 thyroid disease, S152 schizophrenia, S43 ischemic, S112, S114 type 2 diabetes school/child care, S150 in older adults, S139, S142 cancer evaluation, S39 scientific evidence-grading system, S2 risk reduction, S65, S105–S106, S111, S113 cardiovascular disease and, S65 scientific reviews, S2 screening, S114 CGM in, S76 SEARCH study, S154 SGLT2 inhibitors and, S115–S116 children and adolescents, S17, S18, self-monitoring of blood glucose (SMBG), structured discharge communication, S178–S179 S155–S160 S73–S74 sulfonylureas chronic kidney disease and, S128 accuracy, S74, S75 in combination therapy, S93–S94, S97–S98 classification, S13–S14 A1C testing and, S62 costs, S96 combination therapy, S93–S94, basal insulin/oral agents, S73–S74 gestational diabetes mellitus, S168 S97–S98 glucose assessment by, S62–S63 indications, considerations, S93 diagnosis, S17–S20, S155–S156 hospital care, S177 older patients, S143 DKA in, S18 intensive insulin regimens, S73 SUSTAIN-6 trial, S116–S118, S127 dyslipidemia in, S112 optimization, S73 sweeteners, S5 insulin therapy, S95, S98–S99 recommendations, S73 Internet-based DSMES, S47 semaglutide, S96, S98, S116 obesity management, S82–S83 SGLT2 inhibitors tai chi, S51 pathophysiology, S18 cardiovascular disease and, S65, tapentadol, S132–S133 pharmacology, S92–S98 S92, S98, S114–S116 TCAs, S83 pharmacology, algorithm, S94 in chronic kidney disease, S127, S128 technology. see also continuous glucose pregnancy, S168–S169 in combination therapy, S93–S94, monitoring (CGM); self-monitoring of blood prevention/delay, S29–S32, S52 S97–S98 glucose (SMBG) retinopathy, S129, S130 contraindications, S176 definitions, S71 risk factors, S18, S20, S30 costs, S96 in diabetes management, S71–S77 screening/testing, S17–S20, S155 care.diabetesjournals.org Index S193

statins, S110 vaccinations, S36–S39 water intake, S5 VADT study, S64, S65 weight loss. see obesity U-500 Human Regular insulin, S97 vitamin B12 deﬁciency, S31, S92 management UK Prospective Diabetes Study (UKPDS), S64, vitamin C, S51 whites. see Caucasians S66, S115 vitamin E, S51 yoga, S51