PracticeUpdate Diabetes Best of 2018

Best of 2018

ISSN 2208-1488

OUR EXPERTS. YOUR PRACTICE.

VOL. 2 • NO. 4 • 2018

TOP STORIES 2018 GLP-1 Receptor Agonists: HARMONY Outcomes and REWIND Canagliflozin and Renal Outcomes in Type 2 Diabetes New ADA-EASD Type 2 Diabetes Treatment Guidelines

JOURNAL SCANS Medicines for Treatment Intensification in Type 2 Diabetes and Type of Insulin in Type 1 and Type 2 Diabetes in Low-Resource Settings

Semaglutide Versus Dulaglutide Once Weekly in Patients With Type 2 Diabetes (SUSTAIN 7): A Randomised, Open-label, Phase 3b Trial

Gut Microbiota Differs in Composition and Functionality Between Children With Type 1 Diabetes, MODY2, and Healthy Control Subjects: A Case-Control Study

EDITOR’S PICKS

PRACTICEUPDATE DIABETES BOARD PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise.

PracticeUpdate® is a registered trademark of Elsevier Inc. All rights reserved.

ABOUT For a complete listing of disclosures for each board member and editorial contributor, please refer to their profile on PracticeUpdate.com PracticeUpdate ’s mission is to help medical professionals navigate the vast array of available literature and focus on the most critical information for their patients and practice. All journal articles selected for PracticeUpdate receive a Take-Home Message designed to quickly summarize the key findings and explain the importance of that research within the specialty area. The most critical articles also receive Expert Commentaries from experts who are handpicked by the PracticeUpdate Editorial Board, providing additional context on that research for the reader. Expert Opinion pieces give special highlights to important topics and Conference Coverage captures relevant takeaways from a vast array of medical meetings throughout the year. PracticeUpdate Diabetes provides coverage of key research from leading international conferences, and a collection of top journal articles and accompanying expert commentaries in a convenient print periodical. These and more are also available online at PracticeUpdate.com PracticeUpdate and PracticeUpdate Diabetes are commercially supported by advertising, sponsorship, and educational grants. Individual access to PracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by commercial sponsors or content contributors. DISCLAIMER PracticeUpdate Diabetes has been developed for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Please consult the full current Product Information before prescribing any medication mentioned in this publication. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. The printing and distribution of this publication has been made possible through paid advertising. The editorial content herein is independently produced by Elsevier with no involvement by the advertiser. It contains content published in accordance with the editorial policies of Elsevier’s PracticeUpdate.com. All content printed in this publication can be found on PracticeUpdate.com. CONTENT Abstracts are available when the publisher grants permission from MEDLINE/ PubMed, a database of the US National Library of Medicine. • NLM data are produced by a US Government agency and include works of the United States Government that are not protected by US copyright law but may be protected by non-US copyright law, as well as abstracts originating from publications that may be protected by US copyright law. • NLM assumes no responsibility or liability associated with use of copyrighted material, including transmitting, reproducing, redistributing, or making commercial use of the data. NLM does not provide legal advice regarding copyright, fair use, or other aspects of intellectual property rights. Persons contemplating any type of transmission or reproduction of copyrighted material such as abstracts are advised to consult legal counsel. SALES Matthew Buttsworth m.buttsworth@elsevier.com Linnea Mitchell-Taverner l.mitchell@elsevier.com PRODUCTION Content was originally published on PracticeUpdate.com Production of this issue was executed by: Editorial Manager A nne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng • Designer Jana Sokolovskaja Cover: Illustration of type 2 diabetes/gettyimages.com PracticeUpdate Diabetes is published by Elsevier Australia ISSN 2208-1488 (Print) ISSN 2208-1496 (Online)

Editor-in-Chief

Silvio Inzucchi MD Professor of Medicine (Endocrinology); Clinical Director, Section of Endocrinology; Director, Yale Diabetes Center; Director, Endocrinology and Metabolism Fellowship, Yale School of Medicine, New Haven, Connecticut

Associate Editors:

Richard E. Pratley MD Senior Investigator, Florida Hospital/Sanford–Burnham Translational Research Institute for Metabolism and Diabetes; Associate Medical Director, Florida Hospital Diabetes Institute, Orlando, Florida

Deborah Wexler MD, MSc Associate Professor of Medicine, Harvard Medical School; Associate Clinical Chief of the Diabetes Unit, Co-Clinical Director, Massachusetts General Hospital Diabetes Center; Associate Program Director for Clinical Research, Internal Medicine Residency Program, Massachusetts General Hospital, Boston, Massachusetts

Editorial Contributors:

Anika Anam MD Clinical Fellow in Endocrinology, Yale School of Medicine/ Yale–New Haven Hospital, New Haven, Connecticut Ana Perdigoto MD, PhD Fellow in Endocrinology, Yale New Haven Hospital, New Haven, Connecticut

Jason Sloane MD Endocrinology Fellow at Massachusetts General Hospital, Boston, Massachusetts

CARDIOMETABOLIC DISEASE AND DIABETES FACULTY Our center of excellence in the treatment of cardiometabolic disease and diabetes leverages technology to create a collaborative and comprehensive way to improve patient care. This unique center has the key advantages of a real world academic center as well as the features and enhancements that only PracticeUpdate and Elsevier can provide to foster an expert-led team approach that helps you stay ahead. Editor-in-Chief Silvio E. Inzucchi MD Professor of Medicine (Endocrinology); Clinical Director, Section of Endocrinology; Director, Yale Diabetes Center; Director, Endocrinology and Metabolism Fellowship, Yale School of Medicine, New Haven, Connecticut

Associate Editors

Richard E. Pratley MD Senior Investigator, Florida Hospital/Sanford–Burnham Translational Research Institute for Metabolism and Diabetes; Associate Medical Director, Florida Hospital Diabetes Institute, Orlando, Florida

Deborah Wexler MD, MSc Associate Professor of Medicine, Harvard Medical School; Associate Clinical Chief of the Diabetes Unit, Co-Clinical Director, Massachusetts General Hospital Diabetes Center; Associate Program Director for Clinical Research, Internal Medicine Residency Program, Massachusetts General Hospital, Boston, Massachusetts

Advisory Board

Kathleen Dungan MD, MPH Assistant Professor of Internal Medicine, Division of Endocrinology, Diabetes & Metabolism, The Ohio State University, Columbus, Ohio

Peter Libby MD Mallinckrodt Professor of Medicine, Harvard Medical School, Boston, Massachusetts

Benjamin Morgan Scirica MD Cardiologist and Director, Innovation, Cardiovascular Division, Brigham and Women's Hospital; Associate Professor of Medicine, Harvard Medical School; Senior Investigator, TIMI Study Group, Boston, Massachusetts

ABN 70 001 002 357 475 Victoria Avenue Chatswood NSW 2067 Australia Locked Bag 7500 Chatswood DC NSW 2067 EMEN121801

CONTENTS 5

CONFERENCE 20 American Diabetes Association 78th Scientific Sessions

TOP STORIES 2018 6 GLP-1 Receptor Agonists: HARMONY Outcomes and REWIND By Kathleen Dungan MD, MPH 7 Canagliflozin and Renal Outcomes in Type 2 Diabetes By Deborah Wexler MD, MSc 8 New ADA-EASD Type 2 Diabetes Treatment Guidelines By Silvio E. Inzucchi MD

20 Clinically Relevant Data on Pioglitazone and CV Risk Reduction Interview with Silvio E. Inzucchi MD 21 SGLT2 Inhibitors in the Management of Type 2 Diabetes Interview with John (Jack) L. Leahy MD by Jason Sloane MD 22 Sequencing Injectable Therapies in Type 2 Diabetes Interview with John (Jack) L. Leahy MD by Jason Sloane MD 22 Enteroendocrine Function of the Intestine By Jason Sloane MD 23 European Association for the Study of Diabetes 54th Annual Meeting By the PracticeUpdate Editorial Team

EXPERT OPINION 16 An Overview of New Diabetes Treatments Interview with John (Jack) L. Leahy MD by Jason Sloane MD 18 My Approach to Triglyceride Levels in EDITOR’S PICKS 10 Treatment in Type 1 and Type 2 Diabetes in Low-Resource Settings Comment by Sylvia Kehlenbrink MD and Meredith Hawkins MD, MS 11 12-Month Weight Loss Similar With Low-Fat and Low-Carbohydrate Diet Comment by Katherine Duffy MS, RD, CD-N, CDE 12 Differences in Gut Microbiota Composition and Functionality Among Children With Type 1 and MODY2 Comment by Li Wen MD, PhD 13 Semaglutide vs Dulaglutide Once Weekly in Patients With Type 2 Diabetes Comment by Kathleen Dungan MD, MPH

23 DISCOVER Study Finds High Complication Rate in Type 2 Diabetes 24 Very Tight Control in Gestational Diabetes Not More Beneficial 25 Consensus Guidelines for Managing Hyperglycemia in Type 2 Diabetes Released by American and European Diabetes Associations 26 Diuretics Linked With Greater Amputation Risk in Type 2 Diabetes 26 PIONEER Shows Safety and Efficacy of Oral Formulation GLP-1 Receptor Agonist

Specific Patient Scenarios Interview with Paul D. Thompson MD by Jennifer N. Caudle DO

VOL. 2 • NO. 4 • 2018

TOP STORIES 2018 6

GLP-1 Receptor Agonists: HARMONY Outcomes and REWIND By Kathleen Dungan MD, MPH

G lucagon-like peptide receptor agonists (GLP-1 RA) have gained a foothold in the management of type 2 diabetes due to their clinical efficacy in improving glycemic control and body weight without causing hypoglycemia. Although cardiovascular (CV) outcomes trials to date have all demonstrated CV safety, they have shown disparate results with respect to CV benefit. 1-5 It has been difficult to sort out whether dif- ferences in outcomes may be related to study design/ population characteristics or to drug-specific attributes. This year, a pair of CV outcomes trials were completed (HARMONY Outcomes 5 and REWIND 6,7 ), shedding fur- ther light on this issue. In the HARMONY Outcomes trial, 9463 patients with type 2 diabetes and known CV disease were randomly assigned to albiglutide once weekly or placebo. After a median follow-up of 1.6 years, it was determined that the primary composite outcome (CV death, myocardial infarction, and stroke) was reduced (HR, 0.78; 95% CI 0.68–0.90; P= .0006 for superiority). 5 This outcome was driven largely by reduction in myocardial infarction, and not in reduc- tion in deaths. Likewise, CV benefit was observed with liraglutide in the LEADER trial, 1 and semaglutide in the SUSTAIN-6 study (superiority was assessed in post hoc analysis). 4 All of these drugs happen to have molecular structures that are based on the GLP-1 molecule. In con- trast, CV outcomes trials for two exendin-based drugs, lixisenatide (ELIXA) 3 and exenatide once weekly (EXS- CEL) 2 did not unequivocally demonstrate CV benefit. Unfortunately, it cannot be assumed that this is related to the exendin molecule as there were crucial differ- ences in study attributes. For example, not only is ELIXA the only CV trial studying a short-acting GLP-1 RA, but ELIXA enrolled a very high-risk cohort of patients who experienced acute coronary syndrome. 3 In the EXSCEL study, there was a 43% drug discontinuation rate, and this could have influenced the results, for which the point estimate favored benefit in the primary outcome, and death from any cause (a secondary outcome) was significantly reduced. 3 All of the previous studies enrolled fairly high-risk

cohorts, with the majority of patients having estab- lished CV disease at study entry and relatively short follow-up. Recently, high-level results from the REWIND study were released, indicating superiority for dula- glutide over placebo for CV benefit (composite of CV death, nonfatal myocardial infarction, and nonfatal stroke). 6 This study is exceptional in that it was con- ducted in a lower-risk population (only 31% of patients had CV disease at baseline), and the median follow-up was longer at 5 years. 7 Although the details of REWIND have not yet been published, the culmination of recent evidence argues in favor of a class effect for CV ben- efit (at least for long-acting GLP-1 RAs) and even more captivating is the possibility of a previously unclaimed role in primary prevention. This could have far-reach- ing effects in determining choice of therapy for patients with type 2 diabetes. References 1. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375(4):311-322. 2. Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377(13):1228-1239. 3. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373(23):2247-2257. 4. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375(19):1834-1844. 5. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double- blind, randomised placebo-controlled trial. Lancet 2018; 392(10157):1519-1529. 6. Eli Lilly and Company. Trulicity® (dulaglutide) demonstrates superiority in reduction of cardiovascular events for broad range of people with type 2 diabetes [press release]. Accessed 11/6/2018. 7. Gerstein HC, Colhoun HM, Dagenais GR, et al. Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide. Diabetes Obes Metab 2018;20(1):42-49. www.practiceupdate.com/c/76123

PRACTICEUPDATE DIABETES

TOP STORIES 2018 7

Canagliflozin and Renal Outcomes in Type 2 Diabetes By Deborah Wexler MD, MSc T ype 2 diabetes and hypertension are the most common causes of chronic kidney disease (CKD), and almost half of people with CKD have

death from renal causes was reduced by 47% in the canagliflozin compared with the placebo group (abso- lute risk reduction of 1.3 events per 1000 patient-years). Each of the elements of the composite renal outcome were clinically and statistically significantly reduced with the exception of ESRD, or death from renal dis- ease. These had hazard ratios favoring canagliflozin with confidence intervals crossing 1, with a small num- ber of events for these outcomes limiting power. As was seen in EMPA-REG, annual eGFR decline was slower in the canagliflozin arm. Similarly, UACR was lower at the end of the trial in the canagliflozin arm compared with the placebo arm, whereas renal-related adverse events were similar. Effects were largely, but not uniformly, consistent across subgroups, including among those with eGFR >60 mL/min and without ele- vation in UACR at baseline, and among those currently treated with RAAS blockade. This report was quickly followed in July 2018 by a press release announcing that the CREDENCE trial, which specifically tested the hypothesis that canagliflozin was beneficial for patients with type 2 diabetes melli- tus, eGFR >30–90, and UACR >300 mg/g treated with RAAS, was stopped early for efficacy. DECLARE–TIMI 58, the cardiovascular outcomes trial of dapagliflozin, will be reported at the American Heart Association Scientific Sessions in November 2018 and is likely to report renal outcomes as well. Numerous other SLGT2 inhibitor studies are ongo- ing, and we still lack long-term follow-up data on large cohorts of patients because these medications were introduced to the market over the last 5 years. Nonetheless, if these results are borne out in pend- ing trials, it is likely that the availability of a class of medications that have glucose-lowering and renopro- tective effects in addition to their other benefits will likely shift the paradigm of care for people with type 2 diabetes. Furthermore, the ongoing studies, Dapa-CKD and EMPA-Kidney, using dapagliflozin and empagli- flozin, are currently recruiting patients with CKD who do not have diabetes. When these report, we will learn whether the benefits of this class extend to the gen- eral CKD population as well. References 1. The National Institute of Diabetes and Digestive and Kidney Diseases. Kidney disease statistics for the United States. Published December 2016. 2. Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol 2018;6(9):691-704. 3. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375(4):323-334. www.practiceupdate.com/c//76124

diabetes. Rates of incident end-stage renal disease have leveled off and then declined recently thanks to advances in blood pressure management (including use of ACE inhibitors or angiotensin receptor block- ers, together called renin–angiotensin–aldosterone system [RAAS] blockade), glycemic control, and statin use. However, there is very high residual risk, with little in the way of new therapy for CKD prevention or treat- ment beyond the measures noted above. 1 One of the biggest stories of 2018, “Canagliflozin and Renal Outcomes in Type 2 Diabetes,” 2 strengthened the evidence base that the SGLT2 inhibitors, devel- oped for management of hyperglycemia in type 2 diabetes, represent a new tool in the therapeutic armamentarium for patients with type 2 diabetes and CKD. This was believed to be the case based on renal phys- iologic effects of SGLT2 inhibitors on renal glomerular function, and it was supported by findings from the EMPA-REG OUTCOME randomized controlled trial. In EMPA-REG, empagliflozin showed an absolute risk reduction of 6.1% in the composite renal outcome of progression to macroalbuminuria (>300 mg/g urinary albumin-to-creatinine ratio [UACR]), doubling of serum creatinine, initiation of renal replacement therapy, and death from renal disease and incident albuminu- ria (>30 mg/g UACR), but renal outcomes were not adjudicated. 3

" …if these results are borne out in pending trials, it is likely that the availability of a class of medications that have glucose-lowering and renoprotective effects in addition to their other benefits will likely shift the paradigm of care for people with type 2 diabetes. "

For many of the cardiovascular outcomes trials in dia- betes, heterogeneous effects for some outcomes have been observed across different medications within a class and across trials. The publication of the CAN- VAS renal outcomes paper in June 2018 strengthened the finding that the effect of SGLT2 inhibitors on renal function is likely a class effect. The CANVAS program studied canagliflozin and is comprised of two differ- ent trials: CANVAS and CANVAS-R, which enrolled 10,142 participants with mean baseline HbA1c 8.3%, eGFR 76 mL/min, and median UACR 12.3 mg/g, 80% of whom were prescribed RAAS blockade. Renal out- comes were adjudicated. The composite outcome of sustained doubling of serum creatinine, ESRD, and

VOL. 2 • NO. 4 • 2018

TOP STORIES 2018 8

New ADA-EASD Type 2 Diabetes Treatment Guidelines By Silvio E. Inzucchi MD

I have selected the new ADA-EASD type 2 diabe- tes treatment guidelines as my Story of the Year. 1 Over the past 2 decades, a multitude of glu- cose-lowering therapies have become available for type 2 diabetes. Because diabetes is a progressive disease, several medications are often necessary in combination to adequately control blood glucose concentrations and HbA1c. A substantial number of patients eventually require insulin injections, often taken several times per day. Primary care clinicians – who probably treat 90% of patients with diabetes in the US – often seek out guidance from authori- tative sources to assist in their management of this increasingly complex disease. Sets of recommendations from the American Diabetes Association (ADA) and the European Asso- ciation for the Study of Diabetes (EASD) began to be published in 2006. 2 That consensus statement recommended initial therapy with lifestyle change and metformin. If additional glucose-lowering was needed to achieve the HbA1c target of <7%, three options were available: a sulfonylurea, a thiazolidin- edione (TZD), and basal insulin. If triple therapy was required, options not already on board could be added (eg, metformin + sulfonylurea + TZD). Some patients would eventually transition to multiple daily insulin injections. A 2008 update incorporated a new drug category: the GLP-1 receptor agonists. 3 That somewhat controversial algorithm distinguished the choices after metformin between those that were “well-validated’ (sulfonylureas, basal insulin) from those that were “less well-validated” (the TZD pio- glitazone, GLP-1 receptor agonists). In 2012, the ADA-EASD published their first posi- tion statement on this topic. 4 In contrast to prior consensus statements, this algorithm was formally endorsed by the professional practice committees of both organizations and approved by their executive committees. The emphasis here was on patient-cen- tered care. Its first section reviewed glycemic targets and how they might be determined for each patient. In most patients, the goal was 7% or less, but lower levels were felt to be reasonable in younger and healthier patients and looser targets advisable in older and sicker individuals. Its second section focused on therapeutic strategies, with metformin remaining as first-line therapy. After metformin, one of six additional drug classes could be considered (sulfonylureas, TZDs, DPP-4 inhibitors, GLP-1 recep- tor agonists, or basal insulin). Given the lack of comparative efficacy data beyond glucose control

and adverse events, the precise choice was left to the clinician – to be individualized to each patient. Some adverse effects of therapy were considered to be key: weight gain, hypoglycemia, edema, and gastrointestinal distress. An update was published in 2015. 5 This included the newer class at that time, the SGLT2 inhibitors, and also described the emerging strategy of a GLP-1 receptor agonist in combination with basal insulin (in lieu of multiple injections of rap- id-acting insulin before meals). Since 2015, several clinical trials (EMPA-REG OUT- COME, CANVAS, LEADER, SUSTAIN-6, and, just recently, HARMONY Outcomes and DECLARE) have demonstrated clear cardiovascular (CV) benefits of specific glucose-lowering drugs within the SGLT2 inhibitor (empagliflozin, canagliflozin) and GLP-1 receptor agonist (liraglutide, semaglutide) classes. In some trials, this included a CV mortality advantage. Moreover, the SGLT2 inhibitor trials have demon- strated a benefit in the prevention of heart failure (HF) hospitalizations as well as in the progression of chronic kidney disease (CKD). So, there was a clear need to develop a new set of recommendations to address this new evidence and how it might be incorporated into the treatment paradigm of type 2 diabetes. The long-anticipated 2018 ADA-EASD guidelines (the Consensus Report) were published in October and simultaneously presented by the writing group at the EASD meeting in Berlin. 1 These are in part sim- ilar to prior versions in that they begin with lifestyle

PRACTICEUPDATE DIABETES

TOP STORIES 2018 9

" I think the writing committee did a great job in incorporating new and emerging data into a solid set of evidence-based guidelines, including user- friendly figures. They represent a true sea-change on the evolution of type 2 diabetes treatment. "

into a solid set of evidence-based guide- lines, including user-friendly figures. They represent a true sea-change on the evolu- tion of type 2 diabetes treatment. I did have three main criticisms. First, piogl- itazone appears to be relegated to almost an afterthought. Although understanda- ble given its known side effects, this very cost-effective agent is well-tolerated by many patients at low doses and has its own evidence for an ASCVD benefit. Second, the committee may have pushed the enve- lope a bit in coming out with such strong recommendations for HF and CKD patients. SGLT2 inhibitor studies published to date have included these outcomes solely as secondary endpoints. The committee should have waited for the dedicated HF and CKD trials to be completed. Finally, there is a recommendation to use a GLP-1 receptor agonist in HF and CKD patients if an SGLT2 inhibitor cannot be used. I’m not sure where the group came up with this recommendation, as there is very little evidence for benefit from this class in HF patients and any benefit on CKD is solely on albuminuria – certainly a “soft” outcome. But, in all, I was very pleased with the new guidelines, and I suspect they will influence

and metformin, with additional therapies added sequentially to achieve the HbA1c target. There are several other important differences from prior algorithms, however. First, the choice of glucose-lowering agents after metformin should be driven by the presence or absence of heart (and, to some degree, renal disease). If athero- sclerotic cardiovascular disease (ASCVD) predominates the clinical picture, either a GLP-1 receptor agonist or an SLGT2 inhibi- tor would now be the preferred next choice – preferably a drug shown to improve out- comes in a large CV outcome trial. If HF or CKD predominates, then an SGLT2 inhibi- tor would be the optimal selection. This is a major departure from the 2015 position statement, where there was no guidance based on these comorbidities. The other big change is that, the Con- sensus Report now recommends that the first choice of injectable therapy (barring any contraindications) should be a GLP-1 receptor agonist and no longer insulin – irrespective of heart or kidney disease. This recommendation is based on several trials showing equivalent glucose-lowering efficacy compared with insulin, with less hypoglycemia and weight gain. I think the writing committee did a great job in incorporating new and emerging data

References 1. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018 Oct 4. doi: 10.2337/ dci18-0033. [Epub ahead of print.] 2. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2006;29(8):1963-1972. 3. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2008;31(1):173-175. 4. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35(6):1364-1379. 5. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38(1):140-149.

clinical care for many years. www.practiceupdate.com/c/76213

VOL. 2 • NO. 4 • 2018

EDITOR’S PICKS 10

Treatment in Type 1 and Type 2 Diabetes in Low-Resource Settings Annals of Internal Medicine Take-home message • This article presents five WHO recommendations for the intensification of treatment of type 2 diabetes and types of insulin to control type 1 and 2 diabetes in low-resource settings. Abstract DESCRIPTION The World Health Organization developed these guidelines to provide guidance on selection of medicines for treatment intensifica- tion in type 2 diabetes and on use of insulin (human or analogue) in type 1 and 2 diabetes. The target audience includes clinicians, policymakers, national diabetes programmanagers, and medicine procurement officers. The target population is adults with type 1 or 2 diabetes in low-resource settings in low- or high-income countries. The guidelines also apply to disadvantaged populations in high-income countries. METHODS The recommendations were formulated by a 12-member guide- line development group and are based on high-quality systematic reviews identified via a search of several bibliographic databases from 1 January 2007 to 1 March 2017. The GRADE (Grading of Recommendations Assess- ment, Development and Evaluation) system was used to assess the quality of the evidence and the strength of the recommendations. The guideline was peer-reviewed by 6 external reviewers. RECOMMENDATION 1 Give a sulfonylurea to patients with type 2 diabetes who do not achieve glycemic control with metformin alone or who have contraindications to metformin (strong recommendation, moderate-qual- ity evidence). RECOMMENDATION 2 Introduce human insulin treatment to patients with type 2 diabetes who do not achieve glycemic control with metformin and/ or a sulfonylurea (strong recommendation, very-low-quality evidence). RECOMMENDATION 3 If insulin is unsuitable, a dipeptidyl peptidase-4 (DPP-4) inhibitor, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or a thiazoli- dinedione (TZD) may be added (weak recommendation, very-low-quality evidence). RECOMMENDATION 4 Use human insulin to manage blood glucose in adults with type 1 diabetes and in adults with type 2 diabetes for whom insulin is indicated (strong recommendation, low-quality evidence). RECOMMENDATION 5 Consider long-acting insulin analogues to manage blood glucose in adults with type 1 or type 2 diabetes who have frequent severe hypoglycemia with human insulin (weak recommendation, mod- erate-quality evidence for severe hypoglycemia). Medicines for Treatment Intensification in Type 2 Diabetes and Type of Insulin in Type 1 and Type 2 Diabetes in Low-Resource Settings: Synopsis of the World Health Organization Guidelines on Second- and Third-Line Medicines and Type of Insulin for the Control of Blood Glucose Levels in Nonpregnant Adults With Diabetes Mellitus. Ann. Intern. Med 2018 Sep 18;[EPub Ahead of Print], G Roglic, SL Norris. www.practiceupdate.com/c/73666 countries currently bear the brunt of the global burden of diabetes, and use of brand- name medications can rapidly deplete national and personal healthcare budgets. " " These guidelines are important and timely considering that low- and middle-income

COMMENT By Sylvia Kehlenbrink MD and Meredith Hawkins MD, MS T he current clinical guidelines by the World Health Organization (WHO) on optimizing glycemic control in non-pregnant adults with diabetes mellitus in low-re- source settings offers a pragmatic and cost-effective guide to decision-making in resource-constrained contexts. These guidelines are important and timely considering that low- and middle-income countries currently bear the brunt of the global burden of diabetes, and use of brand-name medications can rapidly deplete national and personal healthcare budgets. 1 Given their effectiveness and cost, the WHO guidelines recom- mend the addition of a sulfonylurea as second-line therapy to metformin. This is consistent with the recently released ADA/ EASD guidelines, which recommend the use of sulfonylureas or thiazolidinediones as second-line antihyperglycemic agents if cost is an overriding consideration, despite their preference for GLP-1 analogues or SGLT2 inhibitors in the presence of atherosclerotic cardiovascular disease. 2 Indeed, these newer antihyperglycemic agents can be up to 65 times more expen- sive than generic sulfonylureas and metformin. 3 Nonetheless, the benefits of HbA1c-lowering must be carefully weighed with the risk of hypoglycemia, which can lead to increased morbid- ity and mortality. Thus, the WHO guidelines suggest that newer agents be reserved as third-line agents for selected vulnera- ble populations, particularly when the use of insulin is difficult. Moreover, the WHO Expert Committee has repeatedly recom- mended against the addition of analogue insulins to the list of essential medicines, 4 concluding that their modest advan- tages did not justify the inclusion on the list, given their high cost. 5 Indeed, despite the cited “moderate quality evidence” for fewer severe hypoglycemic events with glargine, a recent report suggests that the use of basal insulin analogues in clin- ical practice settings may not be associated with reduced risk of hypoglycemia or improved glycemic control relative to NPH insulin. 6 Acknowledgements: The authors thank Dr. Jill Crandall, Chief of Endocrinology at Albert Einstein College of Medicine, for helpful comments. Disclosures: Sylvia Kehlenbrink serves as a consultant for Health Action International and the Medicines Patent Pool. References 1. International Diabetes Federation Diabetes Atlas 7th Edition: International Diabetes Federation; 2015. Available at: www.idf.org/e-library/ epidemiology-research/diabetes-atlas/13-diabetes-atlas-seventh-edition. html 2. Tucker ME. New ADA/EASD Guidance on Diabetes: Assess CV Status First. Available at: www.medscape.com/viewarticle/898697 . Accessed October 4, 2018. 3. Just a spoonful of medicine helps the sugar go down: Improving the management of type 2 diabetes: Alosa Health; 2016. Available at: http:// alosahealth.org/uploads/Diabetes_EvDoc_Final.pdf 4. WHO Model List of Essential Medicines. World Health Organization, 2017. Available at: www.who.int/medicines/publications/ essentialmedicines/20th_EML2017.pdf 5. The Selection and Use of Essential Medicines: Report of the WHO Expert Committee on Selection and Use of Essential Medicines, 2017; 2017. Available at: http://apps.who.int/iris/bitstream/han dle/10665/259481/9789241210157-eng.pdf 6. Lipska KJ, Parker MM, Moffet HH, et al. Association of initiation of basal insulin analogs vs neutral protamine hagedorn insulin with hypoglycemia- related emergency department visits or hospital admissions and with glycemic control in patients with type 2 diabetes. JAMA 2018;320(1):53-62.

PRACTICEUPDATE DIABETES

EDITOR’S PICKS 11

12-Month Weight Loss Similar With Low-Fat and Low-Carbohydrate Diet The Journal of the American Medical Association

COMMENT By Katherine Duffy MS, RD, CD-N, CDE T his study investigated the effect of diet type on weight loss, while also including the variable of gen- otype pattern. The conclusions this article support the idea that there is not one diet that needs to be prescribed to every individual in order to achieve weight loss, which are in agreement with the Academy of Nutrition and Die- tetics (AND) position paper (2016) that weight loss achieved on a low-fat or a low-carbohydrate diet do not differ sta- tistically. This study takes it a step further in investigating if the genotype pattern of an individual would impact his/her weight loss success when randomly assigned to a diet. It was concluded that it would not have a significant impact on the individual’s ability to lose weight during lifestyle intervention. The par- ticipants in this study went through nutrition counseling with education so they could make their own food choices to implement the changes. Diet educa- tion can work toward long-term success in allowing some flexibility and encour- aging a lifestyle change, rather than making it seem that the person is fol- lowing a temporary restrictive diet. The AND position paper also did note that, although weight loss could be similar between the two groups, the car- diometabolic outcomes can vary. This study and previous studies have shown that a low-fat diet can produce a greater reduction in LDL cholesterol, whereas a low-carbohydrate diet can produce a greater increase in HDL cholesterol while reducing triglycerides. Although weight loss is an important consider- ation in the health of an individual, the desired cardiometabolic outcomes may be a reason to recommend either a low-fat or a low-carbohydrate diet to a patient who is striving for weight loss.

Take-home message • Patients with a body mass index between 28 and 40 were randomized to a healthy low-fat diet or a healthy low-carbohydrate diet for 12months to evaluateweight change and the association of genotype pattern or insulin secretion with the dietary effects on weight loss. The change in weight at 12months was not significantly different between the two groups. In addition, there was no significant diet–genotype pattern interaction or diet–insulin secretion interaction with weight loss over 12 months. • Weight loss over 12 months was similar with a healthy low-fat diet and a healthy low-carbohydrate diet. Genotype pattern and baseline insulin secretion did not correlate with the dietary effects on weight loss, and hence these factors do not help to identify the optimal diet for each individual. Abstract

IMPORTANCE Dietary modification remains key to successful weight loss. Yet, no one dietary strategy is consistently superior to others for the general population. Previous research suggests genotype or insulin-glucose dynamics may mod- ify the effects of diets. OBJECTIVE To determine the effect of a healthy low-fat (HLF) diet vs a healthy low-carbohydrate (HLC) diet on weight change and if genotype pattern or insulin secretion are related to the dietary effects on weight loss. DESIGN, SETTING, AND PARTICIPANTS The Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) randomized clinical trial included 609 adults aged 18 to 50 years without diabetes with a body mass index between 28 and 40. The trial enrollment was from January 29, 2013, through April 14, 2015; the date of final follow-up was May 16, 2016. Participants were randomized to the 12-month HLF or HLC diet. The study also tested whether 3 single-nucleotide polymorphism multilocus genotype responsiveness patterns or insulin secretion (INS-30; blood concentration of insu- lin 30 minutes after a glucose challenge) were associated with weight loss. INTERVENTIONS Health educators delivered the behavior modification intervention to HLF (n = 305) and HLC (n = 304) participants via 22 diet-specific small group sessions administered over 12 months. The sessions focused on ways to achieve the lowest fat or carbohydrate intake that could be maintained long-term and empha- sized diet quality. MAIN OUTCOMES AND MEASURES Primary outcome was 12-month weight change and determination of whether there were significant interactions among diet type and genotype pattern, diet and insulin secretion, and diet and weight loss. RESULTS Among 609 participants randomized (mean age, 40 [SD, 7] years; 57% women; mean body mass index, 33 [SD, 3]; 244 [40%] had a low- fat genotype; 180 [30%] had a low-carbohydrate genotype; mean baseline INS-30, 93 μIU/mL), 481 (79%) completed the trial. In the HLF vs HLC diets, respectively, the mean 12-month macronutrient

distributions were 48% vs 30% for carbohydrates, 29% vs 45% for fat, and 21% vs 23% for protein. Weight change at 12 months was -5.3 kg for the HLF diet vs -6.0 kg for the HLC diet (mean between-group difference, 0.7 kg [95% CI, -0.2 to 1.6 kg]). There was no significant diet-genotype pattern interaction (P=.20) or diet-insulin secre- tion (INS-30) interaction (P= .47) with 12-month weight loss. There were 18 adverse events or serious adverse events that were evenly distrib- uted across the 2 diet groups. CONCLUSIONS AND RELEVANCE In this 12-month weight loss diet study, there was no significant difference in weight change between a healthy low-fat diet vs a healthy low-carbohydrate diet, and neither genotype pattern nor baseline insu- lin secretion was associated with the dietary effects on weight loss. In the context of these 2 common weight loss diet approaches, nei- ther of the 2 hypothesized predisposing factors was helpful in identifying which diet was better for whom. Effect of Low-Fat vs Low-Carbohydrate Diet on 12-Month Weight Loss in Overweight Adults and the Association With Genotype Pattern or Insu- lin Secretion: The DIETFITS Randomized Clinical Trial. JAMA 2018 Feb 20;319(7)667-679, CDGard- ner, JF Trepanowski, LC Del Gobbo, et al. www.practiceupdate.com/c/64505

Ms. Duffy is a Registered Dietitian and Certified Diabetes Educator at the Yale Diabetes Center, Yale-New Haven Hospital in New Haven, Connecticut.

VOL. 2 • NO. 4 • 2018

EDITOR’S PICKS 12

Differences in Gut Microbiota Composition and Functionality Among Children With Type 1 and MODY2 Diabetes Care Take-home message • This study compared the gut microbiota of children with type 1 diabetes (n=15), maturity-onset diabetes of the young 2 (MODY2; n=15), and healthy children (n=13). Children with type 1 diabetes had lower microbiota diversity; altered bacteria abundance (higher levels of Bacteroides , Veillonella , and Streptococcus and lower abundance of Bifidobacterium and Faecalibacterium ); and increased proinflammatory cytokines, lipopolysaccharides, and gut permeability. • The gut microbiota differ taxonomically and functionally in children with type 1 diabetes compared with their healthy counterparts and with children with MODY2. Long-term studies are needed to determine if the microbiota contributes to disease presentation. Abstract

COMMENT By Li Wen MD, PhD

OBJECTIVE Type 1 diabetes is associated with compositional differences in gut microbiota. To date, no microbiome studies have been per- formed in maturity-onset diabetes of the young 2 (MODY2), a monogenic cause of diabetes. Gut microbiota of type 1 diabetes, MODY2, and healthy control subjects was compared. RESEARCH DESIGN AND METHODS This was a case-control study in 15 children with type 1 dia- betes, 15 children with MODY2, and 13 healthy children. Metabolic control and potential fac- tors modifying gut microbiota were controlled. Microbiome composition was determined by 16S rRNA pyrosequencing. RESULTS Compared with healthy control subjects, type 1 diabetes was associated with a signifi- cantly lower microbiota diversity, a significantly higher relative abundance of Bacteroides, Ruminococcus, Veillonella, Blautia, and Strepto- coccus genera, and a lower relative abundance of Bifidobacterium, Roseburia, Faecalibacterium, and Lachnospira. MODY2 showed a signifi- cantly higher Prevotella abundance and a lower Ruminococcus and Bacteroides abundance. Proinflammatory cytokines and lipopolisaccha- rides were increased in type 1 diabetes, and gut permeability (determined by zonulin levels) was significantly increased in type 1 diabetes and MODY2. The PICRUSt analysis found an increment of genes related to lipid and amino acid metabolism, ABC transport, lipopoly- saccharide biosynthesis, arachidonic acid metabolism, antigen processing and presenta- tion, and chemokine signaling pathways in type 1 diabetes. CONCLUSIONS Gut microbiota in type 1 diabetes differs at taxonomic and functional levels not only in comparison with healthy subjects but fundamentally with regard to a model of nonau- toimmune diabetes. Future longitudinal studies should be aimed at evaluating if the modulation of gut microbiota in patients with a high risk of type 1 diabetes could modify the natural history of this autoimmune disease. Gut Microbiota Differs in Composition and Functionality Between Children With Type 1 Diabetes, MODY2, and Healthy Control Sub- jects: A Case-Control Study. Diabetes Care 2018 Sep 17;[EPub Ahead of Print], I Leiva-Gea, L Sánchez-Alcoholado, B Martín-Tejedor, et al.

I ncreasing evidence suggests that the development of type 1 diabetes (T1D) is asso- ciated with the alteration of gut bacteria, but little about whether gut bacteria are also altered in patients with maturity-onset diabetes of the young 2 (MODY2), a monogenic cause of diabetes accounting for 1% to 2% of all diabetes cases in Europe. Leiva-Gea and colleagues conducted a case-controlled cross-sectional study to inves- tigate the composition of gut bacteria in children with T1D, with MODY2, and healthy children. They thoroughly investigated the composition of gut bacteria, gut permea- bility, and inflammatory biomarkers in the three study groups. When analyzing alpha diversity, a measure of gut bacterial richness, the authors found no significant differ- ences among the three study groups, although the alpha diversity was highest in healthy controls and lowest in T1D, whereas MODY2 was in between. However, the authors found that the beta diversity, a measure of the overall composition of gut bac- teria, was very different in T1D patients compared with healthy controls and MODY2 patients, who showed overall similar beta diversity to that in the healthy controls. The authors further analyzed 16 bacterial families belonging to major bacterial phyla, including Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria. Patients with T1D showed the most significant alteration in many of the families analyzed when com- pared with MODY2 patients and healthy controls, although a few bacterial families were also altered in patients with MODY2. Bacterial gene function analysis revealed that genes for energy and carbohydrate metabolism were significantly depleted in T1D patients. The Firmicutes-to-Bacteroidetes ratio was positively correlated with HbA1c in both T1D and MODY2 patients, but negatively correlated with the abundance of Ruminococcus , a butyrate-producing gut bacterium. Interestingly, the authors found that MODY2 patients have the highest levels of circu- lating zonulin, an indicator of gut permeability, suggesting that the MODY2 patients might have leakier guts than T1D patients. This was attributed to the abundance of Prevotella , mucin-degrading bacteria, which could result in a lack of mucin in the gut lumen in MODY2 patients. However, patients with T1D presented with the highest level of circulating endotoxin, LPS, as well as the inflammatory cytokines IL-1β, IL-6, and TNF-α. In summary, this study not only provides further support for the role of gut bacteria in T1D but also the first evidence that gut bacteria are also altered in patients with MODY2.

Dr. Wen is Senior Research Scientist and Director of Core Laboratory of Yale Center for Clinical Investigation, Yale University School of Medicine in New Haven, Connecticut.

www.practiceupdate.com/c/73669

PRACTICEUPDATE DIABETES

EDITOR’S PICKS 13

Semaglutide vs Dulaglutide OnceWeekly in PatientsWith Type 2 Diabetes The Lancet Diabetes & Endocrinology Take-home message

COMMENT By Kathleen Dungan MD, MPH I n this 40-week randomized, open-label, parallel-group study, once weekly glucagon-like peptide-1 receptor agonists (GLP-1RA) semaglutide (0.5-mg and 1.0-mg doses) and dulaglutide (0.75- and 1.5-mg doses) were compared at their respective low and high doses. Semaglutide was associated with superior HbA1c reductions (about 0.4% at either dose) and twiceasmuchweight loss compared with dulaglutide. Gastrointestinal tolerability was somewhat better at the low dose of dulaglutide compared with semaglutide but similar at the higher doses, and tended to cause more treatment discontinuations in the 1.0-mg dose of semaglutide. Safety otherwise appeared similar across therapies and doses, and is consistent with the treatment class. Interestingly, patient-reported outcomes (treatment satisfaction and quality of life) were similar across therapies, although were already high at baseline. Unlike other once-weekly agents, neither semaglutide nor dulaglutide requires reconstitution, and injection site reactions were uncommon across agents (1–3%). Comparisons of this kind are impor- tant because variations in efficacy and tolerability (even among once weekly agents, where adherence is optimal) have been well-documented across agents in the GLP-1RA treatment class. In SUSTAIN-6, semaglutide also demon- strated cardiovascular benefits among high-risk patients whereas dulaglutide’s ongoing cardiovascular outcomes trial (REWIND) results are forthcoming. Over- all, costs and coverage determinations are likely to play a major role in driving treatment decisions. Nevertheless, dif- ferences in efficacy and tolerability are major drivers of treatment decisions. Head-to-head studies such as this are helpful for prescribers navigating the ever-expanding field of treatment choices for type 2 diabetes.

• The authors performed a head-to-head, open-label, phase IIIb trial of semaglutide vs dulaglutide in patients with poorly controlled type 2 diabetes. Patients were ran- domized (1:1:1:1) to a once-weekly subcutaneous injection of 0.5 mg semaglutide, 1.0 mg semaglutide, 0.75 mg dulaglutide, or 1.5 mg dulaglutide. The primary endpoint, change from baseline percentage HbA1c, was 1.5, 1.8, 1.1, and 1.4 percentage points lower across the four treatment groups, respectively. • The results indicate that, at both the low and high doses used in this study, sema- glutide was associated with a more robust improvement in glycemic control and weight reduction than dulaglutide. Abstract

BACKGROUND Despite common mechanisms of actions, glucagon-like peptide-1 receptor ago- nists differ in structure, pharmacokinetic profile, and clinical effects. This head-to-head trial com- pared semaglutide with dulaglutide in patients with inadequately controlled type 2 diabetes. METHODS This was an open-label, parallel-group, phase 3b trial done at 194 hospitals, clinical institutions or private practices in 16 countries. Eligible patients were aged 18 years or older and had type 2 diabetes with HbA1c 7·0-10·5% (53·0-91·0 mmol/mol) on metformin monother- apy. Patients were randomly assigned (1:1:1:1) by use of an interactive web-response system to once a week treatment with either semaglutide 0·5 mg, dulaglutide 0·75 mg, semaglutide 1·0 mg, or dulaglutide 1·5 mg subcutaneously. The primary endpoint was change from baseline in percentage HbA1c; the confirmatory sec- ondary endpoint was change in bodyweight, both at week 40. The primary analysis popu- lation included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment and before the onset of rescue medication. The safety popu- lation included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment. The trial was pow- ered for HbA1c non-inferiority (margin 0·4%) and bodyweight superiority. FINDINGS Between Jan 6, 2016, and June 22, 2016, 1201 patients were randomly assigned to treatment; of these, 301 were exposed to sema- glutide 0·5 mg, 299 to dulaglutide 0·75 mg, 300 to semaglutide 1·0 mg, and 299 to dulaglutide 1·5 mg. 72 (6%) patients withdrew from the trial (22 receiving semaglutide 0·5 mg, 13 receiving dula- glutide 0·75 mg, 21 receiving semaglutide 1·0mg, and 16 receiving dulaglutide 1·5 mg). From over- all baseline mean, mean percentage HbA1c was reduced by 1·5 (SE 0·06) percentage points with semaglutide 0·5 mg versus 1·1 (0·05) percent- age points with dulaglutide 0·75 mg (estimated treatment difference [ETD] -0·40 percentage points [95% CI -0·55 to -0·25]; p<0·0001) and by 1·8 (0·06) percentage points with semaglu- tide 1·0 mg versus 1·4 (0·06) percentage points with dulaglutide 1·5 mg (ETD -0·41 percentage points [-0·57 to -0·25]; p<0·0001). From overall

" Comparisons of this kind are important because variations in efficacy and tolerability (even among once weekly agents, where adherence is optimal) have been well-

baseline mean, mean bodyweight was reduced by 4·6 kg (SE 0·28) with semaglutide 0·5 mg compared with 2·3 kg (0·27) with dulaglutide 0·75 mg (ETD -2·26 kg [-3·02 to -1·51]; p<0·0001) and by 6·5 kg (0·28) with semaglutide 1·0 mg compared with 3·0 kg (0·27) with dulaglutide 1·5 mg (ETD -3·55 kg [-4·32 to -2·78]; p<0·0001). Gastrointestinal disorders were the most fre- quently reported adverse event, occurring in 129 (43%) of 301 patients receiving semaglutide 0·5 mg, 133 (44%) of 300 patients receiving semaglu- tide 1·0 mg, 100 (33%) of 299 patients receiving dulaglutide 0·75 mg, and in 143 (48%) of 299 patients receiving dulaglutide 1·5 mg. Gastroin- testinal disorders were also the most common reason for discontinuing treatment with sema- glutide and dulaglutide. There were six fatalities: one in each semaglutide group and two in each dulaglutide group. INTERPRETATION At low and high doses, sema- glutide was superior to dulaglutide in improving glycaemic control and reducing bodyweight, enabling a significantly greater number of patients with type 2 diabetes to achieve clini- cally meaningful glycaemic targets and weight loss, with a similar safety profile. Semaglutide Versus Dulaglutide Once Weekly in Patients With Type 2 Diabetes (SUSTAIN 7): A Randomised, Open-label, Phase 3b Trial. Lancet Diabetes Endocrinol 2018 Jan 31;[EPub Ahead of Print], RE Pratley, VR Aroda, I Lingvay, et al. www.practiceupdate.com/c/63701 documented across agents in the GLP-1RA treatment class. "

VOL. 2 • NO. 4 • 2018