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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

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