PracticeUpdate: Endocrinology

DIABETES

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Semaglutide improves cardiovascular outcomes in type 2 diabetes Comment by Benjamin Scirica, MD U nexpectedly, in the SUSTAIN-6 study, a small safety study of the once-weekly GLP1 analog semaglutide, semaglutide

placebo in 3297 patients with diabetes and at high cardiovascular risk. Designed to assess safety, and thus fulfill the first step of the regu- latory approval process by excluding significant excess risk, the study was neither planned nor powered to test for superiority, and is therefore one-third to one-fifth the size of other ongoing or completed cardiovascular outcome trials with antihyperglycaemic agents. Although semaglutide is now the third glucose-lowering agent after empagliflozin (EMPA-REG) and liraglutide (LEADER) to semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglu- tide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsen- ing nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitre- ous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photoco- agulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal. CONCLUSIONS In patients with type 2 diabetes who were at high cardiovascular risk, the rate of car- diovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. N Engl J Med 2016 Sep 16;[Epub ahead of print], Marso SP, Bain SC, Consoli A, et al.

show a cardiovascular benefit, the design and size of SUSTAIN-6 should temper the excitement until a larger study with follow-up extended beyond 2 years can confirm these preliminary findings. There are for example, differences between the LEADER and SUS- TAIN-6 results that are difficult to reconcile. In LEADER, the 22% reduction in cardiovas- cular death with liraglutide drove the lower risk of the primary composite endpoint, while MI and stroke were only reduced by 12% and 11%, respectively. In contrast, in SUSTAIN-6 there was no difference in cardiovascular mortality, but a 26% reduction in MI and 49% reduction in stroke. These differences, combined with the lack of benefit with the GLP1 analogue lixisenatide in the ELIXA study, highlight the fact that there is still much to learn about the role of GLP1 in cardioprotection. The data from SUSTAIN-6 are neverthe- less encouraging for the entire field of cardio- metabolic drug development. The decades-long equipoise surrounding the choice between first- or second-line glucose-lowering agents appears to be crumbling as several agents now have proven cardiovascular benefit. But, it is only through further randomised trials powered for “superiority” that continued progress will be made.

significantly reduced the risk of cardiovascular death, MI, or stroke by 26% compared with

The decades-long equipoise surrounding the choice between first- or second-line glucose-lowering agents appears to be crumbling as several agents now have proven cardiovascular benefit. But, it is only through further randomised trials powered for “superiority” that continued progress will be made.

Semaglutide and cardiovascular outcomes in patients with type 2 diabetes The New England Journal of Medicine TAKE-HOME MESSAGE • The authors of this study evaluated the efficacy of weekly semaglutide compared with placebo in 3297 patients with type 2 diabetes, most of whom had cardiovascular disease and/or kidney disease. The primary composite outcome, defined as the first occurrence of cardiovascular death, nonfatal MI, and nonfatal stroke, occurred in fewer patients in the semaglutide group than the placebo group (6.6% vs 8.9%, respectively; P < 0.001 for noninferiority). Compared with the placebo group, the semaglutide group had lower rates of nonfatal MI (3.9% vs 2.9%, respectively) and nonfatal stroke (2.7% vs 1.6%, respectively), whereas no between-group difference was found in rates of cardiovascular death. The semaglutide group had lower rates of nephropathy and serious adverse events but higher rates of retinopathy and drug discontinuation due to adverse events. • Patients with type 2 diabetes who are at high cardiovascular risk may benefit from weekly semaglutide treatment. Abstract

or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of car- diovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio. RESULTS At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the

BACKGROUND Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon- like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown. METHODS We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regi- men to receive once-weekly semaglutide (0.5 mg

Dr Scirica is Attending Cardiologist and Director, Quality Initiatives, Cardiovascular Division, Brigham and Women’s Hospital; Associate Professor of Medicine, Harvard

Medical School; Senior Investigator, TIMI Study Group, Boston, Massachusetts.

Optimised mealtime insulin dosing for fat and protein in type 1 diabetes Comment by Deborah Wexler, MD

Optimized mealtime insulin dosing for fat and protein in type 1 diabetes: application of a model-based approach to derive insulin doses for open-loop diabetes management Diabetes Care Take-home message • The authors of this study evaluated insulin dosing for meals that are high in fat and protein in 10 adults with type 1 dia- betes. Compared with low-fat, low-protein meals, high-fat, high-protein meals with the same carbohydrate content required 65% more insulin with a 30%/70% split over 2.4 hours to achieve target postprandial glucose control. • Regardless of carbohydrate content, the fat and protein content of meals appears to increase insulin requirements in patients with type 1 diabetes. Abstract OBJECTIVE To determine insulin dose adjustments required for coverage of high-fat, high-protein (HFHP) meals in type 1 diabetes (T1D). RESEARCHDESIGNANDMETHODS Ten adults with T1D received low-fat, low-protein (LFLP) andHFHPmeals with identical carbohydrate con- tent, coveredwith identical insulin doses. On subsequent occasions, subjects repeated theHFHPmeal with an adaptivemodel-predictive insulin bolus until target postprandial glycemic control was achieved. RESULTS With the same insulin dose, the HFHP increased the glucose incremental area under the curve over twofold (13,320 ± 2,960 vs. 27,092 ± 1,709 mg/dL ⋅ min; P = 0.0013). To achieve target glucose control following the HFHP, 65% more insulin was required (range 17–124%) with a 30%/70% split over 2.4 h. CONCLUSIONS This study demonstrates that insulin dose calcula- tions need to consider meal composition in addition to carbohy- drate content and provides the foundation for new insulin-dosing algorithms to cover meals of varying macronutrient composition. Diabetes Care 2016;39:1631-1634, Bell KJ, Toschi E, Steil GM, et al.

I nsulin users know that blood glucose is higher after high-fat, high-protein (HFHP) meals than those low-fat, low-protein (LFLP) meals with identi- cal carbohydrate content. Smith et al determined the incremental difference in postprandial hyperglycaemia following high-fat, high-protein meals and deter- mined the additional insulin required to cover such meals in 10 adults with type 1 diabetes using insulin pumps and con- tinuous glucose monitors with optimised

insulin settings. Dosing insulin for carbo- hydrate content of the meal alone using the standard carbohydrate-to-insulin ratio resulted in glucose incremental area under the curve that was elevated over twofold for HFHP compared with LFLP. Insulin doses were 65% +/− 10% higher than those calculated from the carbohydrate-to-insulin ratio alone. The optimal bolus delivery pattern was a dual-wave bolus with 30%/70% split, on average, over 2.5 hours with a large degree of variability. For diabetologists who have been advising patients to increase dosing for larger meals, this study allows them to give more precise advice: adept patients, especially those with CGM, may wish to experiment with increasing their bolus dose by 50% to 75% or more and delivering it in a dual-wave pattern when consuming high-fat, high-protein meals. Dr Wexler is Associate Professor of Medicine at Harvard Medical School, Associate Clinical Chief of the MGH Diabetes Unit, and Co-Clinical Director of the MGH Diabetes Center, Boston.

VOL. 1 • No. 3 • 2016