In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular 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. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).

BACKGROUNDObesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed. METHODSIn this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions. RESULTSThe mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points (95% confidence interval [CI], −13.4 to −11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]). CONCLUSIONSIn participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

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OBJECTIVE -To compare the abilities and associated hypoglycemia risks of insulin glargine and human NPH insulin added to oral therapy of type 2 diabetes to achieve 7% HbA 1c .RESEARCH DESIGN AND METHODS -In a randomized, open-label, parallel, 24-week multicenter trial, 756 overweight men and women with inadequate glycemic control (HbA 1c Ͼ7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily, titrated using a simple algorithm seeking a target fasting plasma glucose (FPG) Յ100 mg/dl (5.5 mmol/l). Outcome measures were FPG, HbA 1c , hypoglycemia, and percentage of patients reaching HbA 1c Յ7% without documented nocturnal hypoglycemia.RESULTS -Mean FPG at end point was similar with glargine and NPH (117 vs. 120 mg/dl [6.5 vs. 6.7 mmol/l]), as was HbA 1c (6.96 vs. 6.97%). A majority of patients (ϳ60%) attained HbA 1c Յ7% with each insulin type. However, nearly 25% more patients attained this without documented nocturnal hypoglycemia (Յ72 mg/dl [4.0 mmol/l]) with glargine (33.2 vs. 26.7%, P Ͻ 0.05). Moreover, rates of other categories of symptomatic hypoglycemia were 21-48% lower with glargine.CONCLUSIONS -Systematically titrating bedtime basal insulin added to oral therapy can safely achieve 7% HbA 1c in a majority of overweight patients with type 2 diabetes with HbA 1c between 7.5 and 10.0% on oral agents alone. In doing this, glargine causes significantly less nocturnal hypoglycemia than NPH, thus reducing a leading barrier to initiating insulin. This simple regimen may facilitate earlier and effective insulin use in routine medical practice, improving achievement of recommended standards of diabetes care.

OBJECTIVE -This study evaluated the effects of exenatide, a novel incretin mimetic, in hyperglycemic patients with type 2 diabetes unable to achieve glycemic control with metforminsulfonylurea combination therapy. RESULTS -Week 30 A1C changes from baseline (ϮSE) were Ϫ0.8 Ϯ 0.1% (10 g), Ϫ0.6 Ϯ 0.1% (5 g), and ϩ0.2 Ϯ 0.1% (placebo; adjusted P Ͻ 0.0001 vs. placebo), yielding placeboadjusted reductions of Ϫ1.0% (10 g) and Ϫ0.8% (5 g). In the evaluable population, exenatide-treated subjects were more likely to achieve A1C Յ7% than placebo-treated subjects (34% [10 g], 27% [5 g], and 9% [placebo]; P Ͻ 0.0001). Both exenatide arms demonstrated significant weight loss (Ϫ1.6 Ϯ 0.2 kg from baseline each exenatide arm, Ϫ0.9 Ϯ 0.2 kg placebo; P Յ 0.01 vs. placebo). Mild or moderate nausea was the most frequent adverse event. The incidence of mild/moderate hypoglycemia was 28% (10 g), 19% (5 g), and 13% (placebo) and appeared lower with MIN than with MAX sulfonylurea treatment. RESEARCH DESIGN AND METHODSCONCLUSIONS -Exenatide significantly reduced A1C in patients with type 2 diabetes unable to achieve adequate glycemic control with maximally effective doses of combined metformin-sulfonylurea therapy. This improvement in glycemic control was associated with no weight gain and was generally well tolerated.