Improvements in Insulin Resistance With Semaglutide Primarily a Result of Weight Loss

doctor weighing patient
doctor weighing patient
Reductions in insulin resistance with semaglutide vs comparators are primarily mediated by semaglutide’s effect on body weight.

Treatment with semaglutide, a once-weekly glucagon-like peptide-1 (GLP-1) analog, consistently reduced body weight and insulin resistance in patients with type 2 diabetes, with improvements in insulin resistance being positively associated with weight loss, according to study results published in The Journal of Clinical Endocrinology & Metabolism. The reductions in insulin resistance with semaglutide vs comparators were primarily mediated by semaglutide’s effect on body weight.

The SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) 1 to 3 clinical trials showed that semaglutide demonstrated superior reductions in body weight and decreased insulin resistance vs comparators (placebo, sitagliptin, and exenatide extended release). The current study was a post hoc analysis of these clinical trials, designed to investigate the relationship between insulin resistance and body weight. The SUSTAIN 1 to 3 clinical trials were conducted at 311 sites in 30 countries. Of the 2432 participants with type 2 diabetes randomly assigned to once-weekly 0.5 mg or 1.0 mg semaglutide or comparators, 2265 (93%) completed the trials and were included in post hoc analysis. The primary outcome measure was to assess the effect on insulin resistance that was and was not mediated (indirect effect and direct effect) by changes in body weight.

Across the SUSTAIN 1 to 3 clinical trials, semaglutide significantly reduced body weight (semaglutide 0.5 mg, 3.7-4.3 kg; P <.0001; and semaglutide 1.0 mg, 4.5-6.1 kg; P <.0001) vs comparators (1.0-1.9 kg). Significantly greater reductions in insulin resistance were observed with 0.5 mg semaglutide (27%-36%) and 1.0 mg semaglutide (32%-46%) vs comparators (17%-28%), with greater body weight reductions being generally associated with greater insulin resistance decreases. In a mediation analysis, the effect of semaglutide on insulin resistance vs comparators was primarily mediated by weight loss (70%-80% for semaglutide 0.5 mg and 34%-94% for semaglutide 1.0 mg).

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Although study investigators indicate the potential of semaglutide to slow the progression of type 2 diabetes and positively impact associated comorbidities through decreases in insulin resistance, “[f]urther studies are warranted to fully elucidate the mechanism by which GLP-1 [receptor agonists] reduce [insulin resistance], and to determine the extent to which such reductions underpin the clinical benefits of this drug class.”

Study funding was provided by Novo Nordisk A/S.

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Fonseca VA, Capehorn MS, Garg SK, et al. Reductions in insulin resistance are mediated primarily via weight loss in subjects with type 2 diabetes on semaglutide [published online April 2, 2019]. J Clin Endocrinol Metab. doi:10.1210/jc.2018-02685