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Context  Semaglutide, a once-weekly glucagon-like peptide-1 analog approved for use in patients with type 2 diabetes (T2D), demonstrated superior body weight (BW) reductions and decreased insulin resistance (IR) vs comparators across the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) 1–3 clinical trials.    Objective  To investigate the relationship between IR and BW across the SUSTAIN 1–3 trials.    Design  Post hoc analysis of the SUSTAIN 1–3 trials.    Setting  Three hundred and eleven sites in 30 countries.    Patients or other participants  2432 subjects with T2D.    Interventions  Semaglutide 0.5 or 1.0 mg, placebo or active comparator (sitagliptin 100 mg, exenatide extended release 2.0 mg).    Main Outcome Measure  To assess the extent of the effect on IR that is mediated (indirect effect) and not mediated (direct effect) by the effect on BW.    Results  Across SUSTAIN 1–3, mean BW was significantly reduced with semaglutide 0.5 mg (3.7 kg to 4.3 kg; P &lt; 0.0001) and semaglutide 1.0 mg (4.5 kg to 6.1 kg; P &lt; 0.0001) vs comparators (1.0 kg to 1.9 kg). There were greater reductions in IR with semaglutide 0.5 mg (27% to 36%) and semaglutide 1.0 mg (32% to 46%) vs comparators (17% to 28%). Greater reductions in BW were generally associated with greater decreases in IR. The effect on IR was primarily mediated by weight loss (70% to 80% and 34% to 94%, for semaglutide 0.5 mg and 1.0 mg, respectively, vs comparator).    Conclusions  Semaglutide consistently reduced BW and IR in subjects with T2D in SUSTAIN 1–3. In this analysis, IR improvement was positively associated with, and primarily mediated by, the effect of semaglutide on BW.

Reductions in Insulin Resistance are Mediated Primarily via Weight Loss in Subjects With Type 2 Diabetes on Semaglutide