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- Title
Reductions in insulin resistance are mediated primarily via weight loss in subjects with type 2 diabetes on semaglutide.
- Authors
Fonseca, Vivian A; Capehorn, Matthew S; Garg, Satish K; Jódar Gimeno, Esteban; Hansen, Oluf Hoejbjerg; Holst, Anders Gaarsdal; Nayak, Gurudutt; Seufert, Jochen
- Abstract
<bold>Context: </bold>Semaglutide, a once-weekly glucagon-like peptide 1 (GLP-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 SUSTAIN 1-3 clinical trials.<bold>Objective: </bold>To investigate the relationship between IR and BW across the SUSTAIN 1-3 trials.<bold>Design: </bold>Post hoc analysis of the SUSTAIN 1-3 trials.<bold>Setting: </bold>311 sites in 30 countries. Patients or Other Participants: 2,432 subjects with T2D.<bold>Interventions: </bold>Semaglutide 0.5 or 1.0 mg, placebo or active comparator (sitagliptin 100 mg, exenatide extended release 2.0 mg).<bold>Main Outcome Measure: </bold>To assess the extent of the effect on IR that is mediated (indirect effect) and not mediated (direct effect) by the effect on BW.<bold>Results: </bold>Across SUSTAIN 1-3, mean BW was significantly reduced with semaglutide 0.5 mg (3.7-4.3 kg; p<0.0001) and semaglutide 1.0 mg (4.5-6.1 kg; p<0.0001) vs comparators (1.0-1.9 kg). There were significantly greater reductions in IR with semaglutide 0.5 mg (27-36%) and semaglutide 1.0 mg (32-46%) vs comparators (17-28%). Greater reductions in BW were generally associated with greater decreases in IR. The effect on IR was primarily mediated by weight loss (70-80% and 34-94%, respectively, for semaglutide 0.5 mg and 1.0 mg vs comparator).<bold>Conclusions: </bold>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.
- Subjects
IRELAND; WEIGHT loss; TYPE 2 diabetes; INSULIN resistance; GLUCAGON-like peptide 1; BODY weight; COMPARATOR circuits
- Publication
Journal of Clinical Endocrinology & Metabolism, 2019, pN.PAG
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/jc.2018-02685