Superior weight loss with once-weekly semaglutide versus other glucagon-like peptide-1 receptor agonists is independent of gastrointestinal adverse events

INTRODUCTION: Gastrointestinal (GI) adverse events (AEs) are the most common AEs with glucagon-like peptide-1 receptor agonists (GLP-1RAs). Weight loss (WL) is slightly greater in people who experience GI AEs than those who do not. A previous mediation analysis of the SUSTAIN 1–5 trials indicated minor contribution of nausea/vomiting to the greater WL with once-weekly semaglutide versus comparators. Semaglutide demonstrated superior glycated hemoglobin and body weight (BW) reductions versus other GLP-1RAs in SUSTAIN 3 (versus exenatide extended release 2.0 mg), SUSTAIN 7 (versus dulaglutide) and SUSTAIN 10 (liraglutide 1.2 mg). The objective of this analysis was to assess if significantly greater WL with semaglutide versus other GLP-1RAs is mediated by nausea/vomiting and other GI AEs (diarrhea, constipation, dyspepsia) during dose escalation (baseline to week 12, when GI AEs are generally most prevalent) and from baseline to end of treatment (EOT: week 56 (SUSTAIN 3), 40 (SUSTAIN 7) or 30 (SUSTAIN 10)). RESEARCH DESIGN AND METHODS: Subjects within trials were subdivided into those who reported (yes/no) nausea/vomiting or any other GI AE. Change from baseline in BW was assessed within each trial and subgroup. A mediation analysis separated WL into direct or indirect (mediated by GI AEs) effects. RESULTS: From baseline to week 12 or EOT, the nausea/vomiting-mediated difference in WL was, respectively: 0.05 or 0.09 kg of 3.78 kg at EOT (SUSTAIN 3); 0.06 or 0.03 kg of 2.26 kg at EOT (low-dose comparison) and 0.08 or 0.04 kg of 3.55 kg at EOT (high-dose comparison) (SUSTAIN 7) and 0.05 or 0.09 kg of 3.82 kg at EOT (SUSTAIN 10). CONCLUSIONS: In SUSTAIN 3, 7 and 10, nausea/vomiting by week 12 (end of dose escalation) or throughout treatment contributed minimally (<0.1 kg) to the superior WL with semaglutide versus GLP-1RA comparators at EOT.