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

Abstract

IntroductionGastrointestinal (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 methodsSubjects 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.ResultsFrom 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).ConclusionsIn 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.

Safety of Semaglutide

“…In a mediation analysis of the SUSTAIN 1 to 5 trials, a small component (0.07 to 0.5 kg) of the total treatment difference in weight loss was explained by nausea or vomiting ( 52 ). In contrast, when combining data from SUSTAIN 3, 7 and 10, the occurrence of nausea and vomiting was not associated with superior weight loss ( 53 ). Whether this route plays a role in the beneficial effects of GLP-1RA on body weight needs further studying.…”

Gastric Sensory and Motor Functions and Energy Intake in Health and Obesity—Therapeutic Implications

“…However, it is clear that both groups slow gastric emptying, lower pre-prandial and postprandial glucose levels, and promote weight loss. Nausea and vomiting are the most frequently reported gastrointestinal adverse events for GLP-1RAs, especially for long-acting formulations, and may contribute to greater weight loss in this group [ 188 , 189 ]. The weight loss achieved with subcutaneous semaglutide is independent of gastrointestinal adverse events though other studies confirm that both weekly and oral semaglutide retard gastric emptying [ 154 , 189 , 190 ].…”

“…Nausea and vomiting are the most frequently reported gastrointestinal adverse events for GLP-1RAs, especially for long-acting formulations, and may contribute to greater weight loss in this group [ 188 , 189 ]. The weight loss achieved with subcutaneous semaglutide is independent of gastrointestinal adverse events though other studies confirm that both weekly and oral semaglutide retard gastric emptying [ 154 , 189 , 190 ]. Nevertheless, weight loss associated with GLP-1 receptor agonists may be independent of gastric motor changes and related to central appetite regulation [ 191 , 192 , 193 ].…”

Efficacy and Safety of Semaglutide in Glycemic Control and Body Weight Management Among Obese Type 2 Diabetes Patients Initiated or Switched to Semaglutide From Other GLP-1 Receptor Agonists

“…The anorexigenic mechanism of semaglutide differs from that of other GLP-1 RAs [12] and may be related to its potent weight loss effect. Weight loss associated with semaglutide is considered independent of gastrointestinal adverse reactions such as nausea and vomiting, and gastrointestinal adverse reactions are not directly related to weight loss [20]. In addition to GLP-1 RAs, SGLT2 inhibitors promote a reduction in body weight [21].…”