Gastrointestinal tolerability of once‐weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss

Abstract Aim We evaluated gastrointestinal (GI) adverse events (AEs) with once‐weekly semaglutide 2.4 mg in adults with overweight or obesity and their contribution to weight loss (WL). Materials and methods AE analyses pooled data from the Semaglutide Treatment Effect in People With Obesity (STEP) 1‐3 trials for participants randomized to 68 weeks of semaglutide 2.4 mg (n = 2117) or placebo (n = 1262). WL was analysed by presence/absence of GI AEs. Mediation analysis estimated WL effects mediated by and unrelated to GI AEs. GI tolerability with semaglutide 2.4 mg maintenance and cessation after dose escalation was evaluated using STEP 4 data among 803 participants tolerating 20 weeks of semaglutide run‐in. Results GI AEs were more common with semaglutide 2.4 mg than placebo, with most frequently nausea (43.9% vs. 16.1% of participants), diarrhoea (29.7% vs. 15.9%), vomiting (24.5% vs. 6.3%) and constipation (24.2% vs. 11.1%). Most GI AEs with semaglutide were non‐serious (99.5% of AEs), mild‐to‐moderate (98.1%), transient and occurred most frequently during/shortly after dose escalation. Few semaglutide‐treated participants (4.3%) permanently discontinued treatment for GI AEs. In STEP 1‐3, mean WL with semaglutide 2.4 mg was similar in participants without (9.6%‐17.1%) versus with GI AEs (11.4%‐17.7%). Consistent with this observation, mediation analysis found that GI AEs contributed little to semaglutide‐induced WL: of the additional 7.6%‐14.4% WL with semaglutide versus placebo, <1 percentage point was mediated by GI AEs. In STEP 4, semaglutide 2.4 mg maintenance was well tolerated. Conclusions GI AEs were more common with semaglutide 2.4 mg than placebo, but typically mild‐to‐moderate and transient. Semaglutide‐induced WL was largely independent of GI AEs.