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.

Keywords: GLP-1 analogue; antiobesity drug; obesity therapy; phase III study; randomized trial; weight control.

FIGURE 1

In the STEP 1‐3 trials: (A) Time to onset of first gastrointestinal adverse event; (B) Gastrointestinal adverse events leading to permanent treatment discontinuation. Data are on‐treatment adverse events (participants were considered to be on treatment if any dose of trial product was administered within the previous 49 days). Numbers below the plots represent the number of participants at risk. Equivalent data for the individual treatment arms (including semaglutide 1.0 mg) in the STEP 2 trial are shown in Figure S2

FIGURE 2

Prevalence of adverse events (nausea, diarrhoea, constipation and vomiting) over time in the (A‐D) STEP 1‐3 trials and (E‐H) STEP 4 trial. NA, not applicable. Data are on‐treatment adverse events (participants were considered to be on treatment if any dose of trial product was administered within the previous 49 days)

FIGURE 3

Change in body weight from baseline to week 68 among participants with and without gastrointestinal adverse events in: (A) STEP 1; (B) STEP 2; and (C) STEP 3. Bars present the mean percentage change from baseline in body weight ± standard error of the mean. Body weight data are observed on‐treatment data (any dose of trial product within previous 2 weeks) among participants who had a week 68 body weight assessment. Gastrointestinal adverse events comprise any type of gastrointestinal disorder, including on‐treatment adverse events (for assessment of adverse events, participants were considered to be on treatment if any dose of trial product was administered within the previous 49 days). Additional information on these analyses is included in Table S4

FIGURE 4

Mediation analysis of body weight changes mediated by or unrelated to GI AEs in the STEP 1‐3 trials. AE, adverse event; CI, confidence interval; ETD, estimated treatment difference; GI, gastrointestinal; HbA1c, glycated haemoglobin. Based on the on‐treatment data excluding measurements after initiation of antiobesity therapy (other obesity pharmacotherapy or bariatric surgery) from all randomized participants. Changes in body weight were analysed using a mixed model for repeated measurements, which included randomized treatment, stratification groups and their interaction (for STEP 2 only, including oral antihyperglycaemic drug treatment status and HbA1c category at screening) as factors, and baseline body weight as covariate, all nested within visit. Effects were estimated using a natural effects model (interaction between treatment and any GI AEs together with the baseline variables of body weight and stratification factors [STEP 2 only] as main effects, assuming no interaction between natural effects and baseline variables) with imputation‐based estimation. CIs are 95% Wald CIs. GI AEs comprise any type of GI disorder, including on‐treatment AEs (participants were considered to be on treatment if any dose of trial product was administered within the previous 49 days)