Evaluating GI Events With Semaglutide for Weight Loss

An obese patient speaking with a physician
An obese patient speaking with a physician
Researchers analyzed GI adverse events in STEP trial participants taking semaglutide weekly for weight loss.

Authors of an analysis of pooled data from the phase 3 Semaglutide Treatment Effect in People with obesity (STEP) 1-4 trials have concluded that the gastrointestinal (GI) adverse events (AEs) that participants reported were mild-to-moderate and did not significantly contribute to treatment discontinuation. The analysis was published in Diabetes, Obesity and Metabolism.

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) used to treat type 2 diabetes (T2D), was approved by the US Food and Drug Administration in June 2021 for weight management in people diagnosed as overweight or obese at a once-weekly subcutaneous dose of 2.4 mg.

In the STEP 1-3 trials, investigators randomized 2117 participants for treatment with semaglutide at 2.4 mg, and 1262 participants received placebo. In STEP 4, researchers enrolled 902 participants in the 20-week semaglutide run-in period; following the run-in period, 535 were randomized to treatment with semaglutide group and 268 were randomized to placebo. Using pooled STEP 1-3 data for participants in the semaglutamide 2.4 mg and placebo arms, the researchers evaluated on-treatment GI AE incidence in post hoc analyses. Because of differences in its study design, the STEP 4 trial was not included in the current pooled analysis; instead, it was analyzed separately to assess the incidence of GI AEs after participants reached the maintenance target dose of 2.4 mg.

Each STEP trial included a dose escalation of semaglutide, beginning with 0.25 mg once weekly for 4 weeks. The dose was increased at 4-week intervals to 0.5 mg, 1.0 mg, 1.7 mg, and then 2.4 mg at week 16. Participants unable to tolerate the 2.4-mg dose were allowed to continue treatment at lower doses, with at least 1 attempt made to increase the dose to 2.4 mg.  Participants who discontinued treatment prematurely remained in each trial. The duration of all STEP trials was 68 weeks.

Evaluation of outcomes associated with weekly administration of semaglutide at 2.4 mg included assessment of the types of GI AEs reported, the GI tolerance of the drug, and whether GI AEs played a role in achieving weight loss. Researchers collected the GI AE information throughout the trials, classifying them according to severity and seriousness.

GI AEs were more common in the semaglutide group (72.9%) than in the placebo group (47.1%). They included nausea (43.9% vs 16.1%), diarrhea (29.7% vs 15.9%), vomiting (24.5% vs 6.3%) and constipation (24.2% vs 11.1%), respectively.

Weight loss was comparable in participants with vs without GI AEs (11.4% to 17.7% and 9.6% to 17.1%, respectively), and researchers reported that GI AEs were not significant factors influencing weight loss.

The frequency of GI AEs was increased during or following dose escalation.  The GI AEs were mostly transient (with the exception of constipation), not serious (99.5%), and of mild-to-moderate severity (98.1%). Relative to the placebo arm, the prevalences of nausea, diarrhea, and vomiting in the semaglutide 2.4-mg group peaked around week 20 and decreased thereafter, especially nausea.

Among participants who discontinued treatment, GI AEs were cited as the reason by 4.3% of participants in the semaglutide 2.4-mg group and 0.7% of those in the placebo group. In the semaglutide group, 12.5% of participants temporarily reduced or ceased treatment due to GI AEs, compared with 1.7% in the placebo group.

Limitations of this study included the post hoc analyses (which are considered to be exploratory), the fact that the contribution of GI AE duration to weight loss was not fully accounted for, and the exclusion of participants who did not complete the 68-week trial from the descriptive analyses detailing the impact of GI AEs on body weight changes. Further, STEP 4 trial participants were aware of the randomization into a treatment vs placebo group, and this may have influenced their AE reporting.

The authors suggested that physicians and patients alike “must balance the typically short-term impact of potential GI AEs against the significant health benefits offered by long-term GLP-1RA treatment.”

Disclosure: The STEP 1-4 trials were funded by Novo Nordisk A/S, the manufacturers of the approved formulation of semaglutide (Wegovy), in the United States. In addition, several study authors declared affiliations with pharmaceutical companies. Please see the original reference for a full list of authors’ disclosures.


Wharton S, Calanna S, Davies M, et al. 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. Published online September 13, 2021. Diabetes Obes Metab. doi:10.1111/dom.14551