Gastrointestinal Effects of GLP-1 Drive Discontinuation for Nondiabetic Adults

A systematic review and meta-analysis published in Medicine examined 4 randomized controlled trials encompassing 3613 participants with overweight or obesity but without type 2 diabetes, comparing subcutaneous semaglutide against placebo.¹

The analysis, conducted according to PRISMA 2020 guidelines, pooled data from the STEP 1 (NCT03548935), STEP 3 (NCT03611582), and STEP 4 (NCT03548987) trials along with a phase 2 dose-ranging trial.¹

Across the pooled cohort of 2350 patients receiving semaglutide and 1263 receiving placebo, the mean difference in percentage weight loss favored semaglutide by 11.85% (95% CI, −12.81 to −10.90; P < .00001). The trials showed moderate heterogeneity (I² = 43%), which the study authors attributed largely to one trial's unique protocol combining a very-low-calorie diet with a higher physical activity regimen; excluding that trial reduced heterogeneity to 0%.¹

"Subcutaneous semaglutide is an effective treatment for weight reduction in adults with overweight or obesity without type 2 diabetes mellitus but is associated with an increased risk of gastrointestinal adverse events, particularly nausea, vomiting, diarrhea, and constipation, as well as higher treatment discontinuation," the study authors concluded.¹

Gastrointestinal Tolerability Remains the Key Trade-Off

The Medicine meta-analysis found that overall gastrointestinal adverse events were significantly more common with semaglutide than placebo, with a risk ratio (RR) of 1.62 (95% CI, 1.45-1.82; P < .00001), though heterogeneity was substantial (I² = 81%).¹

Treatment discontinuation due to adverse events was more than 2.5 times as likely with semaglutide (RR, 2.62; 95% CI, 1.70-4.03; P = .001), with discontinuation rates of 6% in the semaglutide group compared with 2.9% in the placebo group. Serious adverse events, including acute pancreatitis and cholelithiasis, were uncommon across the included trials.¹

A separate systematic review and dose-response network meta-analysis published in the International Journal of Obesity, which pooled 39 studies and 33,354 individuals, offers a more granular look at how semaglutide's gastrointestinal profile compares with other glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in nondiabetic patients with overweight or obesity.²

That analysis found semaglutide was associated with significantly increased risk across all 4 major gastrointestinal adverse events: nausea (RR, 2.95; 95% CI, 2.61-3.32), vomiting (RR, 4.21; 95% CI, 3.58-4.95), diarrhea (RR, 1.77; 95% CI, 1.47-2.14), and constipation (RR, 2.10; 95% CI, 1.67-2.63).²

Notably, semaglutide was also the only agent in that analysis significantly associated with increased risk of gastroesophageal reflux disease (RR, 2.43; 95% CI, 1.10-5.37) and abdominal distention (RR, 1.42; 95% CI, 1.13-1.79). The dose-response analysis found that for most GLP-1 RAs, including semaglutide, the risk of nausea, vomiting, constipation, and decreased appetite rose quickly at lower doses before plateauing at higher doses.²

The review's authors noted that "even mild but persistent symptoms can lead to treatment discontinuation, particularly in nondiabetic individuals using these agents primarily for weight management, who may have lower thresholds for tolerability than diabetic patients."²

How Semaglutide Compares With Other FDA-Approved Agents

A third analysis, a systematic review and network meta-analysis published in Obesity, directly compared the 3 FDA-approved agents for chronic weight management in nondiabetic adults: liraglutide, semaglutide, and tirzepatide.³

Drawing on 15 phase 3 randomized-controlled trials with 14,059 patients, the analysis found that all 3 agents significantly reduced body weight compared with placebo, but tirzepatide at its maximum tolerated dose produced the greatest reduction, followed by tirzepatide 15 mg and 10 mg, semaglutide 2.4 mg, tirzepatide 5 mg, and liraglutide 3 mg.³

In the primary network meta-analysis of 12 trials with 11,183 participants, semaglutide 2.4 mg reduced body weight by a mean difference of −13.39% versus placebo (95% CI, −15.46 to −11.33). Compared with placebo, semaglutide showed a modest but statistically significant increase in risk of any adverse event (RR, 1.03; 95% CI, 1.00-1.07), similar to tirzepatide, whereas liraglutide did not show a significant increase.³

For serious adverse events specifically, semaglutide 2.4 mg was associated with significantly higher risk than placebo (RR, 1.41; 95% CI, 1.11-1.79), as was liraglutide 3 mg (RR, 1.31; 95% CI, 1.01-1.71); no tirzepatide dose reached statistical significance for serious adverse events.³

The Obesity review's authors noted that "no clinically meaningful differences in adverse event rates were observed among the three FDA-approved agents" with respect to gastrointestinal tolerability, though liraglutide showed a slightly lower risk of diarrhea and constipation compared with semaglutide and tirzepatide.³

What This Means for Pharmacists

Taken together, these 3 analyses reinforce a consistent message for pharmacists counseling patients on GLP-1 RA therapy for weight management: semaglutide delivers substantial, clinically meaningful weight loss, but gastrointestinal adverse events—nausea, vomiting, diarrhea, and constipation—remain the primary driver of early discontinuation.^1,2

Because the dose-response data suggest that these adverse events tend to increase most steeply during dose escalation before plateauing, pharmacists are well positioned to counsel patients on anticipated timing of symptoms and reinforce adherence to the gradual titration schedule.²

The Medicine review's authors emphasized that treatment effects reflected in these trials likely represent the combined benefit of pharmacotherapy and concurrent lifestyle intervention, including calorie restriction and increased physical activity, rather than semaglutide alone—reinforcing counseling points around diet and exercise as adjuncts to drug therapy rather than optional add-ons.¹

All 3 study teams noted limitations relevant to counseling and formulary considerations. The Medicine authors cited the small number of included trials and relatively short follow-up periods, which limit conclusions about long-term efficacy, safety, and weight regain after treatment discontinuation.¹

The International Journal of Obesity authors noted significant heterogeneity in study design, dosing regimens, and follow-up duration. The Obesity review's authors cautioned that most comparisons were indirect, since only 2 of the 15 included trials offered head-to-head data between agents.^2,3

REFERENCES

1. Naz F, Qaiser F, Mumtaz A, et al. Effectiveness & safety of semaglutide in weight reduction in obese nondiabetic patients: A systematic review and meta-analysis. Medicine (Baltimore). 2026;105(31):e49986. doi:10.1097/MD.0000000000049986

2. Ismaiel A, Scarlata GGM, Boitos I, et al. Gastrointestinal adverse events associated with GLP-1 RA in non-diabetic patients with overweight or obesity: a systematic review and network meta-analysis. Int J Obes (Lond). 2025;49(10):1946-1957. doi:10.1038/s41366-025-01859-6

3. Lim M, Gokhale P, Akosah A, Villa-Zapata L. Weight Loss With GLP-1 Agonists in Nondiabetic Adults: Systematic Review and Network Meta-Analysis. Obesity (Silver Spring). 2026;34(6):1210-1229. doi:10.1002/oby.70169