Efficacy and Safety of Oral Semaglutide for Weight Loss in Patients Without Diabetes: A Systematic Review and Meta-Analyses

Obesity is a major global health burden with limited long-term pharmacological options. Injectable semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has shown substantial weight loss, particularly in type 2 diabetes mellitus (T2DM). The efficacy of oral semaglutide in non-diabetic populations remains uncertain. To evaluate the efficacy and safety of oral semaglutide in adults without T2DM. A systematic review and meta-analysis was conducted in accordance with PRISMA 2020 and Grade of Recommendation Assessment, Development and Evaluation guidance. MEDLINE, EMBASE, and Cochrane databases were searched. Randomized controlled trials (RCTs) comparing oral semaglutide with placebo in non-diabetic adults were included. Primary outcomes were changes in body weight and body mass index (BMI). Secondary outcomes included adverse events and serious adverse events. Five RCTs (n = 1096) with treatment durations of 10-68 weeks were included. Oral semaglutide significantly reduced body weight (mean difference (MD) −9.40 kg, 95% CI −13.53 to −5.27) and BMI (MD −3.27 kg/m2, 95% CI −5.00 to −1.53) compared with placebo. Although heterogeneity was high across studies (I2 > 90%), the direction of the effect was consistent, with all trials favoring oral semaglutide for weight-reduction outcomes. Adverse events were more frequent with oral semaglutide, particularly in the longer-duration trials, which showed a pooled odds ratio (OR) of 1.79 (95% CI 1.15-2.78). These events were predominantly gastrointestinal, including nausea, vomiting, diarrhea, and constipation, consistent with the known safety profile of GLP-1 receptor agonists. Across all included studies, the overall adverse event estimate was also statistically significant (OR 1.93, 95% CI 1.30-2.86), indicating a higher likelihood of adverse events with oral semaglutide compared with placebo. However, serious adverse events were not increased (OR 0.97, 95% CI 0.60-1.55). Overall, oral semaglutide appears to produce clinically meaningful reductions in body weight and BMI in adults without diabetes, while maintaining a safety profile consistent with other GLP-1 receptor agonists. 

Cite this article as: Garcia-Sierra AM, Cuya-Martínez JC, Giron F, Yepes-Núñez JJ. Efficacy and safety of oral semaglutide for weight loss in patients without diabetes: a systematic review and meta-analyses. Endocrinol Res Pract. Published online August 1, 2026. doi: 10.5152/ erp.2026.26919.