Efficacy and safety of semaglutide versus placebo in adults with overweight or obesity without diabetes: updated meta-analysis of randomized trials

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Abstract

[BACKGROUND] Obesity poses significant challenges for those seeking long-term weight loss through diet and exercise alone. Semaglutide is a GLP-1 receptor agonist approved for chronic weight management in eligible adults. [METHODS] In this systematic review and meta-analysis, we aimed to evaluate the efficacy and safety of semaglutide for treating obesity in adults without diabetes. The protocol was registered in PROSPERO (CRD420261338170). PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched through February 28, 2026. We included randomized controlled trials (RCTs) comparing semaglutide with placebo in adults without diabetes with BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 and at least one obesity-related comorbidity. The Cochrane Risk of Bias 2 Tool, GRADE methodology, RevMan v5.4, and CMA v3 were used for risk-of-bias assessment, certainty-of-evidence assessment, data analyses, and meta-regression analyses respectively. [RESULTS] We included 10 RCTs with a total of 7,131 participants. Risk-of-bias was judged at the level of each outcome: all included trials were at low risk-of-bias for the efficacy outcomes and the prespecified safety outcomes, while cardiovascular and psychiatric disorders raised some concerns. Compared to placebo, semaglutide produced significantly greater reductions in percentage change in body weight (WMD -12.29%, 95% CI -13.38 to -11.20, I2 88%, 95% PI -16.06 to -8.52; 10 studies, n = 6975), absolute change in body weight from baseline (WMD -12.67 kg, 95% CI -13.53 to -11.81, I2 77%, 95% PI -15.36 to -9.98; 10 studies, n = 6975), BMI (WMD -4.55 kg/m2, 95% CI -5.08 to -4.03, I2 86%, 95% PI -6.33 to -2.78; 8 studies, n = 6573), and waist circumference (WMD -9.42 cm, 95% CI -10.27 to -8.56, I2 79%, 95% PI -12.12 to -6.71; 10 studies, n = 6970). Participants assigned to semaglutide also had a higher probability of reaching a ≥ 5%, 10%, 15%, or 20% loss of body weight (9 studies, n = 6103). However, substantial between-study heterogeneity was observed for efficacy outcomes, indicating that the magnitude of benefit varied across trials. With semaglutide, individuals experienced a greater number of total adverse events (aggregate proportions 90.0% vs. 85.0%; RR 1.06, 95% CI 1.03 to 1.10, I2 72%; 9 studies, n = 6922) and discontinuation due to adverse events (aggregate proportions 6.0% vs. 3.0%; RR 1.86, 95% CI 1.41 to 2.45, I2 0%; 10 studies, n = 7129) than did individuals taking the placebo; while for serious adverse events (RR 1.16, 95% CI 0.90 to 1.51, I2 40%; 10 studies, n = 7129) the estimate was imprecise, did not establish a clear difference and the interval remains compatible with a potentially important increase in risk. These pooled figures represent average effects and may not apply equally across different semaglutide doses, formulations, treatment duration, or patient populations. Certainty-of-evidence was low for the primary outcome of percentage change in body weight and for absolute change in body weight and change in BMI, and very low for change in waist circumference. [CONCLUSION] Semaglutide was associated with clinically meaningful weight loss during trial treatment periods in adults with overweight or obesity without diabetes; however, low-certainty evidence and substantial between-study heterogeneity warrant cautious interpretation of the magnitude of benefit. [SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at https://doi.org/10.1007/s40200-026-02108-x.

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