BackgroundObesity is a chronic multifactorial disease characterized by excess adiposity and persistent low-grade systemic inflammation, contributing substantially to cardiometabolic morbidity and mortality. Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist approved for chronic weight management, promotes weight loss by reducing appetite, delaying gastric emptying, and decreasing energy intake while also demonstrating potential anti-inflammatory effects. Although semaglutide has shown promising efficacy for weight reduction, an updated evaluation of its efficacy and safety in nondiabetic individuals with overweight or obesity is warranted.MethodsA systematic review and meta-analysis was conducted according to PRISMA 2020 guidelines. PubMed/MEDLINE, Embase, Scopus, and CINAHL were searched from inception to March 2025 for randomized controlled trials evaluating subcutaneous semaglutide in adults with overweight or obesity without type 2 diabetes mellitus. The primary outcome was the percentage change in body weight from baseline. Secondary outcomes included overall gastrointestinal adverse events, nausea, vomiting, diarrhea, constipation, treatment discontinuation due to adverse events, and serious adverse events. Pooled estimates were calculated using a random-effects model.ResultsFour randomized controlled trials involving 3613 participants met the eligibility criteria. Semaglutide produced significantly greater weight loss than placebo (mean difference: -11.85%; 95% confidence interval [CI]: -12.81 to - 10.90; P < .00001). Overall gastrointestinal adverse events were significantly more frequent with semaglutide, with nausea, vomiting, diarrhea, and constipation representing the most commonly reported events. Treatment discontinuation due to adverse events was also significantly higher in the semaglutide group (RR 2.62, 95% CI: 1.70-4.03; P = .001). Serious adverse events, including acute pancreatitis and cholelithiasis, were uncommon.ConclusionsSubcutaneous 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. Serious adverse events were rare. Further long-term randomized trials are needed to evaluate the durability of weight loss and the long-term safety profile of semaglutide.
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