Efficacy and safety of semaglutide for weight loss among adults with overweight or obesity: a systematic review and narrative synthesis

Semaglutide is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) available in subcutaneous and oral formulations. It reduces appetite and energy intake through central and gastrointestinal mechanisms and is used across obesity and type 2 diabetes mellitus (T2DM), with formulation- and indication-specific dosing. This systematic review evaluated the efficacy and safety of semaglutide for weight-related outcomes among adults with overweight or obesity. This systematic review was conducted in accordance with PRISMA 2020. PubMed, Web of Science, Cochrane CENTRAL, and Google Scholar were searched for peer-reviewed studies published from 2015 to 2025. Randomized controlled trials (RCTs) and observational studies reporting weight-related outcomes with oral or subcutaneous semaglutide were eligible. Because the included studies differed substantially in population, formulation, dose, indication, comparator, design, and follow-up, evidence was synthesized narratively and was not quantitatively pooled. Fifteen studies were included, comprising randomized trials, an off-treatment extension, and one propensity-matched observational cohort. In obesity-focused trials without diabetes, once-weekly subcutaneous semaglutide 2.4 mg generally produced mean weight reductions of approximately 14–17% over 68 weeks, while a 7.2-mg regimen produced greater weight loss in a higher-dose trial. In T2DM studies, weight reductions were smaller and accompanied by clinically important HbA1c improvements. Oral semaglutide studies primarily enrolled participants with T2DM and were interpreted separately from obesity-dose subcutaneous trials. Gastrointestinal adverse events were the most frequent tolerability issue and tended to increase during dose escalation and with higher exposure. Gallbladder events, treatment discontinuation, and a diabetic-retinopathy signal in SUSTAIN-6 warrant population-specific interpretation. Weight regain after discontinuation was substantial in withdrawal/extension studies. Semaglutide is associated with clinically meaningful weight reduction, but the magnitude of benefit and safety profile vary by population, formulation, dose, indication, and study design. The strongest weight-loss evidence derives from obesity-focused subcutaneous trials. Findings from diabetes, cardiovascular-outcome, oral-formulation, and observational studies provide complementary evidence but should not be treated as directly interchangeable. Because no quantitative pooling was performed, conclusions are descriptive and should be interpreted cautiously. This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420261296560. Not applicable.