The efficacy and safety of glucagon-like peptide-1 receptor agonists in non-diabetic adults with overweight/obesity: An umbrella review of systematic reviews and meta-analyses.

AIMS: Obesity and overweight pose significant global health challenges necessitating effective pharmacological interventions. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged for their weight-reducing effects in non-diabetic individuals, but conflicting findings require comprehensive evaluation. This umbrella review synthesizes evidence to assess GLP-1 RAs' efficacy and safety in non-diabetic adults with overweight or obesity. MATERIALS AND METHODS: A systematic search identified systematic reviews/meta-analyses of randomized controlled trials (RCTs) investigating GLP-1 RAs in non-diabetic adults with overweight/obesity. Primary outcomes included weight/body mass index (BMI) changes, cardiometabolic parameters, and adverse events. Heterogeneity was assessed using I statistics; the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evaluated evidence quality. RESULTS: Fifteen systematic reviews and meta-analyses covering six GLP-1 RAs were included. Among these, tirzepatide demonstrated the greatest mean weight reduction (mean difference [MD]: -17.60 kg; 95 % confidence interval [CI]: -32.15 to -2.95), followed by semaglutide (MD: -11.85 kg; 95 % CI: -13.19 to -10.51). Liraglutide (3 mg) showed moderate effects (MD: -4.59 kg; 95 % CI: -5.13 to -4.06). Semaglutide and liraglutide were also associated with significant reductions in BMI (MD: -4.26 kg/m and -1.66 kg/m, respectively). Gastrointestinal side effects were common but generally mild. CONCLUSIONS: GLP-1 RAs appear to be effective and generally well-tolerated in non-diabetic adults with overweight or obesity. Although some reviews reported more favorable weight outcomes with semaglutide, no definitive conclusions regarding the superiority of individual agents can be drawn from this umbrella review. Further head-to-head trials and network meta-analyses are warranted to clarify their comparative efficacy. REGISTRATION: PROSPERO registration no. CRD42024603661.