Comparative efficacy and safety of GLP-1 receptor agonists for weight reduction: A model-based meta-analysis of placebo-controlled trials.

Aim: Obesity is a global epidemic. The FDA has approved glucagon-like peptide-1 (GLP-1) receptor agonists such as Liraglutide, Semaglutide, and the GLP-1/gastric inhibitory polypeptide (GIP) dual agonist Tirzepatide for the treatment of obesity. Clinical trials of GLP-1/GIP/glucagon(GCG) triple agonists are ongoing. This study compared the efficacy and safety profiles of different GLP-1 receptor agonists (GLP-1RAs) for weight reduction and explored the related influencing factors, providing quantitative information for the development of GLP-1RAs and their clinical use. Methods: This systematic review of public databases included placebo-controlled randomized clinical trials of GLP-1RAs. Time-course, dose-response, and covariate models were used to describe the efficacy characteristics and influencing factors of different GLP-1RAs. Subgroup analyses were performed to explore efficacy differences in receptor specificity. Meta-analyses compared the incidence of adverse event and dropout rates among different GLP-1RAs. Results: Fifty-five studies involving 16,269 participants and 12 GLP-1RAs were included. Six drugs showed significant dose-response relationships. The maximum weight reduction effect ranged from 4.25 kg (Liraglutide) to 22.6 kg (Retatrutide). Reported onset times ranged from 6.4 weeks (Orforglipron) to 19.5 weeks (Tirzepatide). At 52 weeks, weight reduction effects were 7.03 kg, 11.07 kg, and 24.15 kg for mono-agonists, dual-agonists, and tri-agonists, respectively. There was a significant negative correlation in the exponential pattern between age and weight reduction effect, whereas baseline weight and BMI had no significant impact. Common adverse events of GLP-1RAs, reported in the literature include nausea, vomiting, diarrhea, and constipation, with a significantly higher incidence of nausea than that of placebo. Conclusions: This study provides a quantitative evaluation of the efficacy and safety of GLP-1RAs and offers valuable insights into the assessment of new drugs for weight reduction.