Weight Loss With GLP-1 Agonists in Nondiabetic Adults: Systematic Review and Network Meta-Analysis.

OBJECTIVE: Two glucagon-like peptide-1 receptor agonists (GLP-1 RAs) (semaglutide and liraglutide) and one dual agonist (tirzepatide) are FDA-approved for weight loss in adults with obesity without type 2 diabetes mellitus. This systematic review and network meta-analysis aims to compare the efficacy of these agents against each other. METHODS: A comprehensive search of PubMed/MEDLINE, Embase, Web of Science, and Cochrane Library was conducted from inception to May 2025. Phase 3 randomized controlled trials (RCTs) in adult patients (≥ 18 years) with at least one arm of tirzepatide, semaglutide, or liraglutide were included. A frequentist random-effects network meta-analysis was performed using R 4.3.3. RESULTS: Of 1420 articles identified, 15 RCTs with 14,059 patients were included. All agents significantly reduced body weight compared to placebo. The largest reduction occurred with the maximum tolerated dose of tirzepatide, followed by tirzepatide 15 mg and 10 mg, semaglutide 2.4 mg, tirzepatide 5 mg, and liraglutide 3 mg. Tirzepatide and semaglutide were associated with a higher risk of any adverse event compared with placebo, whereas liraglutide was not. CONCLUSIONS: Tirzepatide, particularly at higher doses, provides the greatest weight reduction in adults without diabetes. Future studies should evaluate discontinuation, weight regain, metabolic outcomes, cost-effectiveness, and patient preferences.