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

PubMed5 Apr 2026·Obesity (Silver Spring, Md.)● 7/10i

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

Lim M, Gokhale P, Akosah A, Villa-Zapata L

Tirzepatide provides greater weight loss than semaglutide or liraglutide in adults with obesity without diabetes, with maximum tolerated doses achieving the largest reductions followed by tirzepatide 15mg, 10mg, semaglutide 2.4mg, tirzepatide 5mg, and liraglutide 3mg. Network meta-analysis of 15 RCTs, 14,059 patients. This is the first head-to-head comparison across all three FDA-approved obesity medications in adults without diabetes, establishing tirzepatide's superiority over existing GLP-1 options.

Strategic signal

This comparative efficacy ranking will reshape US payer coverage decisions and formulary positioning for obesity treatments. Eli Lilly can now reference peer-reviewed head-to-head data showing tirzepatide's superior weight loss versus Novo's agents, strengthening prior authorization appeals and step therapy negotiations. The dose-response relationship for tirzepatide validates higher-dose positioning strategies, while the safety signal may prompt payer scrutiny of adverse event profiles in coverage reviews.

GLP-1Weight lossDrug comparisonsEli Lilly Novo Nordisk

Original Abstract

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.

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