Analysis of the efficacy and safety of liraglutide, semaglutide, and tirzepatide for the treatment of overweight and obesity: a systematic review and network meta-analysis

A systematic review and network meta-analysis of 24 phase 3 randomized controlled trials found that GLP-1 and GLP-1/GIP receptor agonists all reduced body weight, waist circumference, and BMI versus placebo over at least one year. Tirzepatide 15 mg ranked highest for weight and waist reduction; semaglutide 7.2 mg ranked above 2.4 mg, but the average incremental benefit was modest (~2-3% points).

Journal article — systematic review and network meta-analysis. Population: Adults (≥18 years) with BMI ≥25 kg/m². Sample size: 24 randomized controlled trials (23 in NMA). Follow-up: ≥ 52 weeks. Interventions: liraglutide 3.0 mg; semaglutide 2.4 mg; semaglutide 7.2 mg; tirzepatide 15 mg.

Twenty-four RCTs were included (23 in the NMA). All active treatments reduced body weight, waist circumference, and BMI versus placebo; tirzepatide 15 mg ranked highest for weight and waist reduction. Semaglutide 7.2 mg ranked above 2.4 mg for all efficacy endpoints, with an average incremental benefit of ~2-3% points in body weight, but the difference was statistically significant only in the diabetes subgroup; liraglutide 3.0 mg yielded the smallest weight loss. No significant between-treatment differences were seen for serious adverse events, though tirzepatide had a higher risk of injection site reactions and liraglutide had higher risks of any adverse events and discontinuation due to adverse events.

For researchers working on tirzepatide or liraglutide, this paper provides comparative rankings and safety signals against semaglutide in the same meta-analytic framework. It places tirzepatide 15 mg as the highest-ranked option for weight and waist reduction and identifies liraglutide 3.0 mg as the smallest weight-loss agent, with distinct adverse-event profiles. It does not establish mechanisms, long-term outcomes beyond the included trial durations, or definitive head-to-head superiority of any agent, especially semaglutide 7.2 mg over 2.4 mg.

Key findings

All active treatments (liraglutide, semaglutide, tirzepatide) reduced body weight, waist circumference, and BMI versus placebo.
Tirzepatide 15 mg ranked highest for weight and waist reduction across analyses based on P-scores.
Semaglutide 7.2 mg ranked above 2.4 mg for all efficacy endpoints, but the difference in percentage bodyweight change was statistically significant only in the diabetes subgroup.
Semaglutide 7.2 mg showed a modest average incremental benefit of approximately 2-3% points over 2.4 mg.
Liraglutide 3.0 mg yielded the smallest weight loss among active treatments.
No significant between-treatment differences in serious adverse events were found; tirzepatide had higher injection site reactions and liraglutide had higher any-AE and AE-discontinuation risks.

Limitations

Considerable heterogeneity was present for efficacy outcomes (reported by the authors).
Limited statistically significant differences between semaglutide 7.2 mg and 2.4 mg mean the incremental benefit is uncertain.
Network meta-analysis relies largely on indirect comparisons, and head-to-head trials are lacking for many dose pairs.
Only trials with duration ≥52 weeks were included; longer-term safety and real-world outcomes are not addressed.

The record

Journal: Journal of endocrinological investigation
Published: 2026-08-06
PMID: 42560457 — DOI: 10.1007/s40618-026-03006-y
Author countries: Poland

Peptide profiles: Tirzepatide, Liraglutide.

All indexed evidence: Tirzepatide trials & papers, Liraglutide trials & papers.