GLP-1 Receptor/Dual Agonists for Weight Loss: A Systematic Review and Network Meta-Analysis of RCTs.

PubMed23 Mar 2026·Diabetes, obesity & metabolism● 8/10i

GLP-1 Receptor/Dual Agonists for Weight Loss: A Systematic Review and Network Meta-Analysis of RCTs.

Vienghirun J, Sawangjit R, Suttiruksa S, Chaiyakunapruk N, Jinathongthai P et al.

Tirzepatide achieved 7.17-fold greater likelihood of ≥5% weight loss versus placebo in adults with type 2 diabetes, outperforming subcutaneous semaglutide (4.74-fold) and oral semaglutide (2.85-fold). Network meta-analysis of 127 RCTs, 58,976 participants across seven GLP-1 receptor agonists. This provides the first comprehensive head-to-head comparison showing tirzepatide's superior weight loss efficacy across both diabetes and non-diabetes populations. Higher nausea and vomiting rates occurred with tirzepatide versus semaglutide formulations.

Strategic signal

This comprehensive head-to-head evidence strengthens Eli Lilly's market access positioning against Novo's Wegovy across US and EU payers by establishing tirzepatide's superiority margin. The dual efficacy in diabetic and non-diabetic populations supports Lilly's strategy to compete across both Ozempic and Wegovy franchises simultaneously. However, the higher GI side effect profile may trigger stricter step therapy requirements from US PBMs and European HTA bodies, potentially offsetting efficacy advantages in reimbursement decisions.

GLP-1Weight lossType 2 diabetesDrug comparisonsEli Lilly Novo Nordisk

Original Abstract

AIM: This study used a network meta-analysis (NMA) as the primary approach to compare the efficacy and tolerability of GLP-1 receptor agonists and dual agonists in overweight or obese adults with and without Type 2 diabetes. MATERIALS AND METHODS: PubMed, Embase, Scopus, CENTRAL, and trial registries were searched through April 30, 2025. Randomized clinical trials (RCTs) of GLP-1 receptor agonists in adults with and without Type 2 diabetes were included. Data were extracted according to PRISMA 2020. Pairwise and using random-effects models were performed, with treatment rankings derived using SUCRA. Outcomes included ≥ 5% and ≥ 10% weight loss, weight change (absolute and percentage weight loss) at 24-52 weeks, and adverse events. RESULTS: A total of 127 RCTs (58 976) Participants; (39 520 with and 19 456 without T2DM) assessed seven GLP-1RAs. Compared to placebo, NMA indicated that tirzepatide, subcutaneous semaglutide (Semaglutide_SC), and oral semaglutide (Semaglutide_oral) increased ≥ 5% weight loss (RR 7.17 [95% CI 4.38-11.73], 4.74 [3.17-7.08], 2.85 [1.78-4.58]) in T2DM. Only tirzepatide and Semaglutide_SC were effective (2.99 [1.20-7.44], 2.75 [1.14-6.61]) in non-T2DM. For ≥ 10% loss, tirzepatide was most effective (14.34 [5.98-34.35]), followed by Semaglutide_oral (6.86 [2.63-17.90]) and Semaglutide_SC (6.12 [2.97-12.59]) in T2DM. In non-T2DM, Semaglutide_SC (10.72 [3.29-34.90]) and tirzepatide (4.70 [1.02-21.73]) were effective when compared to placebo. Mixed treatment effects (direct head to head and indirect comparisons) showed that tirzepatide reduced weight more than Semaglutide_oral (MD -6.75% [-8.34 to -5.17]) and Semaglutide_SC (-4.94% [-6.35 to -3.52]) in T2DM and was the only effective agent in non-T2DM (-16.48% [-21.70 to -11.27]) when compared to placebo. Higher doses enhanced weight loss; nausea/vomiting were more common with tirzepatide (RR 3.64 [2.40-5.52]). CONCLUSIONS: Tirzepatide and Semaglutide_SC are most effective for clinically meaningful weight loss. Optimal dosing and adherence remain essential in practice. TRAIL REGISTRATION: PROSPERO (CRD42024539634).

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