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

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).