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 (SemaglutideSC), and oral semaglutide (Semaglutideₒral) 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 SemaglutideSC 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 Semaglutideₒral (6. 86 2. 63–17. 90) and SemaglutideSC (6. 12 2. 97–12. 59) in T2DM. In non‐T2DM, SemaglutideSC (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 Semaglutideₒral (MD –6. 75% −8. 34 to −5. 17) and SemaglutideSC (−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 SemaglutideSC are most effective for clinically meaningful weight loss. Optimal dosing and adherence remain essential in practice. Trail Registration: PROSPERO (CRD42024539634).
Vienghirun et al. (2026) studied this question.