MON-667 - Tirzepatide Vs Semaglutide For Glycemic Control And Weight Loss: Updated Network Meta-Analysis Of Phase 3 Trials Incorporating 2025 SURMOUNT-5 Data

Background
Direct comparative evidence between high-dose tirzepatide and semaglutide has remained limited until the release of the 2025 SURMOUNT-5 head-to-head trial. We conducted an updated frequentist network meta-analysis evaluating relative efficacy across all available phase 3 randomized controlled trials (RCTs).
Methods
Four phase 3 RCTs were included (SURPASS-2, STEP-1, STEP-2, SURMOUNT-5; total n = 5,199). Interventions were tirzepatide 5/10/15 mg, semaglutide 1.0 mg, semaglutide 2.4 mg, and placebo. Primary outcomes were change in HbA1c (%) and percent body-weight reduction. Random-effects network meta-analysis (netmeta, R) was performed using the trial-product estimand consistent with ICH E9(R1). A single connected network was formed without imputed arms. Treatment rankings were generated using P-scores.
Results
Glycemic Control:
Tirzepatide 15 mg ranked highest for HbA1c reduction (P-score 0.99). Validated contrasts showed:
Tirzepatide 15 mg vs semaglutide 1 mg: MD −0.73% (95% CI −0.85 to −0.61; p < 0.001)
Tirzepatide 15 mg vs semaglutide 2.4 mg: MD −0.39% (−0.53 to −0.25; p < 0.001)
Weight Reduction:
Semaglutide 2.4 mg ranked first for weight loss (P-score 0.97), followed closely by tirzepatide 15 mg (P-score 0.93). Validated contrasts showed:
Tirzepatide 15 mg vs semaglutide 1 mg: MD −6.2% (−7.0 to −5.4; p < 0.001)
Tirzepatide 15 mg vs semaglutide 2.4 mg: MD −5.8% (−7.0 to −4.6; p < 0.001)
Heterogeneity across networks was low (I² < 25%).
Conclusion
Tirzepatide 15 mg delivers the greatest HbA1c reduction among all active comparators and significantly outperforms both marketed doses of semaglutide. For weight loss, semaglutide 2.4 mg ranks highest overall; however, tirzepatide 15 mg achieves superior weight reduction compared with semaglutide 1 mg and demonstrates substantially greater weight loss than semaglutide 2.4 mg in the head-to-head SURMOUNT-5 trial. These updated findings support individualized GLP-1/GIP versus GLP-1 agonist selection based on therapeutic priorities (glycemia vs weight loss).

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