High-dose incretin-based therapies are increasingly used for glycemic control and weight reduction, but direct comparisons remain limited. A network meta-analysis presented at the AACE Annual Meeting 2026 evaluated the relative efficacy of tirzepatide and semaglutide across phase 3 randomized controlled trials. 

The analysis included four trials (SURPASS-2, STEP-1, STEP-2, and SURMOUNT-5; total N=5,199). Interventions included tirzepatide 5 mg, 10 mg, and 15 mg; semaglutide 1.0 mg and 2.4 mg; and placebo. Primary outcomes were the change in glycated hemoglobin (HbA1C) and the percent body weight reduction. A random-effects network meta-analysis was performed using the trial-product estimand consistent with International Council for Harmonisation guideline E9(R1).

Tirzepatide 15 mg ranked highest for A1C reduction (P-score 0.99). Compared with semaglutide 1.0 mg and 2.4 mg, tirzepatide 15 mg showed greater HbA1C reductions (MD −0.73% and −0.39%, respectively; both P<0.001). For weight reduction, semaglutide 2.4 mg ranked highest (P-score 0.97), followed by tirzepatide 15 mg (P-score 0.93). Tirzepatide 15 mg showed greater weight reduction versus semaglutide 1.0 mg (MD −6.2%) and 2.4 mg (MD −5.8%) (both P<0.001). Heterogeneity across networks was low (I² <25%).

These findings show differential effects across outcomes, with tirzepatide 15 mg ranking highest for glycemic reduction and semaglutide 2.4 mg ranking highest for weight loss.