Choosing between incretin-based therapies for weight management in type 2 diabetes mellitus (T2DM) often involves balancing efficacy across different dose regimens, particularly because direct head-to-head comparisons remain limited. A model-based analysis published in Diabetes Therapy evaluated dose-response relationships and clinical equivalence between semaglutide and tirzepatide using pooled data from phase III randomized controlled trials.

The analysis included arm-level data from the SUSTAIN and STEP semaglutide programs and the SURPASS and SURMOUNT-2 tirzepatide programs. Generalized additive models and Bayesian hierarchical spline models were used to assess percent weight change across treatment doses. Clinical equivalence was evaluated using a prespecified equivalence margin of ±2 percentage points. Treatment intensification scenarios were also modeled to estimate incremental benefit associated with dose escalation or switching therapies. The analysis included 48 treatment arms involving 16,524 participants with T2DM.

Findings

• Both semaglutide and tirzepatide demonstrated nonlinear dose-response relationships, with attenuation of incremental weight-loss effects at higher doses.
• Semaglutide 2.4 mg and tirzepatide 10 mg showed 99.4% probability of clinical equivalence for weight reduction.
• Semaglutide 7.2 mg and tirzepatide 15 mg demonstrated 94.8% probability of equivalence.
• Lower doses of semaglutide were not considered clinically equivalent to higher doses of tirzepatide.
• In treatment intensification analyses, both dose escalation and switching strategies were associated with additional weight loss, although probabilities of achieving at least 2 additional percentage points varied across regimens.

This model-based analysis suggested that weight-loss efficacy with semaglutide and tirzepatide may depend more on dose intensity than drug identity at select dose combinations. The findings may help inform individualized treatment selection when direct comparative trial data are unavailable.