Quantitative Insights into Tirzepatide and Semaglutide Using Longitudinal Systems Modeling

In a 28-week clinical trial of patients with type 2 diabetes (T2D), tirzepatide 15 mg (a dual GIP/GLP-1 receptor agonist) and semaglutide 1 mg (a GLP-1 receptor agonist) both improved fasting glucose, with tirzepatide showing superior efficacy. The longitudinal metabolic mechanisms underlying this difference remain incompletely defined.

To compare the longitudinal metabolic effects of tirzepatide and semaglutide using model-based analysis of fasting measures, elucidate underlying mechanisms, and explore strategies to enhance outcomes in low responders.

A mechanistic longitudinal model was developed based on the trial data from patients treated with tirzepatide or semaglutide. The model integrates fasting glucose, fasting insulin, insulin sensitivity, and beta-cell function over time, enabling quantification of hepatic glucose production (HGP) and isolation of insulin-independent drug effects on HGP.

Beta-cell function, as assessed by HOMA-B, initially increased and then declined as insulin sensitivity improved, a reversal of the canonical T2D progression pathway. Tirzepatide's superior fasting glucose control versus semaglutide was driven primarily by greater insulin-independent suppression of HGP. Low responders exhibited deficient HGP suppression, and simulations suggested that enhancing HGP suppression improves fasting glucose without inducing β-cell stress associated with sustained hypersecretion. Simulated enhancement of weight loss accelerated early glycemic improvement but did not further reduce long-term fasting glucose levels.

Greater suppression of hepatic glucose production was associated with greater efficacy of tirzepatide 15 mg versus semaglutide 1 mg in improving fasting glucose. Therapeutic strategies targeting suppression of hepatic glucose production may provide metabolic benefit beyond direct enhancement of beta-cell function or additional weight loss.