Quantitative Insights into Tirzepatide and Semaglutide Using Longitudinal Systems Modeling.

CONTEXT: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.