Effects of Tirzepatide vs Semaglutide on β-cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test.

CONTEXT:In a clinical study, tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA), provided superior glycemic control vs the GLP-1RA semaglutide. The physiologic mechanisms are incompletely understood. OBJECTIVE:To evaluate treatment effects by model-based analyses of mixed-meal tolerance test (MMTT) data. DESIGN:A 28-week double-blind, randomized, placebo-controlled trial. SETTING:Two clinical research centers in Germany. PATIENTS:Patients with type 2 diabetes treated with metformin. INTERVENTIONS:Tirzepatide 15 mg, semaglutide 1 mg, placebo. MAIN OUTCOME MEASURES:Glycemic control, model-derived β-cell function indices including insulin secretion rate (ISR) at 7.2-mmol/L glucose (ISR7.2), β-cell glucose (β-CG) sensitivity, insulin sensitivity, and estimated hepatic insulin-to-glucagon ratio. RESULTS:Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide (P < 0.01). Incremental glucose AUC did not differ significantly between treatments; therefore, greater total glucose AUC reduction with tirzepatide was mainly attributable to greater suppression of fasting glucose. A greater reduction in total ISR AUC was achieved with tirzepatide vs semaglutide (P < 0.01), in the context of greater improvement in insulin sensitivity with tirzepatide (P < 0.01). ISR7.2 was significantly increased with tirzepatide vs semaglutide (P < 0.05), showing improved β-CG responsiveness. MMTT-derived β-CG sensitivity was increased but not significantly different between treatments. Both treatments reduced fasting glucagon and total glucagon AUC, with glucagon AUC significantly reduced with tirzepatide vs semaglutide (P < 0.01). The estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment. CONCLUSIONS:These results suggest that the greater glycemic control observed for tirzepatide manifests as improved fasting glucose and glucose excursion control, due to improvements in ISR, insulin sensitivity, and glucagon suppression.