Context: Novel dual GIP and GLP-1 receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide.

Objective: Explore mechanisms of glucose control by tirzepatide.

Design: Post-hoc analyses of fasting biomarkers and multiple linear regression analysis.

Setting: 47 sites in 4 countries.

Patients or Other Participants: 316 subjects with Type 2 diabetes.

Interventions: Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo.

Main Outcome Measures: Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks.

Results: HOMA2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (p<0.02). Proinsulin/insulin  and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (p<0.007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (p<0.033) and tirzepatide 10 mg significantly decreased HOMA2-IR (p=0.004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by one or more doses of tirzepatide (p<0.05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and HbA1c was conducted. WL significantly (p<0.028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively.

Conclusions: Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.