Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes

Abstract

Context

Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (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

Forty-seven sites in 4 countries.

Patients or other Participants

Three hundred and sixteen 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

Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo ( P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide ( P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin ( P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR ( P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide ( P < .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 glycated hemoglobin A1c was conducted. WL significantly ( P ≤ .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.