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.

Keywords: GIP; GLP-1; beta-cell function; insulin sensitivity; tirzepatide; type 2 diabetes.

Figure 1.

Percent change from baseline in markers of beta-cell function with tirzepatide treatment at 26 weeks. Doses are indicated in figure inset for tirzepatide, dulaglutide, and placebo. Data presented as LSM ± SE at 26 weeks from MMRM; modified intent-to-treat population excluding data after study drug discontinuation or rescue drug initiation. Abbreviations: LSM = least squares mean; MMRM = mixed models repeated measures; SE = standard error. *P < .05 and **P < .001 vs baseline, ^†P < .05 and ^††P < .001 vs placebo, ^‡P < .05 and ^‡‡P < .001 vs dulaglutide.

Figure 2.

Percent change from baseline in markers of insulin sensitivity with tirzepatide treatment at 26 weeks. Doses are indicated in figure inset for tirzepatide, dulaglutide, and placebo. Data presented as LSM ± SE at 26 weeks from MMRM; modified intent-to-treat population excluding data after study drug discontinuation or rescue drug initiation. Abbreviations: LSM, least squares mean; MMRM, mixed models repeated measures; SE, standard error. *P < .05 and **P < .001 vs baseline, ^†P < .05 and ^††P < .001 vs placebo, ^‡P < .05 and ^‡‡P < .001 vs dulaglutide.