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

Abstract

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.

The dual glucose‐dependent insulinotropic peptide and glucagon‐like peptide‐1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes

“…Treatment with tirzepatide reduced both small LDLP and HDLP compared with dulaglutide, despite no differences being observed in either the LDL‐C or HDL‐C levels between the two treatments. These changes in lipoprotein subclass distribution may be secondary to improved insulin sensitivity with tirzepatide 34 . Taken together, the significant reductions in small LDLP, non‐HDL‐C and apoB levels, in addition to reductions of triglycerides and apoC‐III, point towards an overall less atherogenic lipoprotein profile in patients with T2D treated with tirzepatide.…”

GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice

“…The clinical implications of these findings are that the weight-independent insulin sensitization identified here could offer greater treatment durability, in contrast to agents that provide only weight driven benefits. In support of this hypothesis, HOMA-IR analysis has suggested that a significant proportion of tirzepatide-induced insulin sensitization occurs in the absence of weight loss in subjects with T2DM (52). Together with studies showing that GIP can improve insulin sensitivity (23,24), this prompted the hypothesis that engagement of the GIPR may drive the weight-independent insulin sensitization action of tirzepatide.…”

How May GIP Enhance the Therapeutic Efficacy of GLP-1?

“…Post hoc regression analysis of HOMA2-IR suggests that only 20-30% of the improvement in insulin sensitization by tirzepatide is due to weight loss [93], by contrast to GLP-1RAs where insulin sensitivity is attributed to weight loss only [94]. Additional studies with tirzepatide will more directly explore the effect of GIP/GLP-1 receptor agonism on pancreatic α cell function, β cell function, and whole-body insulin sensitivity (ClinicalTrials.gov identifier NCT03951753).…”