Tirzepatide, a dual GIP and GLP-1 receptor agonist, improves markers of beta cell function and insulin sensitivity in type 2 diabetes patients

Tirzepatide (TZP), a novel dual GIP and GLP-1 receptor agonist (RA), showed significantly greater glucose control and weight loss compared to the selective GLP-1 RA dulaglutide (DU) in a 26-week, randomized, double-blind Phase 2b study of type 2 diabetes patients. TZP doses tested were 1, 5, 10, and 15 mg versus placebo (PB) and DU 1.5 mg. Fasting markers of beta cell function and insulin sensitivity were analyzed by mixed model repeated measures to explore differentiated mechanisms of glucose control by TZP. Biomarkers of beta cell function were improved by TZP. Proinsulin to insulin ratios, insulin processing markers of beta cell stress, were significantly reduced by TZP 10 and 15 mg compared with PB and DU. HOMA2-B significantly increased with DU and TZP 5, 10, and 15 mg compared with PB. TZP 10 mg significantly improved insulin sensitivity as reflected by lower HOMA2-IR compared with PB and DU. TZP 10 and 15 mg significantly decreased fasting insulin compared with PB and DU, consistent with reduced insulin resistance. To evaluate weight loss contributions to improvements in insulin sensitivity with TZP, multiple linear regression with potential confounding variables age, sex, metformin use, and baseline HbA1c was conducted. An intercept-free model with weight loss as the only covariate was selected as the most significant of all possible models. Weight loss significantly (p<0.004) explained 22% and 28% of variation in HOMA2-IR with TZP 15 and 10 mg, respectively, suggesting the insulin sensitizing effects of TZP are only partly attributable to weight loss. Multiple markers associated with improved insulin sensitivity were significantly increased by one or more doses of TZP compared with PB or DU, including adiponectin, IGFBP1, and IGFBP2. These data suggest that, compared with the selective GLP-1 RA dulaglutide, TZP has a greater impact on insulin sensitivity and beta cell function, resulting in improved glycemic control. Disclosure M.K. Thomas: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. A. Nikooienejad: Research Support; Self; Eli Lilly and Company. R. Bray: Employee; Self; Eli Lilly and Company. X. Cui: Employee; Self; Eli Lilly and Company. J.M. Wilson: Employee; Self; Eli Lilly and Company. K.L. Duffin: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Pfizer Inc. Z. Milicevic: Employee; Self; Eli Lilly and Company. A. Haupt: Employee; Self; Lilly Diabetes. Stock/Shareholder; Self; Lilly Diabetes. D.A. Robins: Employee; Self; Eli Lilly and Company. Funding Eli Lilly and Company