Abstract
INTRODUCTION: The objective of this work was to assess the association of tirzepatide with changes in insulin sensitivity and beta-cell function in Japanese patients with type 2 diabetes (T2D). METHODS: This was a prespecified analysis of SURPASS J-mono, a multicenter, randomized, double-blind, active-controlled phase 3 study in Japanese participants with T2D. Participants were randomly assigned to receive tirzepatide 5, 10, 15 mg, or dulaglutide 0.75 mg once weekly for 52 weeks. Changes from baseline in homeostatic model assessment (HOMA2) parameters were assessed by a mixed model for repeated measures. Post hoc subgroup analyses were conducted based on high and low baseline C-peptide categories (cutoff: median 1.86 µg/l). RESULTS: This analysis included 636 participants (tirzepatide 5 mg: n = 159; 10 mg: n = 158; 15 mg: n = 160; dulaglutide 0.75 mg: n = 159). Fasting insulin and C-peptide levels were significantly reduced from baseline at week 52 at all three tirzepatide doses compared with dulaglutide 0.75 mg (estimated treatment differences [ETDs] for tirzepatide 5, 10, and 15 mg, respectively: insulin, - 22.6%, - 29.8%, and - 31.0%; C-peptide, - 14.2%, - 21.5%, and - 20.7%; p < 0.001 all comparisons). Insulin sensitivity and beta-cell function indices significantly increased in all tirzepatide groups compared with the dulaglutide 0.75-mg group (ETDs for tirzepatide 5, 10, and 15 mg, respectively: HOMA2-%S [insulin], 31.8%, 43.2%, and 49.9%; HOMA2-%S [C-peptide], 24.8%, 33.9%, and 38.2%; HOMA2-%B [insulin], 27.3%, 34.9%, and 40.6%; HOMA2-%B [C-peptide], 31.6%, 40.1%, and 46.7%; p < 0.001 all comparisons). Regardless of baseline C-peptide level, the tirzepatide groups showed significant improvement in glycated hemoglobin at week 52 compared with the dulaglutide group (C-peptide < 1.86 µg/l: - 2.31% to - 2.75% vs. - 1.45%; ≥ 1.86 µg/l: - 2.43% to - 2.89% vs. - 1.12%; p < 0.001). CONCLUSIONS: In these prespecified and post hoc analyses, tirzepatide was associated with improved insulin sensitivity and insulin secretion in Japanese participants with T2D, which may result in reduced fasting insulin levels. CLINICALTRIALS: GOV: NCT03861052.