Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2)

Abstract

Context: In previous SURPASS studies tirzepatide reduced hemoglobin glycated A1c (HbA1c) and body weight and improved markers of insulin sensitivity and β-cell function to a greater extent than comparators.

Objective: Explore changes in biomarkers of β-cell function and insulin sensitivity and in efficacy profiles in baseline biomarker quartile analyses with tirzepatide compared to semaglutide.

Design: Post hoc analysis of SURPASS-2 phase 3 trial (participants randomly assigned to receive weekly subcutaneous tirzepatide or semaglutide for 40 weeks).

Setting: Post hoc analysis of 128 sites in 8 countries.

Participants: A total of 1879 participants with type 2 diabetes.

Interventions: Once-weekly tirzepatide (5, 10, 15 mg) or semaglutide 1 mg.

Main outcomes measures: Change in homeostatic model assessment indices for pancreatic β-cell function (HOMA2-B) and for insulin resistance (HOMA2-IR), fasting glucagon, fasting C-peptide, and fasting insulin.

Results: At week 40, a greater increase in HOMA2-B was seen with tirzepatide (5, 10, 15 mg) doses (96.9-120.4%) than with semaglutide 1 mg (84.0%) (P < .05). There was a greater reduction in HOMA2-IR with all doses of tirzepatide (15.5%-24.0%) than with semaglutide 1 mg (5.1%) (P < .05). Tirzepatide 10 and 15 mg resulted in a significant reduction in both fasting C-peptide (5.2%-6.0%) and fasting glucagon (53.0%-55.3%) compared with an increase of C-peptide (3.3%) and a reduction of glucagon (47.7%) with semaglutide 1 mg (P < .05). HbA1c and body weight reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile.

Conclusion: In this post hoc analysis, improvements in HbA1c and weight loss were consistent and significantly higher with tirzepatide, regardless of baseline β-cell function and insulin resistance, compared with semaglutide.

Keywords: beta-cell function; incretin; insulin sensitivity; tirzepatide; type 2 diabetes.

Figure 1.

Percent change from baseline over 40 weeks. (A) Fasting glucagon. (B) Fasting C-peptide. (C) HOMA2-B (calculated with C-peptide). (D) Fasting insulin. (E) HOMA2-IR (calculated with insulin). *P < .05 and **P < .001 for LS mean difference between tirzepatide dose group vs semaglutide. Maintenance doses were achieved at week 4 for tirzepatide 5 mg, week 12 for tirzepatide 10 mg, week 20 for tirzepatide 15 mg, and week 8 for semaglutide. Percent change was derived from the MMRM model for change on log-scale with model terms log (baseline), pooled country, baseline HbA1c group (≤8.5%, vs >8.5%), treatment group, visit, and treatment group by visit interaction. The change from baseline for fasting serum glucose was derived from the MMRM model with model terms of baseline value, pooled country, baseline HbA1c group (≤8.5% vs >8.5%), treatment group, visit, and treatment by visit interaction. HbA1c, glycated hemoglobin A1c; HOMA2-B, homeostasis model assessment (updated version) for β-cell function (C-peptide); HOMA2-IR, homeostasis model assessment for β-cell function (calculated with insulin); LS, least squares; MMRM, mixed model for repeated measures.

Figure 2.

(A) HbA1c change from baseline to week 40 by HOMA2-B baseline quartile. (B) HbA1c change from baseline to week 40 by HOMA2-IR baseline quartile. (C) Body weight change from baseline to week 40 by HOMA2-B baseline quartile. (D) Body weight change from baseline to week 40 by HOMA2-IR baseline quartile. *P < .05 and **P < .001 for LS mean difference between tirzepatide dose group vs semaglutide. Notes: n values are for week 40. LS means were calculated from MMRM model with model terms of baseline value, pooled country, treatment group, visit, and treatment by visit interaction within each baseline quartile. Weight analysis also included baseline HbA1c group (≤8.5% vs >8.5%) in the model. HbA1c, glycated hemoglobin A1c; HOMA2-B, homeostasis model assessment (updated version) for β-cell function (calculated with C-peptide); HOMA2-IR, homeostasis model assessment for β-cell function (calculated with insulin); LS, least squares; MMRM, mixed model for repeated measures; quartiles from low to high: Q1, first quartile; Q2, second quartile; Q3, third quartile; Q4, fourth quartile.