Tirzepatide as Monotherapy Improved Markers of Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes (SURPASS-1)

Clare J Lee; Huzhang Mao; Vivian T Thieu; Laura Fernández Landó; Melissa K Thomas

doi:10.1210/jendso/bvad056

Tirzepatide as Monotherapy Improved Markers of Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes (SURPASS-1)

J Endocr Soc. 2023 Apr 22;7(5):bvad056. doi: 10.1210/jendso/bvad056. eCollection 2023 Mar 6.

Authors

Clare J Lee¹, Huzhang Mao¹, Vivian T Thieu¹, Laura Fernández Landó¹, Melissa K Thomas¹

Affiliation

¹ Eli Lilly and Company, Indianapolis, IN, 46285, USA.

Abstract

Context: Tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for treatment of type 2 diabetes (T2D). SURPASS-1, a phase 3 trial of tirzepatide monotherapy in people with early T2D, enables evaluating effects of tirzepatide on pancreatic beta-cell function and insulin sensitivity (IS) without other background antihyperglycemic medications.

Objective: Explore changes in biomarkers of beta-cell function and IS with tirzepatide monotherapy.

Design: Post hoc analyses of fasting biomarkers with analysis of variance and mixed model repeated measures.

Setting: Forty-seven sites in 4 countries.

Patients: Four hundred seventy-eight T2D participants.

Intervention: Tirzepatide (5, 10, 15 mg), placebo.

Main outcome measures: Analyze biomarkers of beta-cell function and IS at 40 weeks.

Results: At 40 weeks, markers of beta-cell function improved with tirzepatide monotherapy vs placebo with reductions from baseline in fasting proinsulin levels (49-55% vs -0.6%) and in intact proinsulin/C-peptide ratios (47-49% vs -0.1%) (P < .001, all doses vs placebo). Increases from baseline in homeostatic model assessment for beta-cell function (computed with C-peptide) (77-92% vs -1.4%) and decreases in glucose-adjusted glucagon levels (37-44% vs +4.8%) were observed with tirzepatide vs placebo (P < .001, all doses vs placebo). IS improved as indicated by reductions from baseline in homeostatic model assessment for insulin resistance (9-23% vs +14.7%) and fasting insulin levels (2-12% vs +15%), and increases in total adiponectin (16-23% vs -0.2%) and insulin-like growth factor binding protein 2 (38-70% vs +4.1%) with tirzepatide vs placebo at 40 weeks (P ≤ .031, all doses vs placebo, except for fasting insulin levels with tirzepatide 10 mg).

Conclusions: As monotherapy for early T2D, tirzepatide achieved significant improvements in biomarkers of both pancreatic beta-cell function and IS.

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