Dual Glucagon and GLP-1 Receptor Agonist Survodutide Improves Biomarkers of Beta-Cell Function and Insulin Sensitivity in People With Type 2 Diabetes or Living With Overweight/Obesity.

AIMS: This post hoc analysis evaluated the effect of survodutide on beta-cell function, insulin sensitivity, and glucose biomarkers in two phase 2 trial populations. MATERIALS AND METHODS: Trial 1404-0002 randomised 413 participants with type 2 diabetes on metformin to receive survodutide, placebo, or semaglutide over 16 weeks. Trial 1404-0036 randomised 387 participants with overweight/obesity and normoglycaemia to receive survodutide or placebo for 46 weeks. Descriptive statistics were derived from both trials. Biomarker responses were analysed using mixed models for repeated measures and regression analysis to assess the impact of bodyweight changes. RESULTS: In trial 1404-0002, survodutide was associated with significant and rapid increases in HOMA-β versus placebo, with significant decreases in HOMA-IR, glucagon, and fasting plasma glucose (FPG). No significant changes occurred in high-molecular-weight (HMW) adiponectin, C-peptide, or fasting insulin levels. In trial 1404-0036, there was no significant change in HOMA-β with survodutide versus placebo, likely owing to normoglycaemia in participants. Survodutide was associated with significant decreases in HOMA-IR, glucagon, C-peptide, fasting insulin, and FPG versus placebo, and significant increases in HMW adiponectin. Combining all survodutide dose groups for each trial, absolute change in bodyweight from baseline explained the largest proportion of total variability in changes from baseline in fasting insulin and HOMA-IR. However, it did not explain other changes observed. CONCLUSIONS: Survodutide was associated with significantly improved beta-cell function and insulin sensitivity in adults with type 2 diabetes and with overweight or obesity. The durability of beta-cell improvements after treatment cessation remains unknown. These effects were largely independent of bodyweight changes, suggesting additional metabolic benefit beyond weight loss. TRIAL REGISTRATION: Trial 1404-0002, ClinicalTrials.gov identifier: NCT04153929; EudraCT number: 2019-002390-60. Trial 1404-0036, ClinicalTrials.gov identifier: NCT04667377; EudraCT number: 2020-002479-37.