1693-P: Mazdutide Improves Markers of Insulin Sensitivity in Adults with Obesity without Type 2 Diabetes

Introduction and Objective: In a Phase 2 study (NCT06124807), mazdutide (MAZ), a GLP-1 and glucagon receptor agonist, significantly reduced body weight by up to 22.3% and hemoglobin A1c (HbA1c) by up to 0.6% at 48 weeks among adults with overweight and obesity without T2D. Biomarkers of beta-cell function and insulin sensitivity were assessed to further explore mechanisms by which MAZ influences glycemic control. Methods: Adults (N=179) with a BMI of ≥30 (or ≥27 kg/m2 with weight-related comorbidities) were assigned to MAZ (3/6, 10, or 16 mg) or placebo (PBO). Participants assigned to MAZ 3/6 mg escalated from 3 to 6 mg at week 32. Fasting biomarker changes from baseline to 48 weeks were assessed with mixed model for repeated measures. Homeostatic model assessments of insulin resistance (HOMA2-IR) and beta-cell function (HOMA2-B) were calculated with fasting glucose and insulin. Results: MAZ was associated with PBO-adjusted reductions of up to 10.1 mg/dL in fasting glucose and up to 54.1% in fasting insulin (both p<0.001). HOMA2-IR was reduced by up to 41.6% with MAZ vs a 2.4% increase with PBO (p<0.001). Consistent with improved insulin sensitivity, adiponectin and IGFBP-2 increased by up to 34.3% and 50.2% with MAZ, respectively (vs 6.2% reduction and 5.3% increase with PBO, respectively; both p<0.001). FGF21, a marker of hepatic insulin sensitivity, declined by up to 50.7% with MAZ vs 22.8% with PBO (p<0.05). Intact proinsulin decreased by up to 32.5% with MAZ vs 8.3% with PBO, and fasting glucagon decreased by up to 88.6% vs 16.6% with PBO (both p<0.001). HOMA2-B, a marker of beta-cell function, did not consistently change with MAZ in these participants without T2D. Conclusion: Treatment of people with obesity without T2D with MAZ was associated with improvements not only in body weight and HbA1c, but also in markers of insulin sensitivity. Disclosure M. Thomas: Employee; Current; Eli Lilly and Company. Stock/Shareholder; Current; Eli Lilly and Company. A.K. Weideman: Employee; Current; Eli Lilly and Company. Stock/Shareholder; Current; Eli Lilly and Company. T. Coskun: Employee; Current; Eli Lilly and Company. A. Haupt: Employee; Ended; Lilly. Stock/Shareholder; Ended; Lilly. O. Ferreira Galvao de Araujo: Employee; Current; Eli Lilly and Company. K.J. Mather: Employee; Current; Eli Lilly and Company.