266-OR: Retatrutide, an Agonist of GIP, GLP-1, and Glucagon Receptors, Improves Markers of Pancreatic Beta-Cell Function and Insulin Sensitivity

Retatrutide (RETA), an agonist of GIP, GLP-1 and glucagon receptors, significantly reduced HbA1c up to 2.2% in T2D and body weight up to 17% in T2D at wk 36 and 24% in obesity without T2D (OB) at wk 48 in Ph2 trials. To explore mechanisms by which RETA improved glycemic control, we assessed markers of beta-cell function and insulin sensitivity. Mixed models for repeated measures evaluated fasting biomarkers from two Ph2 double-blind randomized placebo-controlled trials: in T2D (281 subjects, 36-wks) and in OB (338 subjects, 48-wks). Homeostatic model assessment (HOMA2)-IR index (insulin), a measure of insulin resistance, decreased over time from baseline with RETA 12 mg reaching reductions of 39% in T2D at 36 wks and 52% in OB at 48 wks. Adiponectin, a marker of insulin sensitivity, increased with RETA from baseline up to 52% in T2D and up to 70% in OB, (p<0.001). HOMA2-B index (C-peptide), a marker of beta-cell function, rapidly increased with RETA up to 88% from baseline in T2D but did not significantly increase in OB. Proinsulin and proinsulin/C-peptide ratios, measures of beta-cell stress and dysfunction, decreased from baseline with RETA, by up to 71% and 62%, respectively, in T2D (p<0.001). In conclusion, RETA improved markers of beta-cell function in T2D and markers of insulin sensitivity in T2D and OB. Disclosure J. Rosenstock: Research Support; Biomea Fusion, Inc. Other Relationship; Lilly Diabetes. Research Support; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Corcept Therapeutics. Other Relationship; Novo Nordisk. Research Support; Pfizer Inc. Other Relationship; Sanofi, Boehringer-Ingelheim. Research Support; Shionogi & Co., Ltd. Other Relationship; Structure Therapeutics, Inc. Advisory Panel; Terns Pharmaceuticals, Zealand Pharma A/S. Other Relationship; Applied Therapeutics, Hanmi Pharm. Co., Ltd., Oramed Pharmaceuticals. Advisory Panel; Scholar Rock. T. Coskun: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M.L. Hartman: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. J. Lou: None. Q. Wu: None. Y. Du: None. S. Gurbuz: Employee; Eli Lilly and Company. K.J. Mather: Employee; Eli Lilly and Company. Z. Milicevic: Employee; Eli Lilly and Company. M.K. Thomas: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company