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.


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.


Eli Lilly and Company

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at