714-P: Greater Improvement in Insulin Sensitivity Per Unit Weight Loss with Tirzepatide Compared with Selective GLP-1 Receptor Agonism

Tirzepatide (TZP) , a novel GIP-GLP-1 dual agonist, improved fasting measures of insulin sensitivity partially attributable to weight loss in Phase 2 studies. Studies in mice demonstrated that GIP receptor agonism with TZP improved insulin sensitivity independent of weight loss. To further evaluate insulin-sensitizing actions of TZP, we measured insulin sensitivity with hyperinsulinemic euglycemic clamps (M-value) in a 28-week double-blind randomized controlled trial comparing effects of TZP 15mg with placebo or semaglutide 1mg (SEMA) , a selective GLP-1RA, all subcutaneous QW. Linear regression was used to compare relationships of change in M-value versus change in weight across treatment groups. Change in M-value was related to absolute change and % change in weight (Figure) . Slopes of linear relationships with absolute and % weight change differed between TZP and SEMA (absolute change: p=0.015; % change: p=0.03) . Larger negative slopes were observed for TZP compared with SEMA on change in M-value related to absolute change and to % change in weight. These results suggest that TZP may provide greater improvement in insulin sensitivity than a selective GLP-1RA per unit weight loss, most evident in subjects with greater weight loss. Disclosure K.J.Mather: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Mari: Consultant; Lilly, Research Support; Lilly. J.Li: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. T.Heise: Advisory Panel; Novo Nordisk A/S, Research Support; ADOCIA, AstraZeneca, Biocon, Boehringer Ingelheim International GmbH, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Genova, Nestlé, Neuraly Inc., Novo Nordisk A/S, Sanofi, Zealand Pharma A/S, Speaker's Bureau; Eli Lilly and Company, Gan & Lee Pharmaceuticals, Novo Nordisk A/S. J.De vries: Advisory Panel; ADOCIA, Novo Nordisk A/S, Zealand Pharma A/S, Speaker's Bureau; Novo Nordisk A/S. S.Urva: Employee; Eli Lilly and Company. T.Coskun: Employee; Eli Lilly and Company. Z.Milicevic: Employee; Eli Lilly and Company. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. Funding Eli Lilly and Company