1702-P: Molecular Basis of Type 2 Diabetes Prevention by Semaglutide in SELECT

Introduction and Objective: In the randomized SELECT trial, semaglutide (sema) reduced the risk of developing T2D by 73% vs placebo. The molecular mechanisms underlying the delay in progression to biochemical diabetes remain poorly understood. Methods: A post hoc analysis of SELECT participants (pts) with proteomics (SomaScan 7k) included 7209 pts with prediabetes (HbA1c ≥5.7-6.4%), overweight/obesity, and established cardiovascular disease. Pts received once-weekly sema (n=3609) or placebo (n=3600). Baseline proteomics were analyzed to identify proteins prognostic for T2D progression at week 104. Mediation analysis assessed if these proteins mediated sema's preventive effect. Genetic evidence was used to triangulate causal roles of these proteins. Results: Of pts with prediabetes, 19 (0.5%) on sema and 213 (6%) on placebo progressed to T2D. Of the 26 proteins prognostic for T2D progression, sema favorably modulated 21, with 18 mediating up to 8% of its effect (Figure). Among all proteins mediating sema's effect, 32 had genetic evidence for causal roles in T2D. Conclusion: Sema prevents T2D progression through multiple pathways, including hepatic lipid handling. By integrating clinical biomarkers, proteomic profiling, and genetic causal inference, we identified 32 proteins that mediate T2D prevention by sema. The mechanisms by which changes in protein levels mediate the effect are being investigated further. Disclosure D.M. Belmont-Rausch: Employee; Current; Novo Nordisk A/S. Stock/Shareholder; Current; Viking Therapeutics. Stock/Shareholder; Ended; Madrigal Pharmaceuticals, Inc. A. Aguayo Orozco: Employee; Current; Novo Nordisk. W. Gan: Employee; Current; Novo Nordisk A/S, Novo Nordisk. G.D. Carrasquilla: Employee; Current; Novo Nordisk A/S. M. Quiroga: Employee; Current; Novo Nordisk. Stock/Shareholder; Current; Eli Lilly and Company, Genmab, Coloplast, Novo Nordisk. I. Lingvay: Consultant; Current; Aadvarak Therapeutics, Abbvie, Alveus Therapeutics, Amgen, Antag Therapeutics, Arrowhead Pharmaceuticals, Astra Zeneca, Baim Institute, Bain Capital, Bayer, Betagenon AB, Bioio Inc., Biomea, Boehringe. Research Support; Current; Novo Nordisk A/S, Dexcom, Inc., Boehringer Ingelheim International GmbH. Consultant; Current; Eli Lilly, Genentech, Janssen/J Current; AltPep, Amgen Inc., Congruence Therapeutics, Eli Lilly and Company, General Medicines, Kayothera, Merck Current; Boehringer Ingelheim International GmbH, Novo Nordisk. Advisory Panel; Ended; Regeneron Pharmaceuticals Inc. Advisory Panel; Current; Zealand Pharma A/S. L. Bjerre Knudsen: Employee; Current; Novo Nordisk.