1685-P: Exploring Semaglutide's Effect on the ASCVD-Related Proteomic Signature and Their Prediction of MACE in SELECT

Introduction and Objective: We investigated the 70-protein risk score for subsequent atherosclerotic cardiovascular disease (ASCVD), reported in the primary prevention deCODE cohort, on subsequent major adverse CV events (MACE) in SELECT, a trial of semaglutide 2.4 mg vs placebo in patients (pts) with ASCVD, obesity (BMI≥27 kg/m²) but not diabetes. These data were used to consider how semaglutide might alter CV risk independently of weight loss. Methods: Proteins were measured using SomaScan 7K in 10,878 SELECT pts (CVD, BMI ≥27 kg/m², no diabetes) at baseline (BL), 20, and 104 weeks. Cox regression assessed association between 70 proteins BL levels and MACE. Effect of semaglutide vs placebo at 20 and 104 weeks (on-treatment) was tested with univariate linear models adjusted for body weight change. Results: At BL, 8 of the 70 proteins tested (NPPB, WFDC2, GDF15, TREM1, CCL15, MCTS1, TNFRSF11B, MANEA) were prognostic for MACE (HR 1.2-1.6, p0.05). After 104 weeks of treatment, 5 of those were reduced significantly (Fig): cardiac stress markers (NPPB), matrix remodeling enzymes (TNFRSF11B), growth factors (GDF15) and immune/inflammatory mediators (TREM1, CCL15). Two (NPPB, TNFRSF11B) were reduced after 20 weeks. Conclusion: Semaglutide treatment was associated with changes in ASCVD risk proteins that also predict MACE, suggesting potential mechanisms of semaglutide’s weight-independent effect on MACE. Disclosure M. Dermit: None. A. Aguayo Orozco: Employee; Current; Novo Nordisk. A. Bjerregaard: Employee; Current; Novo Nordisk. F. Capelluto: Employee; Current; Novo Nordisk. H.M. Colhoun: Research Support; Current; Diabetes UK, IQVIA Inc., Sanofi, JDRF, Chief Scientist Office. Research Support; Ended; Medical Research Council (UKRI). Other - Personal payment for consultancy (ENDED);Research support (ongoing); Current; Sanofi. Other - Advisory board member (ongoing); Support for attendance at meetings /conferences and travel; Current; Novo Nordisk. Other - Advisory panel member (ongoing);Stockholder (up to January 2025- ENDED); Current; Bayer AG. Other - Stockholder (ongoing);Institutional payment for consultancy (ongoing); Current; Roche Pharmaceuticals. B. Follin: Employee; Current; Novo Nordisk A/S. K.B. Hessellund: Employee; Current; Novo Nordisk A/S. A.M. Lincoff: Consultant; Current; Novo Nordisk, Eli Lilly and Company. Stock/Shareholder; Current; Canary Cure. Research Support; Current; Novartis AG. Consultant; Ended; Alnylam Pharmaceuticals, Inc., Amgen Inc., Ardelyx, Brainstom Cell, Capricor, Johnson 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; Amgen Inc., Boehringer Ingelheim International GmbH, Corcept Therapeutics, Merck Current; Novo Nordisk A/S. S. Stensen: Employee; Current; Novo Nordisk A/S. P.E. Weeke: Employee; Current; Novo Nordisk. T.N. Wistisen: Employee; Current; Novo Nordisk. L. Bjerre Knudsen: Employee; Current; Novo Nordisk. S. Kahn: Advisory Panel; Current; AltPep, Amgen Inc., Congruence Therapeutics, Eli Lilly and Company, General Medicines, Kayothera, Merck & Co., Inc., Neurimmune, Novo Nordisk, Roche Pharmaceuticals.