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, p<0.05). 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 & Johnson. 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&J, Juvena, Keros Therapeutic, Inc, Mediflix, Metsera, Neurocrine, Novo Nordisk, Penguin Bio, Pfizer, Regeneron, Response Pharmaceutical, Roche, Sanofi, Shionogi, Skye B, Tenvie, TERNS Pharma, Verdiva Bio, Viking Therapeutics, and Zealand Pharma. J. Plutzky: Consultant; Current; Amgen Inc., Boehringer Ingelheim International GmbH, Corcept Therapeutics, Merck & Co., Inc., Novo Nordisk Foundation. J.A. Sibbesen: Employee; 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.