Semaglutide altered prespecified proteins, yielding a combined weight-adjusted mediation of 44.0% (95% CI 7.6, >100) for its effect on MACE, suggesting mechanisms beyond weight loss.
RCT (n=9,461)
Does semaglutide reduce MACE through mechanisms independent of weight loss in patients with BMI ≥27 kg/m2 and CVD without diabetes?
Proteomic mediation analysis of the SELECT trial suggests that semaglutide reduces MACE through modulation of specific proteins (THBS2, NPPB, ANGPT2, CD93) independently of weight loss.
Effect estimate: Combined mediation 44.0% (95% CI 7.6, >100)
Introduction and Objective: The SELECT trial of patients with BMI ≥27 kg/m2 and CVD without diabetes found a 20% reduction in major adverse CV events (MACE) with semaglutide. Proteomic analysis in the STEP 1 trial yielded proteins modulated by semaglutide. For six of these proteins with genetic evidence for causal effects on cardiovascular disease (CVD), we conducted a mediation analysis in SELECT. Methods: Thrombospondin 2 (THBS2), N-terminal pro-BNP (NPPB), macrophage scavenger receptor 1 (MSR1), angiopoietin-2 (ANGPT2), complement component C1q receptor (CD93), and tenascin-C (TNC) were measured in 9461/17,604 patients with available samples at baseline and week 20. Mediation analysis of MACE effect at 3 years, with/without adjustment for weight loss at week 20, used the Vansteelandt method. Results: Baseline protein levels were associated with MACE, and semaglutide modulated levels of these proteins in SELECT (Figure). Combined mediation was estimated at 44.0% (95% CI 7.6, 100) and 65.8% (19.7, 100), with and without weight adjustment, respectively (Figure). Weight-adjusted protein-specific estimates were significant for THBS2 (11.1%), NPPB (32.6%), ANGPT2 (19.3%), and CD93 (35.8%). Conclusion: Four prespecified proteins were altered by semaglutide and were significant in weight-adjusted mediation analysis, suggesting additional potential mechanisms of semaglutide’s effect on MACE beyond weight loss. Disclosure 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. J. Deanfield: Other - Received CME honoraria; Ended; Amgen Inc., Aegerion. Consultant; Current; AstraZeneca. Other - Member of Study Steering Committee for SOUL and SELECT; Current; Novo Nordisk. Other - Received CME honoraria; Ended; Bayer AG, Boehringer Ingelheim International GmbH. Other - Received CME honoraria; Current; Novo Nordisk. Research Support; Ended; British Heart Foundation, Alzheimer's Research UK, Pfizer, Colgate, Roche, Pfizer, Aegerion. Other - Advisory agreement.; Current; Caristo Diagnostics, eMed Healthcare, Floe Oral Care Ltd, Friede-Springer Cardiovascular Prevention Center, iOWNA, PMI Harm Reduction Group, Smarter Cardiovascular Outcomes By Research And Education L. S. Kahn: Advisory Panel; Current; AltPep, Amgen Inc., Congruence Therapeutics, Eli Lilly and Company, General Medicines, Kayothera, Merck 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. G.G. Hovingh: Employee; Current; Novo Nordisk A/S. K.J. Kolnes: Employee; Current; Novo Nordisk. Stock/Shareholder; Current; Novo Nordisk. P.E. Weeke: Employee; Current; Novo Nordisk. L. Bjerre Knudsen: Employee; Current; Novo Nordisk. J. Refsgaard: Employee; Current; Novo Nordisk A/S.
COLHOUN et al. (2026) conducted an RCT in Cardiovascular disease without diabetes and BMI ≥27 kg/m2 (n=9,461). Semaglutide was evaluated on Combined mediation of MACE effect at 3 years (weight-adjusted) (Combined mediation 44.0%, 95% CI 7.6, >100). Semaglutide altered prespecified proteins, yielding a combined weight-adjusted mediation of 44.0% (95% CI 7.6, >100) for its effect on MACE, suggesting mechanisms beyond weight loss.