Introduction and Objective: Semaglutide has shown benefits on multiple clinical endpoints, including reduction of all-cause mortality in adults with overweight/obesity and cardiovascular disease (CVD). We investigated the effect of semaglutide on biological age using mortality-based proteomics aging clocks developed in the UK BioBank, which reflect physiological deterioration. Methods: We applied 2nd generation aging clocks to proteomics data from SELECT, STEP 1 and STEP 2 trials participants and assessed effect of semaglutide 2.4 mg treatment on multi-organ (combination of all organ-specific proteins) and organismal (combination of all non-organ-specific proteins) clocks. Results: Semaglutide 2.4 mg reduced biological age assessed by multi-organ clocks, with similar effect sizes between cohorts (Figure), ie, 5.2% in SELECT (p0.0001), 4.5% in STEP 1 (p0.05), and 7.2% in STEP 2 (p0.05). We found no effect of semaglutide on organismal biological age. Conclusion: Semaglutide consistently reduced mortality-trained proteomic multi-organ biological age across patients with obesity and different comorbidities, while organismal clocks were unchanged. These findings suggest semaglutide modifies organ-specific proteomic signatures linked to mortality risk. Disclosure M. Dermit: None. A. Aguayo Orozco: Employee; Current; Novo Nordisk. S.A. Voisin: Employee; Current; Novo Nordisk A/S. K. Adelborg: Employee; Current; Novo Nordisk A/S. Stock/Shareholder; Current; Novo Nordisk A/S. D.M. Belmont-Rausch: Employee; Current; Novo Nordisk A/S. Stock/Shareholder; Current; Viking Therapeutics. Stock/Shareholder; Ended; Madrigal Pharmaceuticals, Inc. 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. L.J. Goeminne: None. V. Gladyshev: None. K.J. Kolnes: Employee; Current; Novo Nordisk. Stock/Shareholder; Current; Novo Nordisk. D. Ryan: Advisory Panel; Current; Abbvie, Altimmune, Amgen, AstraZenica, Boehringer Ingelheim, Biohaven, Carmot/Roche/Genentech. Advisory Panel; Ended; eMed, Fractyl, Nestle. Consultant; Current; Pfizer, Source Bio, Protagonist, PPD, Regeneron, Regor. Advisory Panel; Current; Currax, Structure Therapeutics, Tenvie, Kailera. Speaker's Bureau; Current; LIlly, Novo Nordisk,. Other - I am a consultant to both and received stock options and consulting fees.; Current; Calibrate, Epitomee. Other - Data Monitoring Committee member; Current; CinRx, Rhythm, Lilly. Advisory Panel; Current; Viking, Weight Watchers, Wonder Health, Zealand. Other - ! received non-negotiable stock options from these companies years ago and have not worked for them in years.; Ended; Roman, Scientific Intake. L. Bjerre Knudsen: Employee; Current; Novo Nordisk.
Dermit et al. (Fri,) studied this question.