Semaglutide on liver fibrosis and heart outcomes in patients at high risk of liver fibrosis: a prespecified analysis of the SELECT randomized trial.

“Semaglutide on liver fibrosis and heart outcomes in patients at high risk of liver fibrosis: a prespecified analysis of the SELECT randomized trial. Meyhöfer SM(1)(2), Cariou B(3), Cercato C(4), Colhoun HM(5), Deanfield J(6), Long MT(7)(8), Jeppesen OK(7), Lincoff AM(9), Lingvay I(10), Plutzky J(11), Newsome PN(12), Nicholls SJ(13), Quiroga M(7), Santini F(14), Sanyal AJ(15), Kahn SE(16); SELECT Trial Investigators. Collaborators: Ryan DH, Emerson SS, Kushner RF, Brown-Frandsen K, Hovingh GK, Hardt-Lindberg S, Tornøe CW. Author information: (1)Clinical, Medical & Regulatory, Novo Nordisk Pharma GmbH, Mainz, Germany. SMYF@novonordisk.com. (2)Department of Internal Medicine 1 - Endocrinology & Diabetes, University Medical Centre Lübeck, Lübeck, Germany. SMYF@novonordisk.com. (3)Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France. (4)Obesity Unit, Department of Endocrinology, Clinical Hospital of the University of São Paulo, São Paulo, Brazil. (5)Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK. (6)Institute of Cardiovascular Science, University College London, London, UK. (7)Novo Nordisk A/S, Søborg, Denmark. (8)Department of Medicine, Section of Gastroenterology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA. (9)Department of Cardiovascular Medicine, Cleveland Clinic and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA. (10)Department of Internal Medicine/Endocrinology and Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA. (11)Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (12)Roger Williams Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, Foundation for Liver Research and King's College Hospital, London, UK. (13)Victorian Heart Institute, Monash University, Melbourne, Victoria, Australia. (14)Obesity and Lipodystrophy Centre, University Hospital of Pisa, Pisa, Italy. (15)Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. (16)Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA, USA. In the SELECT trial, once-weekly subcutaneous semaglutide reduced major adverse cardiovascular events (MACE) by 20% versus placebo in patients with atherosclerotic cardiovascular disease and obesity but without diabetes. We examined semaglutide in SELECT patients at high risk for substantial liver fibrosis in a prespecified secondary analysis. Liver biochemical tests and steatosis risk according to fatty liver index were assessed over 104 weeks. Subgroup analyses of the primary MACE (a composite endpoint including cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) outcome used baseline Fibrosis-4 scores ≥ 1.3, age-specific (≥1.3 (<65 years) or ≥2.0 (≥65 years)) and any age with Fibrosis-4 > 2.67. MACE was reduced by 26% (hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.63-0.88; P = 0.0004), 21% (HR 0.79; 95% CI 0.63-0.98; P = 0.035) and 34% (HR 0.66; 95% CI 0.39-1.10; P = 0.11), respectively. Semaglutide led to a 28% greater decrease in fatty liver index versus placebo (HR 0.72; 95% CI 0.71-0.73; P < 0.0001). In conclusion, semaglutide reduced MACE versus placebo in patients at risk for substantial liver fibrosis, as seen in the overall SELECT population. ClinicalTrials.gov registration no. NCT03574597. © 2026. The Author(s). Conflict of interest statement: Competing interests: S.M.M. has received consulting honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daichii-Sankyo, Eli Lilly, esanum, Gilead, Ipsen, Novartis, Novo Nordisk, Sandoz and Sanofi, and has received research grants from AstraZeneca, Eli Lilly and Novo Nordisk. B.C. has received consulting honoraria from Abbott, Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Novartis, Novo Nordisk, Sanofi and Ultragenyx, and research funding to his institution from Air Liquide, Sanofi and Ypsomed. C.C. has received consulting honoraria from Brace Pharma, Eli Lilly, Eurofarma, Merck and Novo Nordisk. H.M.C. has served on advisory panels for Bayer and Novo Nordisk, has received research funding from IQVIA, Roche and Sanofi, has received grants from the Chief Scientist Office, Diabetes UK, the European Commission, the Juvenile Diabetes Research Foundation and the Medical Research Council, has served on a speaker’s bureau for Novo Nordisk and holds stock in Bayer and Roche Pharmaceuticals. J.D. has received consulting honoraria from Aegerion, Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi and Takeda, and research grants from Aegerion, the British Heart Foundation, Colgate, the Medical Research Council (UK), Merck Sharp & Dohme, the National Institute for Health and Care Research, Pfizer, Public Health England and Roche. M.T.L., O.K.J. and M.Q. are employees of Novo Nordisk. A.M.L. has received research grants from AbbVie, AstraZeneca, CSL Behring, Eli Lilly, Esperion Therapeutics and Novartis, paid to his institution, and has served as a consultant for Akebia Therapeutics, Alnylam Pharmaceuticals, Ardelyx, Canary Cure, Eli Lilly, FibroGen, GlaxoSmithKline, Intarcia, Medtronic Vascular, the Novartis Pharmaceuticals Corporation, Novo Nordisk, Provention Bio, and ReCor Medical. I.L. has received research grants from Boehringer Ingelheim, Merck, Mylan Pharmaceuticals, Novo Nordisk, Pfizer and Sanofi US Services, has served as a consultant for AstraZeneca, Bayer Healthcare Pharmaceuticals, Biomea, Boehringer Ingelheim, Carmot, Eli Lilly, Intarcia, Intercept Pharmaceuticals, Janssen Global Services, Johnson & Johnson Medical Devices & Diagnostics Group-Latin America, MannKind Corporation, Merck, Novo Nordisk, Pfizer, Sanofi US Services, Shionogi, StructureTherapeutics, Target Pharma, Valeritas and Zealand Pharma, and has received travel expenses from Boehringer Ingelheim, Eli Lilly, Johnson & Johnson Medical Devices & Diagnostics Group-Latin America, Novo Nordisk, Sanofi US Services and Zealand Pharma. J.P. has received consulting honoraria from Altimmune, Amgen, Esperion Therapeutics, Merck, MJH Life Sciences, Novartis and Novo Nordisk, has received a grant, paid to his institution, from Boehringer Ingelheim and holds the position of Director, Preventive Cardiology at Brigham and Women’s Hospital. P.N.N. has received consulting fees from Aligos, Boehringer Ingelheim, Madrigal, Novo Nordisk, Sagimet, Shionogi and 89bio. S.J.N. has received research support from Amgen, Anthera, AstraZeneca, Cerenis, CSL Behring, Cyclarity, Eli Lilly, Esperion, Infraredx, New Amsterdam Pharma, Novartis, Resverlogix and Sanofi-Regeneron, and is a consultant for Akcea, Amgen, AstraZeneca, Boehringer Ingelheim, CSL Behring, CSL Sequiris, Eli Lilly, Esperion, Kowa, Merck, Novo Nordisk, Pfizer, Sanofi-Regeneron, Takeda and Vaxxinity. F.S. has worked as a consultant for, participated in studies for or received travel funds from the following companies that are involved with obesity, lipodystrophy or diabetes: Aegerion/Amryt, BioItalia, Boehringer Ingelheim, Bruno Pharma, Lilly, Novo Nordisk and Pfizer. A.J.S. consults for and advises AstraZeneca and Avant Santé, consults for and has received grants from Akero, Bristol Myers Squibb, Eli Lilly, Intercept, Madrigal and Novo Nordisk, consults for and owns stock in Rivus, consults for 89bio, AGED Diagnostics, Albireo, Alnylam, Altimmune, Boehringer Ingelheim, Echosens, Genentech, Gilead, GlaxoSmithKline, HistoIndex, Mallinckrodt, Merck, NGM Bio, Novartis, PathAI, Pfizer, Poxel, Regeneron, Salix, Siemens, Surrozen, Takeda, Terns and Zydus, owns stock in Durect, Exalenz, Genfit, Indalo, Inversago and Tiziana, and has received royalties from Elsevier and Wolters Kluwer. S.E.K. has received consulting honoraria from Anii Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk and Oramed, and stock options from Altpep.”