• Arun J Sanyal, Pierre Bedossa, Mandy Fraessdorf, Guy W Neff, Eric Lawitz, Elisabetta Bugianesi, Quentin M Anstee, Samina Ajaz Hussain, Philip N Newsome, Vlad Ratziu, Azadeh Hosseini-Tabatabaei, Jörn M Schattenberg, Mazen Noureddin, Naim Alkhouri, Ramy Younes, and 1404-0043 Trial Investigators.
• From the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond (A.J.S.); Liverpat and University of Paris (P.B.), and Sorbonne Université, Institute for Cardiometabolism and Nutrition, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche Scientifique 1138, Centre de Recherche des Cordeliers (V.R.) - all in Paris; Boehringer Ingelheim, Ingelheim am Rhein (M.F., S.A.H and R.Y.), Saarland University Medical Center, Homburg (J.M.S.), and University of the Saarland, Saarbrücken (J.M.S.) - all in Germany; Covenant Metabolic Specialists, Sarasota, FL (G.W.N.); Houston Methodist Hospital and Houston Research Institute, Houston (M.N.), and the Texas Liver Institute, University of Texas Health San Antonio, San Antonio (E.L. and N.A.) - all in Texas; the University of Turin, Turin, Italy (E.B.); the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, and Newcastle National Institute for Health and Care Research Biomedical Research Centre, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne (Q.M.A.), the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham (P.N.N.), and the Institute of Hepatology, Faculty of Life Sciences and Medicine, King's College London and King's College Hospital, London (P.N.N.) - all in the United Kingdom; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (A.H.-T.); and Arizona Liver Health, Chandler (N.A.).
• N. Engl. J. Med. 2024 Jul 25; 391 (4): 311319311-319.

BackgroundDual agonism of glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor may be more effective than GLP-1 receptor agonism alone for treating metabolic dysfunction-associated steatohepatitis (MASH). The efficacy and safety of survodutide (a dual agonist of glucagon receptor and GLP-1 receptor) in persons with MASH and liver fibrosis are unclear.MethodsIn this 48-week, phase 2 trial, we randomly assigned adults with biopsy-confirmed MASH and fibrosis stage F1 through F3 in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of survodutide at a dose of 2.4, 4.8, or 6.0 mg or placebo. The trial had two phases: a 24-week rapid-dose-escalation phase, followed by a 24-week maintenance phase. The primary end point was histologic improvement (reduction) in MASH with no worsening of fibrosis. Secondary end points included a decrease in liver fat content by at least 30% and biopsy-assessed improvement (reduction) in fibrosis by at least one stage.ResultsA total of 293 randomly assigned participants received at least one dose of survodutide or placebo. Improvement in MASH with no worsening of fibrosis occurred in 47% of the participants in the survodutide 2.4-mg group, 62% of those in the 4.8-mg group, and 43% of those in the 6.0-mg group, as compared with 14% of those in the placebo group (P<0.001 for the quadratic dose-response curve as best-fitting model). A decrease in liver fat content by at least 30% occurred in 63% of the participants in the survodutide 2.4-mg group, 67% of those in the 4.8-mg group, 57% of those in the 6.0-mg group, and 14% of those in the placebo group; improvement in fibrosis by at least one stage occurred in 34%, 36%, 34%, and 22%, respectively. Adverse events that were more frequent with survodutide than with placebo included nausea (66% vs. 23%), diarrhea (49% vs. 23%), and vomiting (41% vs. 4%); serious adverse events occurred in 8% with survodutide and 7% with placebo.ConclusionsSurvodutide was superior to placebo with respect to improvement in MASH without worsening of fibrosis, warranting further investigation in phase 3 trials. (Funded by Boehringer Ingelheim; 1404-0043 ClinicalTrials.gov number, NCT04771273; EudraCT number, 2020-002723-11.).Copyright © 2024 Massachusetts Medical Society.

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