• Philip N Newsome, Kristine Buchholtz, Kenneth Cusi, Martin Linder, Takeshi Okanoue, Vlad Ratziu, Arun J Sanyal, Anne-Sophie Sejling, Stephen A Harrison, and NN9931-4296 Investigators.
• From the National Institute for Health Research Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, and the Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham (P.N.N.), and the Radcliffe Department of Medicine, University of Oxford, Oxford (S.A.H.) - all in the United Kingdom; Novo Nordisk, Søborg, Denmark (K.B., M.L., A.-S.S.); the Division of Endocrinology, Diabetes, and Metabolism, University of Florida, Gainesville (K.C.); the Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan (T.O.); the Institute of Cardiometabolism and Nutrition, Sorbonne Université, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche Scientifique 1138 Centre de Recherche des Cordeliers, Paris (V.R.); and the Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University School of Medicine, Richmond (A.J.S.).
• N. Engl. J. Med. 2021 Mar 25; 384 (12): 1113-1124.

BackgroundNonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known.MethodsWe conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients.ResultsIn total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P = 0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed.ConclusionsThis phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.).Copyright © 2020 Massachusetts Medical Society.

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