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¹From the Metabolic Dysfunction-Associated Steatotic Liver Disease Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla (R.L.), and Pacific Rim Pathology, San Diego (C.B.) - both in California; Eli Lilly (M.L.H., Y.T., B.B., D.A.R., A.N., M.C.B., A.H.), the Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine (R.V.), and the Department of Pathology and Laboratory Medicine, Indiana University (O.W.C.) - all in Indianapolis; the Texas Liver Institute, University of Texas Health, San Antonio (E.J.L.); the Department of Hepato-Gastroenterology and Digestive Oncology, Angers University Hospital, and Hemodynamics, Interaction of Fibrosis and Hepatic Tumor Invasiveness Laboratory, Structure Fédérative de Recherche Interactions Cellulaires et Applications Thérapeutiques 4208, Angers University - both in Angers, France (J.B.); the Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy (E.B.); the Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan (M.Y.); and the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health and Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond (A.J.S.).

Abstract

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.

Methods: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.

Results: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.

Conclusions: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).