Relationship Between Metabolic and Histological Responses in People With Metabolic Dysfunction– Associated Steatohepatitis With and Without Type 2 Diabetes: Participant-Level Exploratory Analysis of the SYNERGY-NASH Trial With Tirzepatide

作者：Cyrielle Caussy, Kenneth Cusi, Julio Rosenstock, Elisabetta Bugianesi, Melissa K. Thomas, Yuanyuan Tang, Kieren J. Mather, Rohit S. Loomba, Arun J. Sanyal, Mark L. Hartman · 发表于：Diabetes Care · 年份：2025 · DOI：10.2337/dc25-1306 · 被引用次数：12 · 研究领域：Liver Disease Diagnosis and Treatment、Cardiovascular Disease and Adiposity、Liver Diseases and Immunity

OBJECTIVE: To explore the relationship between metabolic and histological responses in a phase 2 trial of tirzepatide in metabolic dysfunction-associated steatohepatitis (MASH). RESEARCH DESIGN AND METHODS: This is a participant-level post hoc analysis of the 52-week, double-blind, randomized, placebo-controlled SYNERGY-NASH trial (NCT04166773). Participants (n = 190) with MASH and stage 2/3 fibrosis were randomly assigned to receive tirzepatide (5, 10, or 15 mg) or placebo once weekly. The primary end point was MASH resolution without worsening of fibrosis. Secondary end points included fibrosis improvement by at least one stage without worsening of MASH. Metabolic changes were evaluated in responders and nonresponders for histological end points in 154 participants who completed the study on treatment. RESULTS: At baseline, 59% had type 2 diabetes and mean BMI was 35.7 kg/m2. Compared with nonresponders, greater body weight reductions were observed in responders for MASH resolution (-16.0% vs. -7.0%; P < 0.001) and for fibrosis improvement (-13.6% vs. -9.8%; P = 0.023). Reductions in HbA1c were greater for MASH responders (-1.2% vs. -0.6%; P < 0.001) and fibrosis responders (-1.2% vs. -0.7%; P = 0.004) than for nonresponders. Compared with nonresponders, greater improvements in liver fat and measures of adipose tissue insulin sensitivity (adipose tissue insulin resistance index and adiponectin) were observed with MASH responders (P < 0.001). In causal mediation analyses, no...