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

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/m 2. 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 HbA 1c 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, normalization of liver fat was a significant mediator of both MASH resolution and fibrosis improvement. CONCLUSIONS In this post hoc exploratory analysis, MASH resolution and fibrosis improvement were associated with body weight reduction, improved glycemic control, and normalization of liver fat. Weight reduction and metabolic improvements with tirzepatide treatment potentially contributed to disease modification in MASH.