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

Oct 9, 2025Diabetes care

Metabolic and Liver Tissue Changes in People with Fatty Liver Disease With and Without Type 2 Diabetes Treated with Tirzepatide

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Abstract

Participants with MASH who responded to tirzepatide experienced a 16.0% reduction in body weight compared to a 7.0% reduction in nonresponders.

Greater body weight reductions were associated with both MASH resolution and fibrosis improvement.
MASH responders had a reduction in HbA1c of -1.2%, while nonresponders had a reduction of -0.6%.
MASH responders showed significant improvements in liver fat and insulin sensitivity measures compared to nonresponders.
Normalization of liver fat was identified as a significant factor mediating both MASH resolution and fibrosis improvement.

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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, 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.

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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

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