Lipids & metabolic liver disease
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
Authors' conclusion
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.
Study context
- Population
- Participants with MASH and stage 2/3 fibrosis randomised to tirzepatide (5, 10 or 15 mg) or placebo once weekly; 59% T2D, mean BMI 35.7 kg/m²154 completed on treatment
- Participants
- 190 participants
- Comparison
- Responders vs nonresponders for histological end points (MASH resolution; fibrosis improvement) after tirzepatide or placebo
- Primary endpoint
- MASH resolution without worsening of fibrosis
Methodological detailsexploratory, double-blind, placebo-controlled, phase 2, 52-week
- Exploratory
- Double-blind
- Placebo-controlled
- Phase 2
- 52-week
Primary result
As reported in the abstract
Body weight change, MASH resolution responders vs nonresponders
Responders
−16.0%
Nonresponders
−7.0%
P < 0.001
Secondary outcomes
| Outcome | Responders | Nonresponders | P value |
|---|---|---|---|
| Body weight change, fibrosis improvement responders vs nonresponders | −13.6% | −9.8% | P = 0.023 |
| HbA1c change, MASH resolution responders vs nonresponders | −1.2% | −0.6% | P < 0.001 |
| HbA1c change, fibrosis improvement responders vs nonresponders | −1.2% | −0.7% | P = 0.004 |
- Liver fat and adipose tissue insulin sensitivity (adipose tissue insulin resistance index, adiponectin), MASH responders vs nonresponders · greater improvements in responders
- P < 0.001
Causal mediation analysis
- Normalization of liver fat was a significant mediator of both MASH resolution and fibrosis improvement
Original publication
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. Diabetes Care. Published 9 October 2025. doi:10.
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