Consistent improvements in liver histology across subgroups in a post hoc analysis of the SYNERGY-NASH trial with tirzepatide

Background & Aims: In the SYNERGY-NASH trial for metabolic dysfunction-associated steatohepatitis (MASH) with stage 2 or 3 fibrosis, tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, effectively resolved MASH without worsening fibrosis in up to 73% of patients. We explored the extent of histological improvements across clinically relevant subgroups in this trial. Methods: Participants (n = 190) were randomly assigned 1:1:1:1 to receive once-weekly subcutaneous tirzepatide (5, 10, or 15 mg) or placebo for 52 weeks. We analyzed 155 participants who completed the study on treatment with evaluable end-of-treatment biopsies. Post hoc subgroups (n = 34) were defined by demographics, histology, serum, and imaging biomarkers using the median of baseline values for continuous variables. Risk differences (RDs) vs. placebo (95% CI) were calculated using a logistic regression model. Results: Compared with placebo, tirzepatide was consistently associated with improved MASH resolution without worsening fibrosis across subgroups defined by sex, age, ethnicity, BMI, type 2 diabetes status, histological disease activity, fibrosis stage, serum aminotransferases, serum biomarkers of fibrosis and MASH, and imaging assessments of liver fat, fibroinflammation, and stiffness. For tirzepatide 5, 10 and 15 mg, RDs were statistically significant (p <0.05) for 74%, 97%, and 100% of the subgroups, respectively. While most RDs for fibrosis improvement without worsening of MASH favored tirzepatide, statistical significance was not reached in 59–79% of subgroups due to limited sample sizes. Significant fibrosis improvement (p <0.05) was observed with tirzepatide 5 and 15 mg among participants with stage 3 fibrosis. Conclusion: These post hoc analyses suggest that tirzepatide was consistently associated with improved MASH resolution without worsening of fibrosis across subgroups defined by demographics, histology, and biomarkers, compared with placebo. Impact and implications: In participants with metabolic dysfunction-associated steatohepatitis (MASH), tirzepatide demonstrated superiority to placebo for resolution of MASH without worsening of fibrosis, but the extent of MASH resolution across clinically relevant subgroups was not reported. In these post hoc analyses, we show that tirzepatide was consistently associated with improved MASH resolution without worsening of fibrosis across subgroups defined by demographics, histology, serum biomarkers, and imaging tests. These data support further investigation of tirzepatide in larger studies of participants with MASH including representation from diverse populations.