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

<p dir="ltr">Objective: To explore the relationship between metabolic and histological responses in a phase 2 trial of tirzepatide in metabolic dysfunction-associated steatohepatitis (MASH).</p><p dir="ltr">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 randomized to receive tirzepatide (5, 10 or 15 mg) or placebo once-weekly. The primary endpoint was MASH resolution without worsening of fibrosis. Secondary endpoints included fibrosis improvement by ≥1 stage without worsening of MASH. Metabolic changes were evaluated in responders and non-responders for histological endpoints in 154 participants who completed the study on treatment.</p><p dir="ltr">Results: At baseline, 59% had type 2 diabetes and mean BMI was 35.7 kg/m2. Compared with non-responders, 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 non-responders. Compared with non-responders, greater improvements in liver fat and measures of adipose tissue insulin sensitivity (Adipo-IR 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. </p><p dir="ltr">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.</p><p><br></p>