The metabolic dysfunction-associated fatty liver disease definition, regardless of its clinical subclassification, identifies patients at high risk for liver disease progression

Background and aims: MRI-PDFF is the gold standard for noninvasive assessment of hepatic fat fraction (HFF) in non-alcoholic steatohepatitis (NASH) and is commonly used within early clinical trials to determine treatment efficacy on steatosis.HFF reduction has been associated with an increased likelihood of NASH resolution.However it is unclear whether reductions in hepatic steatosis bear a relationship with changes in markers of hepatic inflammation, disease activity and fibrosis.Method: PROXYMO was a 19 week multi-centre phase 2 trial to investigate the safety and efficacy of cotadutide in 74 participants with biopsy confirmed non-cirrhotic NASH with fibrosis (NCT04019561).Post-hoc analysis was performed to investigate whether changes in HFF in the study population were associated with changes in non-invasive markers of hepatic fibrosis, NASH disease activity and inflammation within participants who had baseline and week 19 values.Participants were pooled (active and placebo) and the relative changes in HFF after 19 weeks were assessed against percentage change in non-invasive markers.Results: Within pooled participants, relative change in HFF was significantly correlated with markers of hepatic inflammation (ALT R = 0.52 ( p < 0.0001)), NASH disease activity (NIS-4 R = 0.63 ( p < 0.0001)) and hepatic fibrosis (PRO-C3 R = 0.44 ( p = 0.0012)).Changes in fibrosis biomarkers were correlated with changes in liver enzymes.Change in body weight was significantly correlated with change in HFF.Relative HFF change was divided into quartiles; those in the quartile of greatest relative HFF reduction had significantly greater reductions in ALT, AST, NIS-4 and PRO-C3. Conclusion:Reductions in HFF as assessed by MRI-PDFF were associated with reductions in non-invasive markers of hepatic inflammation, NASH disease activity and fibrosis.Furthermore, subjects with improvements in HFF had significantly greater reductions in ALT, AST, NIS-4 and PRO-C3.