Causal relationship between liver fat reduction and clinical outcomes in human genetic studies and randomized clinical trials of metabolic-dysfunction associated steatohepatitis

MASH therapeutic development is limited by reliance on invasive liver biopsy endpoints, and although liver fat accumulation is considered a driver of early disease, liver fat reduction is not currently recognized by health authorities as a surrogate endpoint.

In the largest-to-date GWAS of liver fat, involving 79,642 people with MRI, researchers developed a polygenic score with liver fat-lowering alleles across 55 genomic loci. In a separate set of 714,886 individuals, a 30% relative liver fat reduction due to the polygenic score was associated with 39% lower odds of liver cirrhosis and 41% lower odds of hepatocellular carcinoma, consistent with a strong causal relationship between lifelong liver fat differences and advanced liver clinical outcomes.

A systematic review and meta-analysis of 20 randomized controlled trials including 3,502 MASH patients found that treatment-induced liver fat reductions were associated with MASH resolution (meta-regression slope in % units of the outcome for each 1% relative reduction in liver fat from baseline, beta = -0.70%, p<0.001) and fibrosis improvement (beta = -0.24%, p<0.001).

These findings demonstrate the profound etiologic impact of liver fat in MASH and provide compelling evidence for liver fat reductions as a reasonably likely surrogate endpoint for future clinical development.