Analysis of Mechanistic Pathways in the Treatment of Non-Alcoholic Steatohepatitis. Evidence from a Bayesian Network Meta-Analysis

Background and Aims: Non-alcoholic steatohepatitis (NASH) is the most common cause of liver disease contributing to significant disease burden worldwide. However, there is lack of comparison of efficacy between different NASH drug classes. We conducted a network meta-analysis evaluating drug classes through comparing histological outcomes and targets of drugs. Approach & Results: Medline, EMBASE and CENTRAL were searched for articles evaluating NASH drugs in biopsy-proven NASH patients. Primary outcomes included NASH resolution without worsening of fibrosis, 2-point reduction in Non-alcoholic fatty liver disease Activity Score (NAS) without worsening of fibrosis and 1-point reduction in fibrosis. Treatments were classified into inflammation, energy, bile acid, and fibrosis modulators. The analysis was conducted with Bayesian network model and surface under the cumulative ranking curve (SUCRA) analysis. From the 48 trials included, treatments modulating energy (Risk ratio (RR): 1.84, Credible intervals (Crl): 1.29 - 2.65) were the most likely to achieve NASH resolution followed by treatments modulating fibrosis (RR 1.68, Crl: 0.55 - 5.28), bile acids (RR: 1.34, Crl: 0.78 - 2.26) and inflammation (RR: 0.94, Crl: 0.59 - 1.46). Energy and bile acids modulation were effective in 2-point NAS reduction without worsening of fibrosis (RR: 1.60, Crl 1.13 - 2.30 and RR: 1.79, Crl 1.14 - 2.86) and 1-point fibrosis (RR: 1.27, Crl:1.05 - 1.52 and RR: 1.54, Crl: 1.20 - 1.97). Conclusions: This network analysis demonstrates the relative superiority of drugs modulating energy pathways and bile acids in NASH treatment. This guides the development and selection of drugs for combination therapies.