Farnesoid X nuclear receptor agonists for the treatment of nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) affects 20-40% of the general population. Despite significant disease burden and mortality associated with advanced disease, i.e., nonalcoholic steatohepatitis (NASH), there is currently no approved medication for NASH. Farnesoid X receptor agonists have been investigated as candidates for the treatment of NASH. Obeticholic acid, approved for the treatment of primary biliary cholangitis, has gained significant attention after showing promising results in patients with NASH and fibrosis. Three trials investigating the effect of obeticholic acid in patients with NASH have been completed and the preliminary results of an ongoing one have also been made public. Generally, treatment with obeticholic acid improved hepatic histology, including inflammation and fibrosis, the latter being the main histological predictor of advanced disease. Nonetheless, there were adverse effects, the most common being pruritus and unfavorable changes in the lipid profile. Pruritus led to discontinuation of treatment in some patients. Obeticholic acid, however, is not the only farnesoid X receptor agonist currently investigated for the treatment of NASH. Another farnesoid X receptor agonist, cilofexor, in combination with firsocostat, an acetyl-CoA carboxylase inhibitor, improved hepatic steatosis, liver stiffness, liver function tests and serum fibrosis markers, without causing pruritus after 12 weeks of treatment. In conclusion, current evidence regarding the effect of farnesoid X receptor agonists on hepatic histology in patients with NASH is promising, but several safety issues need further evaluation.