Farnesoid X receptor agonist for the treatment of liver and metabolic disorders: focus on 6-ethyl-CDCA

6-ethyl-chedeoxycholic acid (6E-CDCA) is a farnesoid X receptor (FXR) ligand endowed with agonistic activity under development for treatment of cholestatic liver diseases including primary biliary cirrhosis (PBC) and liver-related metabolic disorders including non-alc. fatty liver disease (NAFLD) and non-alc. steatohepatitis (NASH). FXR is a bile sensor that acts in coordination with other nuclear receptors to regulate essential steps of bile acid uptake, metab. and excretion. 6E-CDCA has been investigated in preclin. models of cholestasis, liver fibrosis and diet-induced atherosclerosis. In a phase II clin. trial in patients with PBC, 6E-CDCA met the primary endpoint of a redn. in alk. phosphatase levels but safety data indicated that the drug exacerbated pruritus, one of the main symptoms of PBC, suggesting that 6E-CDCA or FXR are mediators of pruritus in humans. Treatment of patients with diabetes and liver steatosis resulted in amelioration of insulin sensitivity despite a slight redn. in HDL and increased levels of LDL were obsd. These side effects on bile acids and lipid metab. were all predicted by pre-clin. studies, suggesting that potent FXR ligands hold promise but potential side effects might limit their development.