Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease

Gastroenterology. 2013 Sep;145(3):574-82.e1. doi: 10.1053/j.gastro.2013.05.042. Epub 2013 May 30.


Background & aims: Obeticholic acid (OCA; INT-747, 6α-ethyl-chenodeoxycholic acid) is a semisynthetic derivative of the primary human bile acid chenodeoxycholic acid, the natural agonist of the farnesoid X receptor, which is a nuclear hormone receptor that regulates glucose and lipid metabolism. In animal models, OCA decreases insulin resistance and hepatic steatosis.

Methods: We performed a double-blind, placebo-controlled, proof-of-concept study to evaluate the effects of OCA on insulin sensitivity in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus. Patients were randomly assigned to groups given placebo (n = 23), 25 mg OCA (n = 20), or 50 mg OCA (n = 21) once daily for 6 weeks. A 2-stage hyperinsulinemic-euglycemic insulin clamp was used to measure insulin sensitivity before and after the 6-week treatment period. We also measured levels of liver enzymes, lipid analytes, fibroblast growth factor 19, 7α-hydroxy-4-cholesten-3-one (a BA precursor), endogenous bile acids, and markers of liver fibrosis.

Results: When patients were given a low-dose insulin infusion, insulin sensitivity increased by 28.0% from baseline in the group treated with 25 mg OCA (P = .019) and 20.1% from baseline in the group treated with 50 mg OCA (P = .060). Insulin sensitivity increased by 24.5% (P = .011) in combined OCA groups, whereas it decreased by 5.5% in the placebo group. A similar pattern was observed in patients given a high-dose insulin infusion. The OCA groups had significant reductions in levels of γ-glutamyltransferase and alanine aminotransferase and dose-related weight loss. They also had increased serum levels of low-density lipoprotein cholesterol and fibroblast growth factor 19, associated with decreased levels of 7α-hydroxy-4-cholesten-3-one and endogenous bile acids, indicating activation of farnesoid X receptor. Markers of liver fibrosis decreased significantly in the group treated with 25 mg OCA. Adverse experiences were similar among groups.

Conclusions: In this phase 2 trial, administration of 25 or 50 mg OCA for 6 weeks was well tolerated, increased insulin sensitivity, and reduced markers of liver inflammation and fibrosis in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Longer and larger studies are warranted. ClinicalTrials.gov, Number: NCT00501592.

Keywords: 7α-hydroxy-4-cholesten-3-one; ALT; AST; BA; C4; Clinical Trial; FGF; FXR; GIR; Metabolic Syndrome; NAFLD; NASH; OCA; Obesity; Treatment; alanine aminotransferase; aspartate aminotransferase; bile acid; farnesoid X receptor; fibroblast growth factor; glucose infusion rate; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; obeticholic acid.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers / blood
  • Chenodeoxycholic Acid / analogs & derivatives*
  • Chenodeoxycholic Acid / therapeutic use
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Fatty Liver / blood
  • Fatty Liver / complications
  • Fatty Liver / drug therapy*
  • Female
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Insulin Resistance
  • Male
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Treatment Outcome


  • Biomarkers
  • Hypoglycemic Agents
  • Receptors, Cytoplasmic and Nuclear
  • obeticholic acid
  • farnesoid X-activated receptor
  • Chenodeoxycholic Acid

Associated data

  • ClinicalTrials.gov/NCT00501592