title: Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease.
abstract: OBJECTIVE
  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.
authors.affiliation: University of California, San Diego, CA, USA. smudaliar@vapop.ucsd.edu
authors.forename: Sunder
authors.initials: S
authors.lastname: Mudaliar
authors.forename: Robert R
authors.initials: RR
authors.lastname: Henry
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
authors.forename: Linda
authors.initials: L
authors.lastname: Morrow
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.forename: Mark
authors.initials: M
authors.lastname: Kipnes
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.forename: Cathi I
authors.initials: CI
authors.lastname: Sciacca
authors.forename: Paul
authors.initials: P
authors.lastname: Clopton
authors.forename: Erin
authors.initials: E
authors.lastname: Castelloe
authors.forename: Paul
authors.initials: P
authors.lastname: Dillon
authors.forename: Mark
authors.initials: M
authors.lastname: Pruzanski
authors.forename: David
authors.initials: D
authors.lastname: Shapiro
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005234:Fatty Liver / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D016896:Treatment Outcome; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D015415:Biomarkers; D002635:Chenodeoxycholic Acid; D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid
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