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

Abstract

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.

• Authors: Sunder Mudaliar, Robert R Henry, Arun J Sanyal, Linda Morrow, Hanns-Ulrich Marschall, Mark Kipnes, Luciano Adorini, Cathi I Sciacca, Paul Clopton, Erin Castelloe, Paul Dillon, Mark Pruzanski, David Shapiro
• Journal: Gastroenterology (Gastroenterology) Vol. 145 Issue 3 Pg. 574-82.e1 (Sep 2013) ISSN: 1528-0012 [Electronic] United States
• PMID: 23727264 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• Adult
• Aged
• Biomarkers (blood)
• Chenodeoxycholic Acid (analogs & derivatives, therapeutic use)
• Diabetes Mellitus, Type 2 (blood, complications, drug therapy)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Fatty Liver (blood, complications, 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