Obeticholic acid (OCA)—an agonist of the farnesoid X receptor (FXR)— increases insulin sensitivity and reduces markers of liver inflammation and fibrosis in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD), according to a study published in the September issue of Gastroenterology.
Type 2 diabetes mellitus and NAFLD are components of the metabolic syndrome—a complex disorder characterized by insulin resistance, dyslipidemia, hypertension, and visceral obesity. Although several drugs are available to improve insulin resistance in patients with diabetes, none are currently approved for NAFLD or nonalcoholic steatohepatitis.
FXR is a bile acid receptor expressed in liver, intestine, kidney, and adipose tissue. It regulates many genes involved in bile acid synthesis and transport, lipid metabolism, and glucose homeostasis. FXR also controls glucose metabolism and glycogenolysis in the liver, and peripheral insulin sensitivity in striated muscle adipose tissue. Factors that activate FXR might therefore be used to control diabetes and fatty liver disease.
OCA is a selective agonist of FXR agonist with anti-cholestatic and hepato-protective properties. In preclinical studies, OCA was found to increase insulin sensitivity, regulate glucose homeostasis, modulate lipid metabolism, and have anti-inflammatory and anti-fibrotic effects in the liver, kidney, and intestine.
Sunder Mudaliar et al. tested the effects of OCA in a Phase 2 study of 64 patients with type 2 diabetes mellitus and NAFLD. Patients were given 25 or 50 mg OCA or placebo, once daily for 6 weeks. The hyperinsulinemic-euglycemic clamp technique was used to assess insulin sensitivity. Various markers of tolerance and safety, and markers of FXR activation (increased plasma levels of FGF19 and reduced bile acid synthesis), were assessed.
Mudaliar et al. found that OCA increased hepatic and peripheral insulin sensitivity (by about 25%), whereas insulin sensitivity decreased by about 5% in subjects given placebo. OCA produced a significant decrease in levels of γ-glutamyltransferase—a marker of fatty liver disease that is a risk factor for development of diabetes in patients with NAFLD.
OCA also caused patients to lose weight (see below figure).
Serum levels of FGF19 increased, whereas levels of C4 and endogenous bile acids decreased, indicating FXR activation in patients given OCA. The authors state that this was the first phase 2 clinical trial of an FXR agonist.
In an editorial that accompanies the article, Saul Karpen says that these findings herald a new era, in which bile-acid–based strategies are used to control metabolic signaling and treat liver and other types of diseases.
However, Karpen points out that the observed increases in low-density lipoprotein, reductions in high-density lipoprotein, and lack of change in alanine aminotransferase or liver fibrosis scores in subjects receiving OCA were notable and require further analysis. Mudaliar et al. did not perform liver biopsies, so they were not able to determine the degree and effect of OCA on liver histology.
Karpen says that studies with a larger sample sizes and more analyses are needed before conclusions can be made.
More Information on Fatty Liver Disease:
- The American Liver Foundation
- The Mayo Clinic Website on NAFLD
- The NIDDK Website on Nonalcoholic Steatohepatitis
Read the article online.
Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid x receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013;145:574–582.e1.
Read the accompanying editorial.
Karpen SJ. Do therapeutic bile acids hit the sweet spot of glucose metabolism in NAFLD? Gastroenterology 2013;145:508–510.