For patients with nonalcoholic steatohepatitis (NASH), a bile acid derivative that acts on a nuclear receptor reduced liver fat and fibrosis, but patients taking the drug also had worsening in serum lipid values and increased insulin resistance.
The lipophilic bile acid obeticholic acid showed promise in the FLINT trial (Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment) for NASH patients whose liver disease improved but did not resolve.
Dr. Brent Neuschwander-Tetri of Saint Louis University, and coinvestigators in the National Institute of Diabetes and Digestive and Kidney Diseases’ NASH Clinical Research Network, conducted the multicenter, randomized, placebo-controlled study. The findings were published in the Lancet.
Obeticholic acid, a farnesoid X nuclear receptor agonist, works at a site whose activation promotes increased insulin sensitivity and decreased serum triglycerides. Serum lipids may also be improved by increased peripheral clearance of VLDL, increased reverse cholesterol transport, and reduced lipid synthesis in the liver. Currently, the only other treatments for NASH, aside from diet and lifestyle modifications, are thiazolidinediones and vitamin E. Long-term safety and efficacy of these medications are unknown, especially in NASH patients with diabetes (Lancet 2015;385:956-65 [doi:10.1016/S0140-6736(14)61933-4]).
Study participants were adults with biopsy-confirmed NASH or borderline NASH with histologic steatosis, ballooning, and lobular inflammation, but without cirrhosis. The study excluded heavy consumers of alcohol. Baseline and final assessments included liver biopsy and demographic and anthropometric information, as well as metabolic and lipid markers and liver enzymes.
FLINT’s primary outcome measure was improved liver histology, defined as a decrease of two or more points on a nonalcoholic fatty liver disease (NAFLD) pathology scoring system, without a worsening of liver fibrosis. Resolution of NASH was a secondary outcome, as were changes in liver enzymes, body measurements, and homeostasis model of assessment of insulin resistance (HOMA-IR) levels.
The study’s Data Safety Monitoring Board recommended stopping biopsies after about half the patients had received biopsies and the primary histologic outcome measure was met, in order to avoid unnecessary patient risk.
An intention-to-treat analysis found that 50 (45%) of 110 patients receiving obeticholic acid had improved liver histology, compared to 23 (21%) of 109 patients receiving placebo (relative risk 1.9, 95% CI 1.3-2.8, P = .0002). This difference did not change with prespecified subgroup analyses. Serum AST and ALT measures decreased significantly for the treatment group. The medication was generally well tolerated, though pruritis developed in 33 (23%) of 141 patients in the intervention group and 9 (6%) of the placebo group.
Total serum cholesterol and LDL cholesterol, however, increased for the obeticholic acid group, while HDL cholesterol decreased. Insulin resistance as measured by HOMA-IR increased slightly for the treatment group, an unexpected effect. Study authors noted that this class of medication’s effect on cholesterol transport is complex. “Future studies of farnesoid X nuclear receptor agonists,” they noted, “will need to address the consequences of these changes on cardiovascular outcomes.”
Dr. Neuschwander-Tetri disclosed ties with Genentech/Roche, Nimbus Discovery, Boehringer Ingelheim, and Bristol-Myers Squibb. Several coinvestigators disclosed ties with various companies, including Intercept Pharmaceuticals, which provided partial funding for the trial under a Collaborative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases.