ArticlesFarnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial
Introduction
Non-alcoholic steatohepatitis is an increasingly common cause of chronic liver disease worldwide and it is associated with increased liver-related mortality and hepatocellular carcinoma, even in the absence of cirrhosis.1, 2, 3 Non-alcoholic steatohepatitis progresses to cirrhosis in 15–20% of affected individuals and is a rising indication for liver transplantation4 but at present there are no approved therapies.
Obesity, diabetes, and insulin resistance (especially in adipose tissue) are all associated with non-alcoholic steatohepatitis and probably contribute to its pathogenesis.5, 6 Consequently, dietary changes and lifestyle modification to achieve weight reduction and improve insulin sensitivity are recommended.7, 8 The long-term effectiveness of these interventions is debatable because many patients are unable to initiate or maintain dietary and lifestyle changes,7, 9 underscoring the need for pharmacological therapy. Vitamin E and thiazolidinediones are the best studied drugs for the treatment of non-alcoholic steatohepatitis.10 Although both improve liver histology in patients without diabetes, their effects in patients with diabetes are unknown. Moreover, thiazolidinediones are associated with weight gain and other adverse outcomes, and the long-term efficacy and safety of vitamin E also remain uncertain.11, 12
Over the last decade, lipophilic bile acids have emerged as potent modulators of metabolism and insulin sensitivity.13, 14 When bound to the farnesoid X nuclear receptor, lipophilic bile acids promote insulin sensitivity and decrease hepatic gluconeogenesis and circulating triglycerides.15 These beneficial effects are mediated by decreased hepatic lipid synthesis and enhanced peripheral clearance of VLDL.16, 17, 18 Farnesoid X nuclear receptor activation also increases the expression of hepatic scavenger receptors (SRB1), which accelerates reverse cholesterol transport by increasing the clearance of HDL. Based on these metabolic effects, pharmacological activation of farnesoid X nuclear receptor has been proposed as a target for the treatment of non-alcoholic steatohepatitis.19
6-ethylchenodeoxycholic acid (obeticholic acid), a synthetic variant of the natural bile acid chenodeoxycholic acid, is a potent activator of farnesoid X nuclear receptor. In pre-clinical studies, it improved hepatic steatosis, fibrosis, and portal hypertension.20, 21, 22 In a small group of patients with type 2 diabetes and suspected non-alcoholic fatty liver disease, obeticholic acid improved insulin sensitivity and reduced serum alanine aminotransferase concentrations.23 The less lipophilic bile acid ursodeoxycholic acid binds negligibly to farnesoid X nuclear receptor and in a randomised clinical trial it did not show efficacy in non-alcoholic steatohepatitis.24
With this background, we designed and undertook a clinical trial to assess the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis.
Section snippets
Study design and participants
The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment (FLINT) trial was a multicentre, randomised trial of 72 weeks of obeticholic acid versus placebo in patients with biopsy evidence of non-alcoholic steatohepatitis. Between March 16, 2011, and Dec 3, 2012, we enrolled patients at eight participating medical centres in the USA (appendix). Details of the trial were approved by local institutional review boards and a central data safety and monitoring board (DSMB) appointed by the
Results
283 patients with histologically proven non-alcoholic steatohepatitis or borderline non-alcoholic steatohepatitis based on the site pathologist reading of the liver biopsy were randomly assigned to receive obeticholic acid (n=141) or placebo (n=142) (figure 1). 15 (5%) patients had minor protocol deviations, mainly from timing targets (entry liver biopsies outside the stated 90-day window by up to 11 days, and baseline laboratory results outside stated time windows, but never after
Discussion
In this randomised, placebo-controlled, clinical trial, the farnesoid X nuclear receptor agonist obeticholic acid improved the biochemical and histological features of non-alcoholic steatohepatitis compared with placebo in patients without cirrhosis. Importantly, all components of the NAFLD activity score (steatosis, hepatocellular ballooning, and lobular inflammation) and fibrosis improved. The improvement in fibrosis, although small, shows that this therapy might be beneficial in preventing
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