Obeticholic acid and resveratrol in nonalcoholic fatty liver disease: All that is gold does not glitter, not all those who wander are lost

Article 1: One hundred forty-one patients without cirrhosis with NASH were randomized to 72 weeks of obeticholic acid (OCA) or placebo. At the end of treatment, OCA significantly improved histological features of NASH. Article 2: Twenty overweight/obese NAFLD patients were randomized to 3 g of resveratrol or placebo for 8 weeks. At end of treatment, resveratrol did not significantly improved any liver-related or metabolic feature. Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world; nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, is the third-leading cause of end-stage liver disease and is projected to become the most common indication for liver transplantation in the next decade. Despite these premises, there are no approved pharmacological therapies for NASH, highlighting the urgent need to develop effective therapeutic strategies for this condition. The results of two long-awaited randomized, placebocontrolled trials (RCTs), targeting two putative mechanisms of liver injury in NAFLD, have been recently published: The multicenter Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment (FLINT) trial evaluated the effect of 72 weeks of obeticholic acid (OCA), a potent semisynthetic bile acid agonist of farnesoid X nuclear receptor (FXR) on liver histology in 283 biopsy-proven NASH patients. The second smaller, placebo-controlled, proof-of-mechanism RCT assessed the impact of the natural polyphenol, resveratrol, on radiological/biochemical markers of liver disease and on multiple, thoroughly assessed metabolic parameters in 20 overweight/obese patients with NAFLD. Although the FLINT trial reported an improvement in liver histology in NASH, high-dose resveratrol supplementation did not ameliorate any liver-related or metabolic parameter. However, some issues warrant clarification to more correctly interpret the results from these RCTs. In the FLINT trial, there was a striking difference between the effect of OCA on the primary outcome (2point improvement in NAFLD activity score [NAS]) and on definite NASH resolution (Table 1, panel A): Among patients on OCA, 45% met the primary endpoint of NAS improvement, but only 22% of patients showed NASH resolution (P 5 0.08 vs. placebo). The discrepancy between the primary endpoint and NASH resolution observed in the FLINT trial could also be observed, but in the opposite direction, in the Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial (clinicaltrials.gov: NCT00063622), the other large RCT with histological endpoints in NASH, where, among patients treated with pioglitazone, 34% showed NAS improvement and 47% patients had NASH resolution (Table 1). The different impact of active treatment on these two histological endpoints between the PIVENS and the FLINT trials is attributable to the different primary outcome definitions specified in these two RCTs: Both RCTs targeted a 2-point improvement in NAS score as the primary outcome, but in the FLINT trial, the 2-point NAS improvement could occur in any histological feature of NAS (steatosis, ballooning, and lobular inflammation), whereas the PIVENS trial required an improvement in either ballooning or lobular inflammation to occur. Consequently, in the FLINT trial, 78% of patients treated with OCA and 51% of those meeting the primary outcome at the end of treatment still had NASH (Table 1, panel A). These observations raise two questions: How do we determine endpoints of effectiveness in NASH therapy? And, extending this issue to future trial design, which endpoint should we target when evaluating strategies aiming at preventing liver disease progression in NAFLD? Within this context, data from follow-up studies indicate that, unlike a diagnosis of NASH, the NAS score does not predict fibrosis progression. On this basis, it seems questionable to continue to pursue NAS improvement as the primary outcome definition in future trials in NASH. Furthermore, OCA did not significantly improve advanced fibrosis, which has been consistently associated with liver-related complications and is a more important endpoint than improvement in earlier stages of fibrosis.