Ezetimibe for the treatment of nonalcoholic steatohepatitis: Assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial)

Abstract

Ezetimibe inhibits intestinal cholesterol absorption and lowers low-density lipoprotein cholesterol. Uncontrolled studies have suggested that it reduces liver fat as estimated by ultrasound in nonalcoholic steatohepatitis (NASH). Therefore, we aimed to examine the efficacy of ezetimibe versus placebo in reducing liver fat by the magnetic resonance imaging-derived proton density-fat fraction (MRI-PDFF) and liver histology in patients with biopsy-proven NASH. In this randomized, double-blind, placebo-controlled trial, 50 patients with biopsy-proven NASH were randomized to either ezetimibe 10 mg orally daily or placebo for 24 weeks. The primary outcome was a change in liver fat as measured by MRI-PDFF in colocalized regions of interest within each of the nine liver segments. Novel assessment by two-dimensional and three-dimensional magnetic resonance elastography was also performed. Ezetimibe was not significantly better than placebo at reducing liver fat as measured by MRI-PDFF (mean difference between the ezetimibe and placebo arms -1.3%, P = 0.4). Compared to baseline, however, end-of-treatment MRI-PDFF was significantly lower in the ezetimibe arm (15%-11.6%, P < 0.016) but not in the placebo arm (18.5%-16.4%, P = 0.15). There were no significant differences in histologic response rates, serum alanine aminotransferase and aspartate aminotransferase levels, or longitudinal changes in two-dimensional and three-dimensional magnetic resonance elastography-derived liver stiffness between the ezetimibe and placebo arms. Compared to histologic nonresponders (25/35), histologic responders (10/35) had a significantly greater reduction in MRI-PDFF (-4.35 ± 4.9% versus -0.30 ± 4.1%, P < 0.019). Conclusions: Ezetimibe did not significantly reduce liver fat in NASH. This trial demonstrates the application of colocalization of MRI-PDFF-derived fat maps and magnetic resonance elastography-derived stiffness maps of the liver before and after treatment to noninvasively assess treatment response in NASH. (Hepatology 2015;61:1239–1250)

EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease

“…Available data on pentoxifylline and orlistat are limited or inconclusive [86,91,97]. Also, data on lipidlowering drugs are poor; recent trials with ezetimibe were negative [101,103], whereas statins have not been adequately tested. Their use in NAFLD is safe, with no increased risk of hepatotoxicity, and may even significantly reduce aminotransferases [137].…”

947 Shared Genetic Effects Between Hepatic Steatosis and Fibrosis: A Prospective Twin Study

“…MRI-PDFF has been previously shown to be a highly precise, accurate, and reproducible noninvasive biomarker to quantify hepatic fat content. (25,26), correlates well with MR spectroscopy (r 2 =0.99, p<0.001) (22,23), and is superior to noninvasive imaging techniques such as ultrasound and computed tomography for measuring hepatic fat content (27) even in iron-overloaded livers that may coexist with NAFLD livers. (28) MRI-PDFF has also been shown to correlate well with histology from contemporaneous liver biopsies.…”

“…All twin pairs underwent clinical research assessments, including medical history, physical and anthropometric exams, and biochemical testing, at the University of California at San Diego (UCSD) NAFLD Research Center. (15,(21)(22)(23) Participants also underwent MRI-PDFF for hepatic steatosis and MRE for hepatic fibrosis at the UCSD MR3T Research Laboratory. Clinical and imaging visits were performed on the same day for each twin pair, and the study took place from 2012 to 2015.…”

NAFLD therapy and monitoring disease progression

“…94,95 Role of lipid-lowering drugs in NAFLD is inconclusive. While there is some data suggesting improvement in NASH with statins, 96 99 While there are few available treatment options of proven efficacy in NAFLD, promising drugs are under development and under evaluation for regulatory approval. 100 Therapeutic interventions which have been found to be effective in the management of NAFLD are shown in Table 2.…”