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.

Figure 1

(A) Individual patient data on liver fat content as assessed by MRI-PDFF before randomization and at the end of 24 weeks stratified by the treatment group assignment (ezetimibe-treated patients are to the left and shown by red lines, and placebo-treated patients are to the right and shown by blue lines). There was no significant difference in the changes in MRI-PDFF between the treatment groups (P = 0.483). (B) Percentage decline in liver fat relative to baseline by MRI-PDFF stratified by the treatment group assignment (ezetimibe-treated patients are to the left and shown by the red bar, and placebo-treated patients are to the right and shown by the blue bar). There was no significant difference in the changes in MRI-PDFF between the treatment groups (P = 0.266).

Figure 2

(A) Whole-liver fat mapping with MRI-PDFF for a single patient. MRI-PDFF measurements of liver segments 1, 2, 4a, 7, and 8 in the superior plane (upper panel) and of liver segments 3, 4b, 5, and 6 in the inferior plane (lower panel) are shown at weeks 0 (left column) and 24 (right column) for a patient. The fat fraction in a single liver segment is estimated by MRI-PDFF. Using nine ROIs, one in each segment, the calculated total liver fat fraction average at week 0 was 28%, and this decreased to 22% at week 24. MRI-PDFF data from all nine liver segments gives a fat map for the entire liver where longitudinal within-segment changes of liver fat can be appreciated. (B) MRS measured fat fraction in the same patient. MRS measurements from a 2 × 2 × 2 cm³ cube (voxel) within the right liver lobe of the same patient in which MRI-PDFF was performed are shown at week 0 (left column) and week 24 (right column). The corresponding MRS fat fraction at week 0 was 28.8%, and this decreased to 22% at week 24. (C) Liver stiffness measured by 2D and 3D MRE in the same patient. The 2D MRE was done at 60 Hz, and the 3D MRE was done at 40 Hz and 60 Hz. The MR shear wave elastograms obtained at week 0 are shown to the left, and those at week 24 are shown to the right. All three shear wave elastograms showed a decrease in the elasticity of the liver.