1 University of California San Diego, La Jolla, CA, USA.
2 Saint Louis University, St. Louis, MO, USA.
3 Virginia Commonwealth University, Richmond, VA, USA.
4 Indiana University, Indianapolis, IN, USA.
5 Duke University, Durham, NC, USA.
6 University of California San Francisco, San Francisco, CA, USA.
7 Swedish Medical Center, Seattle, WA, USA.
8 Cleveland Clinic, Cleveland, OH, USA.
9 The National Cancer Institute, Bethesda, MD, USA.
10 Columbia University, New York, NY, USA.
11 Johns Hopkins University, Baltimore, MD, USA.
BACKGROUND: Emerging data from a single center study suggests that a 30% relative reduction in liver fat content as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) from baseline may be associated with histologic improvement in nonalcoholic steatohepatitis (NASH). There are limited multicenter data comparing an active drug versus placebo on the association between the quantity of liver fat reduction assessed by MRI-PDFF and histologic response in NASH.
AIM: To examine the association between 30% relative reduction in MRI-PDFF and histologic response in obeticholic acid versus placebo-treated patients in the FLINT trial.
METHODS: This is a secondary analysis of the FLINT trial including 78 patients with MRI-PDFF measured before and after treatment along with paired liver histology assessment. Histologic response was defined as a two-point improvement in NAFLD Activity Score without worsening of fibrosis.
RESULTS: Obeticholic acid at 25 mg orally once daily was better than placebo in improving MRI-PDFF by an absolute difference of -3.4% (95% CI, -6.5 to -0.2%, p-value=0.04), and relative difference of -17% (95% CI, -34 to 0%, p-value=0.05). The optimal cut-point for relative decline in MRI-PDFF for histologic response was 30%. (using Youden's index). The rate of histologic response in those who achieved < 30% decline in MRI-PDFF versus those who achieved a ≥ 30% decline in MRI-PDFF (MRI-PDFF responders) relative to baseline was 19% versus 50%, respectively. Compared to MRI-PDFF non-responders, MRI-PDFF responders demonstrated both a statistically and clinically significant higher odds 4.86 (95% CI, 1.4-12.8, p-value <0.009) of histologic response including significant improvements in both steatosis and ballooning.
CONCLUSIONS: Obeticholic acid was better than placebo in reducing liver fat. This multicenter trial provides novel data regarding the association between 30% decline in MRI-PDFF relative to baseline and histologic response in NASH.