1 Virginia Commonwealth University, Richmond, VA, United States. Electronic address: Mohammad.firstname.lastname@example.org.
2 John Hopkins University, Baltimore, MD, United States.
3 Laboratory Corporation of America Holdings (LabCorp), Inc, Morrisville, NC, United States.
4 Indiana University, Indianapolis, IN, United States.
5 Saint Louis University, St. Louis, MO, United States.
6 Duke University, Durham, NC, United States.
7 University of California at San Diego, San Diego, CA, United States.
8 Cleveland Clinic, Cleveland, OH, United States.
9 Columbia University, New York, NY, United States.
10 Virginia Commonwealth University, Richmond, VA, United States.
BACKGROUND & AIMS: Obeticholic acid (OCA), a farnesoid X receptor agonist, increases total and low-density lipoprotein cholesterol (LDL-C) in patients with non-alcoholic steatohepatitis. In the present study, we aimed to evaluate the impact of OCA therapy on lipoprotein sub-particles.
METHOD: This study included 196 patients (99 OCA group and 97 placebo group) who were enrolled in the FLINT trial and had samples available for lipid analysis and liver biopsies at enrollment and end-of-treatment (EOT) at 72?weeks. Very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) particles were evaluated at baseline, 12 and 72?weeks after randomization, and 24?weeks following EOT.
RESULTS: Baseline lipoprotein profiles were similar among OCA and placebo groups. OCA did not affect total VLDL particle concentrations, but OCA vs. placebo treatment was associated with decreased large VLDL particle concentration at 12?weeks (baseline-adjusted mean: 6.8 vs. 8.9?nmol/L; p?=?0.002), mirrored by an increase in less atherogenic, small VLDL particle concentration (33.9 vs. 28.0?nmol/L; p?=?0.02). After 12?weeks, total LDL particle concentration was higher in the OCA group than the placebo group (1,667 vs. 1,329?nmol/L; p?<0.0001), characterized by corresponding increases in both less atherogenic, large-buoyant LDL (475 vs. 308?nmol/L; p?≤0.001) and more atherogenic small-dense LDL particles (1,015 vs. 872?nmol/L; p?=?0.002). The changes in LDL particle concentrations were similar between treatment groups (OCA and placebo) 24?weeks following EOT due to improvement in the OCA cohort. Compared to placebo, a reduction in total HDL particle concentration, particularly large and medium HDL particles, was noted in the OCA-treated patients, but this resolved after drug discontinuation.
CONCLUSION: OCA therapy is associated with increases in small VLDL particles, large and small LDL particles, and a reduction in HDL particles at 12?weeks. These lipoprotein concentrations reverted to baseline values 24?weeks after drug discontinuation.
LAY SUMMARY: Non-alcoholic steatohepatitis is a chronic liver disease that is associated with an increased risk of developing cirrhosis and cardiovascular disease. Recently, obeticholic acid (OCA), a farnesoid X receptor agonist, improved liver disease but led to an increase in cholesterol. However, the impact of OCA on cholesterol is not well understood. In the present study, we show that OCAtherapy is associated with a detrimental increase in lipoprotein levels, which improves after drug discontinuation. ClinicalTrials.gov numbers: NCT01265498.