Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis

for the NASH CRN

Research output: Contribution to journalArticle

Abstract

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 OCA therapy is associated with a detrimental increase in lipoprotein levels, which improves after drug discontinuation. ClinicalTrials.gov numbers: NCT01265498.

Original languageEnglish (US)
JournalJournal of Hepatology
DOIs
StateAccepted/In press - Jan 1 2019

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Fatty Liver
Lipoproteins
LDL Lipoproteins
VLDL Lipoproteins
Placebos
HDL Lipoproteins
Therapeutics
6-ethylchenodeoxycholic acid
Liver Diseases
Cholesterol
Pharmaceutical Preparations
Random Allocation
LDL Cholesterol
Fibrosis
Chronic Disease
Cardiovascular Diseases

Keywords

  • Cholesterol
  • High-density lipoprotein
  • Lipoproteins
  • Low-density lipoprotein
  • NASH
  • Nonalcoholic steatohepatitis
  • OCA
  • Very low-density lipoprotein

ASJC Scopus subject areas

  • Hepatology

Cite this

Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis. / for the NASH CRN.

In: Journal of Hepatology, 01.01.2019.

Research output: Contribution to journalArticle

@article{f26eb73a407d4335a2806e152fc48320,
title = "Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis",
abstract = "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 OCA therapy is associated with a detrimental increase in lipoprotein levels, which improves after drug discontinuation. ClinicalTrials.gov numbers: NCT01265498.",
keywords = "Cholesterol, High-density lipoprotein, Lipoproteins, Low-density lipoprotein, NASH, Nonalcoholic steatohepatitis, OCA, Very low-density lipoprotein",
author = "{for the NASH CRN} and Siddiqui, {Mohammad Shadab} and {Van Natta}, {Mark L.} and Connelly, {Margery A.} and Raj Vuppalanchi and Neuschwander-Tetri, {Brent A.} and James Tonascia and Cynthia Guy and Rohit Loomba and Srinivasan Dasarathy and Julia Wattacheril and Naga Chalasani and Sanyal, {Arun J.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.jhep.2019.10.006",
language = "English (US)",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "Elsevier",

}

TY - JOUR

T1 - Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis

AU - for the NASH CRN

AU - Siddiqui, Mohammad Shadab

AU - Van Natta, Mark L.

AU - Connelly, Margery A.

AU - Vuppalanchi, Raj

AU - Neuschwander-Tetri, Brent A.

AU - Tonascia, James

AU - Guy, Cynthia

AU - Loomba, Rohit

AU - Dasarathy, Srinivasan

AU - Wattacheril, Julia

AU - Chalasani, Naga

AU - Sanyal, Arun J.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 OCA therapy is associated with a detrimental increase in lipoprotein levels, which improves after drug discontinuation. ClinicalTrials.gov numbers: NCT01265498.

AB - 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 OCA therapy is associated with a detrimental increase in lipoprotein levels, which improves after drug discontinuation. ClinicalTrials.gov numbers: NCT01265498.

KW - Cholesterol

KW - High-density lipoprotein

KW - Lipoproteins

KW - Low-density lipoprotein

KW - NASH

KW - Nonalcoholic steatohepatitis

KW - OCA

KW - Very low-density lipoprotein

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U2 - 10.1016/j.jhep.2019.10.006

DO - 10.1016/j.jhep.2019.10.006

M3 - Article

C2 - 31634532

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JO - Journal of Hepatology

JF - Journal of Hepatology

SN - 0168-8278

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