Bempedoic Acid Lowers Low-Density Lipoprotein Cholesterol and Attenuates Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient ( LDLR+/- and LDLR-/-) Yucatan Miniature Pigs

Arterioscler Thromb Vasc Biol. 2018 May;38(5):1178-1190. doi: 10.1161/ATVBAHA.117.310676. Epub 2018 Feb 15.


Objective: Bempedoic acid (BemA; ETC-1002) is a novel drug that targets hepatic ATP-citrate lyase to reduce cholesterol biosynthesis. In phase 2 studies, BemA lowers elevated low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients. In the present study, we tested the ability of BemA to decrease plasma cholesterol and LDL-C and attenuate atherosclerosis in a large animal model of familial hypercholesterolemia.

Approach and results: Gene targeting has been used to generate Yucatan miniature pigs heterozygous (LDLR+/-) or homozygous (LDLR-/-) for LDL receptor deficiency (ExeGen). LDLR+/- and LDLR-/- pigs were fed a high-fat, cholesterol-containing diet (34% kcal fat; 0.2% cholesterol) and orally administered placebo or BemA for 160 days. In LDLR+/- pigs, compared with placebo, BemA decreased plasma cholesterol and LDL-C up to 40% and 61%, respectively. In LDLR-/- pigs, in which plasma cholesterol and LDL-C were 5-fold higher than in LDLR+/- pigs, BemA decreased plasma cholesterol and LDL-C up to 27% and 29%, respectively. Plasma levels of triglycerides and high-density lipoprotein cholesterol, fasting glucose and insulin, and liver lipids were unaffected by treatment in either genotype. In the aorta of LDLR+/- pigs, BemA robustly attenuated en face raised lesion area (-58%) and left anterior descending coronary artery cross-sectional lesion area (-40%). In LDLR-/- pigs, in which lesions were substantially more advanced, BemA decreased aortic lesion area (-47%) and left anterior descending coronary artery lesion area (-48%).

Conclusions: In a large animal model of LDLR deficiency and atherosclerosis, long-term treatment with BemA reduces LDL-C and attenuates the development of aortic and coronary atherosclerosis in both LDLR+/- and LDLR-/- miniature pigs.

Keywords: atherosclerosis; cholesterol, LDL; lipids; receptors, LDL; swine; therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Anticholesteremic Agents / pharmacokinetics
  • Anticholesteremic Agents / pharmacology*
  • Aortic Diseases / blood
  • Aortic Diseases / genetics
  • Aortic Diseases / pathology
  • Aortic Diseases / prevention & control*
  • Atherosclerosis / blood
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • Biomarkers / blood
  • Cholesterol, LDL / blood*
  • Coronary Artery Disease / blood
  • Coronary Artery Disease / genetics
  • Coronary Artery Disease / pathology
  • Coronary Artery Disease / prevention & control*
  • Dicarboxylic Acids / pharmacokinetics
  • Dicarboxylic Acids / pharmacology*
  • Disease Models, Animal
  • Down-Regulation
  • Fatty Acids / pharmacokinetics
  • Fatty Acids / pharmacology*
  • Female
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Hyperlipoproteinemia Type II / blood
  • Hyperlipoproteinemia Type II / drug therapy*
  • Hyperlipoproteinemia Type II / genetics
  • Male
  • Phenotype
  • Plaque, Atherosclerotic
  • Receptors, LDL / deficiency*
  • Receptors, LDL / genetics
  • Swine
  • Swine, Miniature


  • Anticholesteremic Agents
  • Biomarkers
  • Cholesterol, LDL
  • Dicarboxylic Acids
  • Fatty Acids
  • Receptors, LDL
  • 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid

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