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

Abstract

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.

• Authors: Amy C Burke, Dawn E Telford, Brian G Sutherland, Jane Y Edwards, Cynthia G Sawyez, P Hugh R Barrett, Roger S Newton, J Geoffrey Pickering, Murray W Huff
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 38 Issue 5 Pg. 1178-1190 (05 2018) ISSN: 1524-4636 [Electronic] United States
• PMID: 29449335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 American Heart Association, Inc.

Chemical References

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

Topics

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