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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 38; no. 5; pp. 1178 - 1190
• Main Authors: Burke, Amy C, Telford, Dawn E, Sutherland, Brian G, Edwards, Jane Y, Sawyez, Cynthia G, Barrett, P. Hugh R, Newton, Roger S, Pickering, J Geoffrey, Huff, Murray W
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.05.2018
• Subjects: 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; atherosclerosis; swine; receptors, LDL; lipids; therapeutics; cholesterol, LDL
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.117.310676

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.