Title: | Bempedoic Acid Lowers Low-Density Lipoprotein Cholesterol and Attenuates Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient (LDLR+/− and LDLR−/−) Yucatan Miniature Pigs |
Contributor(s): | Burke, Amy C (author); Telford, Dawn E (author); Sutherland, Brian G (author); Edwards, Jane Y (author); Sawyez, Cynthia G (author); Barrett, P Hugh R (author) ; Newton, Roger S (author); Pickering, J Geoffrey (author); Huff, Murray W (author) |
Publication Date: | 2018-05 |
Early Online Version: | 2018-02-15 |
Open Access: | Yes |
DOI: | 10.1161/ATVBAHA.117.310676![Open Access Link](/web/OA.png) |
Handle Link: | https://hdl.handle.net/1959.11/31277 |
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.
Publication Type: | Journal Article |
Source of Publication: | Arteriosclerosis, Thrombosis, and Vascular Biology, 38(5), p. 1178-1190 |
Publisher: | Lippincott Williams & Wilkins |
Place of Publication: | United States of America |
ISSN: | 1524-4636 1079-5642 |
Fields of Research (FoR) 2020: | 320101 Cardiology (incl. cardiovascular diseases) 320803 Systems physiology |
Socio-Economic Objective (SEO) 2020: | 200105 Treatment of human diseases and conditions |
Peer Reviewed: | Yes |
HERDC Category Description: | C1 Refereed Article in a Scholarly Journal |
Appears in Collections: | Journal Article
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