Format

Send to

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

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

Author information

1
From the Robarts Research Institute (A.C.B., D.E.T., B.G.S., J.Y.E., C.G.S., J.G.P., M.W.H.).
2
Department of Biochemistry (A.C.B., J.G.P., M.W.H.).
3
Department of Medicine (D.E.T., J.Y.E., C.G.S., J.G.P., M.W.H.), The University of Western Ontario, London, Canada.
4
School of Biomedical Sciences, University of Western Australia, Perth (P.H.R.B.).
5
Esperion Therapeutics Inc, Ann Arbor, MI (R.S.N.).
6
From the Robarts Research Institute (A.C.B., D.E.T., B.G.S., J.Y.E., C.G.S., J.G.P., M.W.H.) mhuff@uwo.ca.

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.

KEYWORDS:

atherosclerosis; cholesterol, LDL; lipids; receptors, LDL; swine; therapeutics

PMID:
29449335
DOI:
10.1161/ATVBAHA.117.310676

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center