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

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

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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.
Original languageEnglish
Pages (from-to)1178-1190
JournalArteriosclerosis, thrombosis, and vascular biology
Volume38
Issue number5
DOIs
Publication statusPublished - 15 Feb 2018

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LDL Lipoproteins
LDL Cholesterol
Atherosclerosis
Swine
Cholesterol
Acids
Coronary Vessels
Animal Models
ATP Citrate (pro-S)-Lyase
Fats
Placebos
Hyperlipoproteinemia Type II
Aptitude
LDL Receptors
Liver
HDL Cholesterol
Aorta
Coronary Artery Disease
Fasting
Triglycerides

Cite this

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. / Bempedoic Acid Lowers Low-Density Lipoprotein Cholesterol and Attenuates Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient (LDLR+/− and LDLR−/−) Yucatan Miniature Pigs. In: Arteriosclerosis, thrombosis, and vascular biology. 2018 ; Vol. 38, No. 5. pp. 1178-1190.
@article{a2401832ce0547fa9639c00e8c739aec,
title = "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.",
author = "Burke, {Amy C.} and Telford, {Dawn E.} and Sutherland, {Brian G.} and Edwards, {Jane Y.} and Sawyez, {Cynthia G.} and Barrett, {P. Hugh R.} and Newton, {Roger S.} and Pickering, {J. Geoffrey} and Huff, {Murray W.}",
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language = "English",
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pages = "1178--1190",
journal = "ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY",
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}

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

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 38, No. 5, 15.02.2018, p. 1178-1190.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Bempedoic Acid Lowers Low-Density Lipoprotein Cholesterol and Attenuates Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient (LDLR+/− and LDLR−/−) Yucatan Miniature Pigs

AU - Burke, Amy C.

AU - Telford, Dawn E.

AU - Sutherland, Brian G.

AU - Edwards, Jane Y.

AU - Sawyez, Cynthia G.

AU - Barrett, P. Hugh R.

AU - Newton, Roger S.

AU - Pickering, J. Geoffrey

AU - Huff, Murray W.

PY - 2018/2/15

Y1 - 2018/2/15

N2 - 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.

AB - 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.

U2 - 10.1161/ATVBAHA.117.310676

DO - 10.1161/ATVBAHA.117.310676

M3 - Article

VL - 38

SP - 1178

EP - 1190

JO - ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY

JF - ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY

SN - 1079-5642

IS - 5

ER -