PCSK9: Regulation and Target for Drug Development for Dyslipidemia

Burke, Amy C.; Dron, Jacqueline S.; Hegele, Robert A.; Huff, Murray W.

doi:10.1146/annurev-pharmtox-010716-104944

Cited by 74

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PCSK9: Regulation and Target for Drug Development for Dyslipidemia

Burke, Amy C., Dron, Jacqueline S., Hegele, Robert A., Huff, Murray W.·2017·Annual Review of Pharmacology and Toxicology

DOI 10.1146/annurev-pharmtox-010716-104944

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Abstract

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.

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Targeted PCSK9 inhibition restores hepatic LDLR levels, decreases plasma LDL-C levels and improves cardiovascular outcomes.
“targeted PCSK9 inhibition restores hepatic LDLR levels, decreases plasma LDL-C levels and improves cardiovascular outcomes.7,9–11”
From Sirtuin-1 directly binds and deacetylates hepatic PCSK9 thereby promoting the inhibition of LDL receptor degradation (2025) · cites this paper as [9]

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Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes
Cannon, C. P., Blazing, M. A., Giugliano, R. P., McCagg, A., White, J. A., Theroux, P., Darius, H., Lewis, B. S., Ophuis, T. O., Jukema, J. W., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1410489 · Cited by 4,487
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215593 · Cited by 4,092
Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease
Cohen, J. C., Boerwinkle, E., Mosley, T. H., & Hobbs, H. H. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa054013 · Cited by 3,181
Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events
Sabatine, M. S., Giugliano, R. P., Wiviott, S. D., Raal, F. J., Blom, D. J., Robinson, J., Ballantyne, C. M., Somaratne, R., Legg, J., Wasserman, S. M., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1500858 · Cited by 1,509
Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9
Cohen, J., Pertsemlidis, A., Kotowski, I. K., Graham, R., Garcia, C. K., & Hobbs, H. H. (2005) · Nature Genetics · doi:10.1038/ng1509 · Cited by 1,381
Association of LDL Cholesterol, Non–HDL Cholesterol, and Apolipoprotein B Levels With Risk of Cardiovascular Events Among Patients Treated With Statins: A Meta-analysis
Boekholdt, S. M., Arsenault, B. J., Mora, S., Pedersen, T. R., LaRosa, J. C., Nestel, P. J., Simes, R. J., Durrington, P., Hitman, G. A., Welch, K. M. A., et al. (2012) · JAMA · doi:10.1001/jama.2012.366 · Cited by 795
PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial
Raal, F. J., Stein, E. A., Dufour, R., Turner, T., Civeira, F., Burgess, L., Langslet, G., Scott, R., Olsson, A. G., Sullivan, D., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(14)61399-4 · Cited by 756
Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol
Stein, E. A., Mellis, S., Yancopoulos, G. D., Stahl, N., Logan, D., Smith, W. B., Lisbon, E., Gutierrez, M., Webb, C., Wu, R., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1105803 · Cited by 664
The Proprotein Convertase PCSK9 Induces the Degradation of Low Density Lipoprotein Receptor (LDLR) and Its Closest Family Members VLDLR and ApoER2
Poirier, S., Mayer, G., Benjannet, S., Bergeron, E., Marcinkiewicz, J., Nassoury, N., Mayer, H., Nimpf, J., Prat, A., & Seidah, N. G. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m708098200 · Cited by 477
Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial
Moriarty, P. M., Thompson, P. D., Cannon, C. P., Guyton, J. R., Bergeron, J., Zieve, F. J., Bruckert, E., Jacobson, T. A., Kopecky, S. L., Baccara-Dinet, M. T., et al. (2015) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2015.08.006 · Cited by 470
Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin
Kühnast, S., van der Hoorn, J. W. A., Pieterman, E. J., van den Hoek, A. M., Sasiela, W. J., Gusarova, V., Peyman, A., Schäfer, H.-L., Schwahn, U., Jukema, J. W., et al. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m051326 · Cited by 204
Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation
Kosenko, T., Golder, M., Leblond, G., Weng, W., & Lagace, T. A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.421370 · Cited by 181
Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update
Mancini, G. B. J., Tashakkor, A. Y., Baker, S., Bergeron, J., Fitchett, D., Frohlich, J., Genest, J., Gupta, M., Hegele, R. A., Ng, D. S., et al. (2013) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2013.09.023 · Cited by 173
Self-citation

Flagged first, then by citations

Research works printed but not linked: 117

10.1373/clinchem.2010.159350 · DOI
10.1161/CIRCOUTCOMES.110.959247 · DOI · Paper page
10.1007/s00392-006-0403-x · DOI · Paper page
10.1016/j.jacc.2009.10.042 · DOI
10.1016/j.nmd.2013.09.011 · DOI · Paper page
10.1002/humu.20882 · DOI
10.1038/ng1161 · DOI · Paper page
10.1161/CIRCRESAHA.114.301621 · DOI
10.1073/pnas.0903849106 · DOI · Paper page
10.1093/eurheartj/ehv174 · DOI · Paper page
10.1038/nrd3699 · DOI · Paper page
10.1073/pnas.0335507100 · DOI · Paper page
10.1038/nsmb1235 · DOI · Paper page
10.1194/jlr.R800091-JLR200 · DOI · Paper page
10.1074/jbc.M409699200 · DOI · Paper page
10.1073/pnas.0402133101 · DOI · Paper page
10.1074/jbc.M410077200 · DOI · Paper page
10.1126/science.3513311 · DOI · Paper page
10.1186/1471-2121-8-9 · DOI
10.1074/jbc.M109.037085 · DOI · Paper page
10.1073/pnas.0707269105 · DOI
10.1074/jbc.M112.394023 · DOI
10.1016/j.bbrc.2008.07.106 · DOI · Paper page
10.1371/journal.pone.0064145 · DOI · Paper page
10.1161/ATVBAHA.110.220988 · DOI · Paper page
10.1086/507488 · DOI
10.1007/s00125-015-3659-8 · DOI
10.1161/ATVBAHA.115.306032 · DOI · Paper page
10.1002/hep.22354 · DOI · Paper page
10.1056/NEJMoa1501031 · DOI · Paper page
10.1002/hep.22911 · DOI
10.1161/01.ATV.0000134621.14315.43 · DOI · Paper page
10.1194/jlr.M700443-JLR200 · DOI · Paper page
10.1194/jlr.P009860 · DOI
10.1161/ATVBAHA.110.214130 · DOI · Paper page
10.1016/j.tibs.2006.12.008 · DOI · Paper page
10.1097/MOL.0000000000000114 · DOI · Paper page
10.1210/en.2006-0098 · DOI
10.1161/ATVBAHA.112.250043 · DOI
10.1074/jbc.M109.052407 · DOI
10.1194/jlr.M003566 · DOI
10.1172/JCI61919 · DOI
10.1161/ATVBAHA.114.304326 · DOI
10.1161/ATVBAHA.111.242461 · DOI
10.1172/JCI29383 · DOI · Paper page
10.1161/CIRCULATIONAHA.111.057406 · DOI · Paper page
10.1126/scitranslmed.3004853 · DOI
10.1073/pnas.0501652102 · DOI · Paper page
10.1194/jlr.M053207 · DOI
10.1371/journal.pone.0041865 · DOI · Paper page
10.1161/ATVBAHA.112.300263 · DOI
10.1016/j.febslet.2009.12.018 · DOI
10.1373/clinchem.2009.126987 · DOI
10.1210/jc.2009-0141 · DOI · Paper page
10.1017/S0007114511003436 · DOI
10.1074/jbc.M508582200 · DOI
10.1161/01.ATV.0000204337.81286.1c · DOI · Paper page
10.1371/journal.pone.0060095 · DOI
10.1093/eurheartj/eht273 · DOI · Paper page
10.1086/302370 · DOI
10.1161/01.ATV.20.4.1089 · DOI
10.1086/500615 · DOI · Paper page
10.1111/j.1365-2796.2012.02586.x · DOI
10.1097/MOL.0000000000000280 · DOI
10.1007/s11883-014-0439-8 · DOI
10.1373/clinchem.2011.165191 · DOI · Paper page
10.1016/j.jacc.2010.02.044 · DOI
10.1161/01.ATV.0000190668.94752.ab · DOI
10.1161/CIRCGENETICS.115.001129 · DOI
10.1016/j.jacc.2015.08.871 · DOI
10.1016/j.atherosclerosis.2006.08.039 · DOI
10.1194/jlr.M011445 · DOI
10.7150/ijbs.3524 · DOI
10.1093/protein/gzq097 · DOI
10.1124/jpet.114.214221 · DOI
10.1016/S0735-1097(14)61372-3 · DOI
10.1073/pnas.0805434105 · DOI
10.1038/ncomms10154 · DOI
10.1016/S0140-6736(13)61914-5 · DOI
10.1194/jlr.C600025-JLR200 · DOI
10.1371/journal.pone.0010682 · DOI · Paper page
10.1038/mt.2011.260 · DOI
10.1074/jbc.M808802200 · DOI
10.1016/j.ejmech.2015.01.022 · DOI
10.1074/jbc.M111.273474 · DOI
10.1074/jbc.M113.514067 · DOI
10.1016/j.chembiol.2013.11.014 · DOI
10.1038/embor.2011.205 · DOI · Paper page
10.1161/JAHA.115.002224 · DOI
10.1016/j.jacc.2012.03.007 · DOI
10.1016/j.jacc.2012.08.986 · DOI
10.7326/M14-2957 · DOI
10.1161/JAHA.115.001937 · DOI
10.1186/s12916-015-0358-8 · DOI · Paper page
10.1093/eurheartj/ehv563 · DOI · Paper page
10.1016/j.atherosclerosis.2016.02.011 · DOI
10.1111/bcp.12905 · DOI · Paper page
10.1016/j.tcm.2015.01.009 · DOI
10.1016/j.jacc.2015.05.001 · DOI
10.1161/CIRCULATIONAHA.115.016080 · DOI · Paper page
10.1586/14779072.2015.1111759 · DOI
10.2217/fca.15.78 · DOI
10.1016/j.amjcard.2015.02.006 · DOI
10.1161/CIRCULATIONAHA.112.144055 · DOI
Kastelein JJ, 2015, Eur. Heart. J., 36, 2996
10.1016/S0140-6736(14)61374-X · DOI
10.1016/j.jcjd.2015.09.012 · DOI
10.1016/S2213-8587(16)00003-6 · DOI
10.1016/j.jacc.2014.03.019 · DOI · Paper page
10.1016/j.ahj.2015.11.015 · DOI · Paper page
10.1016/j.ahj.2014.07.028 · DOI · Paper page
Lepor NE, 2015, Am. Health Drug Benefits, 8, 483
10.1001/jamainternmed.2015.7248 · DOI
10.1016/j.ahj.2016.01.019 · DOI
10.1016/j.atherosclerosis.2015.10.023 · DOI
10.1128/JVI.02727-13 · DOI
10.1001/jama.2011.860 · DOI · Paper page

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Dron, J. S., & Hegele, R. A. (2017) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000386 · Cited by 72
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Sirtuin-1 directly binds and deacetylates hepatic PCSK9 thereby promoting the inhibition of LDL receptor degradation
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Authors: Burke, A. C., Dron, J. S., Hegele, R. A., & Huff, M. W.
Affiliations: Department of Biochemistry, Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5B7;, , ,
Venue: Annual Review of Pharmacology and Toxicology
Publisher: Annual Reviews
Published: 2017-01-06
Volume: 57
Issue: 1
Pages: 223-244
ISSN: 0362-1642
1545-4304
DOI: 10.1146/annurev-pharmtox-010716-104944
Cited by: 74
References: 13
Language: en

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PCSK9: Regulation and Target for Drug Development for Dyslipidemia

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