A Review of PCSK9 Inhibitors and their Effects on Cardiovascular Diseases

Author(s): Bo Chen, Xin Shi, Yanping Cui, Aiping Hou, Pengjun Zhao*

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 20 , 2019

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Graphical Abstract:


Background: Cardiovascular diseases remain the leading cause of morbidity and mortality in the world, with elevated Low-Density Lipoprotein-Cholesterol (LDL-C) levels as the major risk factor. Lower levels of LDL-C can effectively reduce the risk of cardiovascular diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulating the degradation of hepatic LDL receptors that remove LDL-C from the circulation. PCSK9 inhibitors are a new class of agents that are becoming increasingly important in the treatment to reduce LDL-C levels. Two PCSK9 inhibitors, alirocumab and evolocumab, have been approved to treat hypercholesterolemia and are available in the United States and the European Union. Through the inhibition of PCSK9 and increased recycling of LDL receptors, serum LDL-C levels can be significantly reduced.

Objective: This review will describe the chemistry, pharmacokinetics, and pharmacodynamics of PCSK9 inhibitors and their clinical effects.

Keywords: Proprotein convertase subtilisin/kexin type 9 (PCSK9), Inhibitors, Pharmacokinetic, Pharmacodynamic profile, Clinical effect, Hypercholesterolemia.

Krogh, H.W.; Mundal, L.; Holven, K.B.; Retterstøl, K. Patients with familial hypercholesterolaemia are characterized by presence of cardiovascular disease at the time of death. Eur. Heart J., 2016, 37(17), 1398-1405.
[http://dx.doi.org/10.1093/eurheartj/ehv602] [PMID: 26586781]
Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA, 2001, 285(19), 2486-2497.
[http://dx.doi.org/10.1001/jama.285.19.2486] [PMID: 11368702]
Nelson, R.H. Hyperlipidemia as a risk factor for cardiovascular disease. Prim. Care, 2013, 40(1), 195-211.
[http://dx.doi.org/10.1016/j.pop.2012.11.003] [PMID: 23402469]
Baigent, C.; Keech, A.; Kearney, P.M.; Blackwell, L.; Buck, G.; Pollicino, C.; Kirby, A.; Sourjina, T.; Peto, R.; Collins, R.; Simes, R. Cholesterol Treatment Trialists, C. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet, 2005, 366(9493), 1267-1278, Katsiki, N.; Mikhailidis, D. P.; Athyros, V. G.; Hatzitolios, A. I.; Karagiannis, A.; Banach, M. Are we getting to lipid targets in real life? Arch. Med. Sci., 2010, 6(5), 639-641.
[PMID: 22419917]
Seidah, N.G.; Benjannet, S.; Wickham, L.; Marcinkiewicz, J.; Jasmin, S.B.; Stifani, S.; Basak, A.; Prat, A.; Chretien, M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc. Natl. Acad. Sci. USA, 2003, 100(3), 928-933.
[http://dx.doi.org/10.1073/pnas.0335507100] [PMID: 12552133]
Abifadel, M.; Varret, M.; Rabès, J.P.; Allard, D.; Ouguerram, K.; Devillers, M.; Cruaud, C.; Benjannet, S.; Wickham, L.; Erlich, D.; Derré, A.; Villéger, L.; Farnier, M.; Beucler, I.; Bruckert, E.; Chambaz, J.; Chanu, B.; Lecerf, J.M.; Luc, G.; Moulin, P.; Weissenbach, J.; Prat, A.; Krempf, M.; Junien, C.; Seidah, N.G.; Boileau, C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet., 2003, 34(2), 154-156.
[http://dx.doi.org/10.1038/ng1161] [PMID: 12730697]
Horton, J.D.; Cohen, J.C.; Hobbs, H.H. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem. Sci., 2007, 32(2), 71-77.
[http://dx.doi.org/10.1016/j.tibs.2006.12.008] [PMID: 17215125]
Alborn, W.E.; Cao, G.; Careskey, H.E.; Qian, Y.W.; Subramaniam, D.R.; Davies, J.; Conner, E.M.; Konrad, R.J. Serum proprotein convertase subtilisin kexin type 9 is correlated directly with serum LDL cholesterol. Clin. Chem., 2007, 53(10), 1814-1819.
[http://dx.doi.org/10.1373/clinchem.2007.091280] [PMID: 17702855]
Cariou, B.; Le May, C.; Costet, P. Clinical aspects of PCSK9. Atherosclerosis, 2011, 216(2), 258-265.
[http://dx.doi.org/10.1016/j.atherosclerosis.2011.04.018] [PMID: 21596380]
a) Davignon, J.; Dubuc, G.; Seidah, N.G. The influence of PCSK9 polymorphisms on serum low-density lipoprotein cholesterol and risk of atherosclerosis. Curr. Atheroscler. Rep., 2010, 12(5), 308-315.
b) Farnier, M. The role of proprotein convertase subtilisin/kexin type 9 in hyperlipidemia: focus on therapeutic implications. Am. J. Cardiovasc. Drugs, 2011, 11(3), 145-152.
c) Timms, K.M.; Wagner, S.; Samuels, M.E.; Forbey, K.; Goldfine, H.; Jammulapati, S.; Skolnick, M.H.; Hopkins, P.N.; Hunt, S.C.; Shattuck, D.M. A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum. Genet., 2004, 114(4), 349-353.
d) Allard, D.; Amsellem, S.; Abifadel, M.; Trillard, M.; Devillers, M.; Luc, G.; Krempf, M.; Reznik, Y.; Girardet, J.P.; Fredenrich, A.; Junien, C.; Varret, M.; Boileau, C.; Benlian, P.; Rabes, J.P. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum. Mutat., 2005, 26(5), 497.
e) Bourbon, M.; Alves, A.C.; Medeiros, A.M.; Silva, S.; Soutar, A.K. Investigators of Portuguese, F. H. S. Familial hypercholesterolaemia in Portugal. Atherosclerosis, 2008, 196(2), 633-642.
f) Cameron, J.; Holla, O.L.; Laerdahl, J.K.; Kulseth, M.A.; Ranheim, T.; Rognes, T.; Berge, K.E.; Leren, T.P. Characterization of novel mutations in the catalytic domain of the PCSK9 gene. J. Intern. Med., 2008, 263(4), 420-431.
g) Homer, V.M.; Marais, A.D.; Charlton, F.; Laurie, A.D.; Hurndell, N.; Scott, R.; Mangili, F.; Sullivan, D.R.; Barter, P.J.; Rye, K.A.; George, P.M.; Lambert, G. Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa. Atherosclerosis, 2008, 196(2), 659-666.
[PMID: 17765244]
Glerup, S.; Schulz, R.; Laufs, U.; Schlüter, K.D. Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease. Basic Res. Cardiol., 2017, 112(3), 32.
[http://dx.doi.org/10.1007/s00395-017-0619-0] [PMID: 28439730]
Avis, H.J.; Hutten, B.A.; Gagné, C.; Langslet, G.; McCrindle, B.W.; Wiegman, A.; Hsia, J.; Kastelein, J.J.; Stein, E.A. Efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia. J. Am. Coll. Cardiol., 2010, 55(11), 1121-1126.
[http://dx.doi.org/10.1016/j.jacc.2009.10.042] [PMID: 20223367]
Tavori, H.; Giunzioni, I.; Fazio, S. PCSK9 inhibition to reduce cardiovascular disease risk: recent findings from the biology of PCSK9. Curr Opin Endocrinol Diabetes Obes, 2015, 22(2), 126-132. (b) Rallidis, L. S.; Fountoulaki, K.; Anastasiou-Nana, M. Managing the underestimated risk of statin-associated myopathy. Int. J. Cardiol., 2012, 159(3), 169-176.
[PMID: 21813193]
Crunkhorn, S. Trial watch: PCSK9 antibody reduces LDL cholesterol. Nat. Rev. Drug Discov., 2012, 11(1), 11.
[http://dx.doi.org/10.1038/nrd3633] [PMID: 22212668]
Naureckiene, S.; Ma, L.; Sreekumar, K.; Purandare, U.; Lo, C.F.; Huang, Y.; Chiang, L.W.; Grenier, J.M.; Ozenberger, B.A.; Jacobsen, J.S.; Kennedy, J.D.; DiStefano, P.S.; Wood, A.; Bingham, B. Functional characterization of Narc 1, a novel proteinase related to proteinase K. Arch. Biochem. Biophys., 2003, 420(1), 55-67.
[http://dx.doi.org/10.1016/j.abb.2003.09.011] [PMID: 14622975]
Zhang, D.W.; Garuti, R.; Tang, W.J.; Cohen, J.C.; Hobbs, H.H. Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor. Proc. Natl. Acad. Sci. USA, 2008, 105(35), 13045-13050.
[http://dx.doi.org/10.1073/pnas.0806312105] [PMID: 18753623]
Lambert, G.; Charlton, F.; Rye, K.A.; Piper, D.E. Molecular basis of PCSK9 function. Atherosclerosis, 2009, 203(1), 1-7.
[http://dx.doi.org/10.1016/j.atherosclerosis.2008.06.010] [PMID: 18649882]
Cunningham, D.; Danley, D.E.; Geoghegan, K.F.; Griffor, M.C.; Hawkins, J.L.; Subashi, T.A.; Varghese, A.H.; Ammirati, M.J.; Culp, J.S.; Hoth, L.R.; Mansour, M.N.; McGrath, K.M.; Seddon, A.P.; Shenolikar, S.; Stutzman-Engwall, K.J.; Warren, L.C.; Xia, D.; Qiu, X. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat Struct Mol Biol, 2007, 14(5), 413-419, Piper, D. E.; Jackson, S.; Liu, Q.; Romanow, W. G.; Shetterly, S.; Thibault, S. T.; Shan, B.; Walker, N. P. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure, 2007, 15(5), 545-552.
[PMID: 17502100]
Seidah, N.G.; Prat, A. The proprotein convertases are potential targets in the treatment of dyslipidemia. J. Mol. Med. (Berl.), 2007, 85(7), 685-696.
[http://dx.doi.org/10.1007/s00109-007-0172-7] [PMID: 17351764]
Hampton, E.N.; Knuth, M.W.; Li, J.; Harris, J.L.; Lesley, S.A.; Spraggon, G. The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain. Proc. Natl. Acad. Sci. USA, 2007, 104(37), 14604-14609.
[http://dx.doi.org/10.1073/pnas.0703402104] [PMID: 17804797]
Kwon, H.J.; Lagace, T.A.; McNutt, M.C.; Horton, J.D.; Deisenhofer, J. Molecular basis for LDL receptor recognition by PCSK9. Proc. Natl. Acad. Sci. USA, 2008, 105(6), 1820-1825.
[http://dx.doi.org/10.1073/pnas.0712064105] [PMID: 18250299]
Lagace, T.A.; Curtis, D.E.; Garuti, R.; McNutt, M.C.; Park, S.W.; Prather, H.B.; Anderson, N.N.; Ho, Y.K.; Hammer, R.E.; Horton, J.D. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J. Clin. Invest., 2006, 116(11), 2995-3005.
[http://dx.doi.org/10.1172/JCI29383] [PMID: 17080197]
Leigh, S.E.; Foster, A.H.; Whittall, R.A.; Hubbart, C.S.; Humphries, S.E. Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. Ann. Hum. Genet., 2008, 72(Pt 4), 485-498.
[http://dx.doi.org/10.1111/j.1469-1809.2008.00436.x] [PMID: 18325082]
a) Jeong, H.J.; Lee, H.S.; Kim, K.S.; Kim, Y.K.; Yoon, D.; Park, S.W. Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J. Lipid Res., 2008, 49(2), 399-409.
b) Horton, J.D.; Goldstein, J.L.; Brown, M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest., 2002, 109(9), 1125-1131.
c) Brown, M.S.; Goldstein, J.L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell, 1997, 89(3), 331-340.
[PMID: 9150132]
Browning, J.D.; Horton, J.D. Fasting reduces plasma proprotein convertase, subtilisin/kexin type 9 and cholesterol biosynthesis in humans. J. Lipid Res., 2010, 51(11), 3359-3363.
[http://dx.doi.org/10.1194/jlr.P009860] [PMID: 20716520]
Wu, M.; Dong, B.; Cao, A.; Li, H.; Liu, J. Delineation of molecular pathways that regulate hepatic PCSK9 and LDL receptor expression during fasting in normolipidemic hamsters. Atherosclerosis, 2012, 224(2), 401-410.
[http://dx.doi.org/10.1016/j.atherosclerosis.2012.08.012] [PMID: 22954675]
Dubuc, G.; Chamberland, A.; Wassef, H.; Davignon, J.; Seidah, N.G.; Bernier, L.; Prat, A. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol., 2004, 24(8), 1454-1459.
[http://dx.doi.org/10.1161/01.ATV.0000134621.14315.43] [PMID: 15178557]
a) Geiger, J.; Honig-Liedl, P.; Schanzenbacher, P.; Walter, U. Ligand specificity and ticlopidine effects distinguish three human platelet ADP receptors. Eur. J. Pharmacol., 1998, 351(2), 235-246.
b) Dong, B.; Wu, M.; Li, H.; Kraemer, F.B.; Adeli, K.; Seidah, N.G.; Park, S.W.; Liu, J. Strong induction of PCSK9 gene expression through HNF1alpha and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters. J. Lipid Res., 2010, 51(6), 1486-1495.
[PMID: 20048381]
Poirier, S.; Mayer, G.; Benjannet, S.; Bergeron, E.; Marcinkiewicz, J.; Nassoury, N.; Mayer, H.; Nimpf, J.; Prat, A.; Seidah, N.G. The proprotein convertase PCSK9 induces the degradation of Low Density Lipoprotein Receptor (LDLR) and its closest family members VLDLR and ApoER2. J. Biol. Chem., 2008, 283(4), 2363-2372.
[http://dx.doi.org/10.1074/jbc.M708098200] [PMID: 18039658]
Shan, L.; Pang, L.; Zhang, R.; Murgolo, N.J.; Lan, H.; Hedrick, J.A. PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide. Biochem. Biophys. Res. Commun., 2008, 375(1), 69-73.
[http://dx.doi.org/10.1016/j.bbrc.2008.07.106] [PMID: 18675252]
Kim, J.; Basak, J.M.; Holtzman, D.M. The role of apolipoprotein E in Alzheimer’s disease. Neuron, 2009, 63(3), 287-303.
[http://dx.doi.org/10.1016/j.neuron.2009.06.026] [PMID: 19679070]
Reddy, S.S.; Connor, T.E.; Weeber, E.J.; Rebeck, W. Similarities and differences in structure, expression, and functions of VLDLR and ApoER2. Mol. Neurodegener., 2011, 6, 30.
[http://dx.doi.org/10.1186/1750-1326-6-30] [PMID: 21554715]
Rashid, S.; Curtis, D.E.; Garuti, R.; Anderson, N.N.; Bashmakov, Y.; Ho, Y.K.; Hammer, R.E.; Moon, Y.A.; Horton, J.D. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc. Natl. Acad. Sci. USA, 2005, 102(15), 5374-5379.
[http://dx.doi.org/10.1073/pnas.0501652102] [PMID: 15805190]
Zaid, A.; Roubtsova, A.; Essalmani, R.; Marcinkiewicz, J.; Chamberland, A.; Hamelin, J.; Tremblay, M.; Jacques, H.; Jin, W.; Davignon, J.; Seidah, N.G.; Prat, A. Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. Hepatology, 2008, 48(2), 646-654.
[http://dx.doi.org/10.1002/hep.22354] [PMID: 18666258]
Roubtsova, A.; Munkonda, M.N.; Awan, Z.; Marcinkiewicz, J.; Chamberland, A.; Lazure, C.; Cianflone, K.; Seidah, N.G.; Prat, A. Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. Arterioscler. Thromb. Vasc. Biol., 2011, 31(4), 785-791.
[http://dx.doi.org/10.1161/ATVBAHA.110.220988] [PMID: 21273557]
Kysenius, K.; Muggalla, P.; Mätlik, K.; Arumäe, U.; Huttunen, H.J. PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling. Cell. Mol. Life Sci., 2012, 69(11), 1903-1916.
[http://dx.doi.org/10.1007/s00018-012-0977-6] [PMID: 22481440]
Chan, J.C.; Piper, D.E.; Cao, Q.; Liu, D.; King, C.; Wang, W.; Tang, J.; Liu, Q.; Higbee, J.; Xia, Z.; Di, Y.; Shetterly, S.; Arimura, Z.; Salomonis, H.; Romanow, W.G.; Thibault, S.T.; Zhang, R.; Cao, P.; Yang, X.P.; Yu, T.; Lu, M.; Retter, M.W.; Kwon, G.; Henne, K.; Pan, O.; Tsai, M.M.; Fuchslocher, B.; Yang, E.; Zhou, L.; Lee, K.J.; Daris, M.; Sheng, J.; Wang, Y.; Shen, W.D.; Yeh, W.C.; Emery, M.; Walker, N.P.; Shan, B.; Schwarz, M.; Jackson, S.M. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc. Natl. Acad. Sci. USA, 2009, 106(24), 9820-9825.
[http://dx.doi.org/10.1073/pnas.0903849106] [PMID: 19443683]
Stein, E.A.; Mellis, S.; Yancopoulos, G.D.; Stahl, N.; Logan, D.; Smith, W.B.; Lisbon, E.; Gutierrez, M.; Webb, C.; Wu, R.; Du, Y.; Kranz, T.; Gasparino, E.; Swergold, G.D. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med., 2012, 366(12), 1108-1118.
[http://dx.doi.org/10.1056/NEJMoa1105803] [PMID: 22435370]
Canuel, M.; Sun, X.; Asselin, M.C.; Paramithiotis, E.; Prat, A.; Seidah, N.G. Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1). PLoS One, 2013, 8(5)e64145
[http://dx.doi.org/10.1371/journal.pone.0064145] [PMID: 23675525]
Levy, E.; Ben Djoudi Ouadda, A.; Spahis, S.; Sane, A.T.; Garofalo, C.; Grenier, É.; Emonnot, L.; Yara, S.; Couture, P.; Beaulieu, J.F.; Ménard, D.; Seidah, N.G.; Elchebly, M. PCSK9 plays a significant role in cholesterol homeostasis and lipid transport in intestinal epithelial cells. Atherosclerosis, 2013, 227(2), 297-306.
[http://dx.doi.org/10.1016/j.atherosclerosis.2013.01.023] [PMID: 23422832]
a) Demers, A.; Samami, S.; Lauzier, B.; Des Rosiers, C.; Ngo Sock, E.T.; Ong, H.; Mayer, G. PCSK9 induces CD36 degradation and affects long-chain fatty acid uptake and triglyceride metabolism in adipocytes and in mouse liver. Arterioscler. Thromb. Vasc. Biol., 2015, 35(12), 2517-2525.
b) Labonte, P.; Begley, S.; Guevin, C.; Asselin, M.C.; Nassoury, N.; Mayer, G.; Prat, A.; Seidah, N.G. PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression. Hepatology, 2009, 50(1), 17-24.
[PMID: 19489072]
Finkelshtein, D.; Werman, A.; Novick, D.; Barak, S.; Rubinstein, M. LDL receptor and its family members serve as the cellular receptors for vesicular stomatitis virus. Proc. Natl. Acad. Sci. USA, 2013, 110(18), 7306-7311.
[http://dx.doi.org/10.1073/pnas.1214441110] [PMID: 23589850]
Fouqué, A.; Legembre, P. study of the CD95-mediated non-apoptotic signaling pathway: PI3K. Methods Mol. Biol., 2017, 1557, 103-110.
[http://dx.doi.org/10.1007/978-1-4939-6780-3_10] [PMID: 28078586]
Sharotri, V.; Collier, D.M.; Olson, D.R.; Zhou, R.; Snyder, P.M. Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9). J. Biol. Chem., 2012, 287(23), 19266-19274.
[http://dx.doi.org/10.1074/jbc.M112.363382] [PMID: 22493497]
Mbikay, M.; Sirois, F.; Mayne, J.; Wang, G.S.; Chen, A.; Dewpura, T.; Prat, A.; Seidah, N.G.; Chretien, M.; Scott, F.W. PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett., 2010, 584(4), 701-706.
[http://dx.doi.org/10.1016/j.febslet.2009.12.018] [PMID: 20026049]
Cariou, B.; Si-Tayeb, K.; Le May, C. Role of PCSK9 beyond liver involvement. Curr. Opin. Lipidol., 2015, 26(3), 155-161.
[http://dx.doi.org/10.1097/MOL.0000000000000180] [PMID: 25887680]
Cohen, J.C.; Boerwinkle, E.; Mosley, T.H., Jr; Hobbs, H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med., 2006, 354(12), 1264-1272.
[http://dx.doi.org/10.1056/NEJMoa054013] [PMID: 16554528]
Kathiresan, S.; Myocardial Infarction Genetics, C.A. Myocardial infarction genetics consortium. A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. N. Engl. J. Med., 2008, 358(21), 2299-2300.
[http://dx.doi.org/10.1056/NEJMc0707445] [PMID: 18499582]
a) Doggrell, S.A.; Lynch, K.A. Is there enough evidence with evolocumab and alirocumab (antibodies to proprotein convertase substilisin-kexin type, PCSK9) on cardiovascular outcomes to use them widely?. Evaluation of Sabatine, M.S.; Giugliano, R.P.; Wiviott, S.D. et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N. Engl. J. Med., 2015, 372, 1500-1509.
a) Latimer, J.; Batty, J.A.; Neely, R.D.; Kunadian, V. PCSK9 inhibitors in the prevention of cardiovascular disease. J. Thromb. Thrombolysis, 2016, 42(3), 405-419.
b) Everett, B.M.; Smith, R.J.; Hiatt, W.R. Reducing LDL with PCSK9 inhibitors--the clinical benefit of lipid drugs. N. Engl. J. Med., 2015, 373(17), 1588-1591.
[PMID: 26444323]
a) Evolocumab (Repatha)--A second PCSK9 Inhibitor to Lower LDL-Cholesterol. JAMA, 2015, 314(21), 2298-2299.
b) Alirocumab (Praluent) to lower LDL-Cholesterol. Med. Lett. Drugs Ther., 2015, 57(1475), 113-115.
[PMID: 26262881]
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.; Scott, R.; Koren, M.J.; Stein, E.A. Open-label study of long-term evaluation against LDL cholesterol (OSLER) investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N. Engl. J. Med., 2015, 372(16), 1500-1509.
[http://dx.doi.org/10.1056/NEJMoa1500858] [PMID: 25773607]
Wiciński, M.; Żak, J.; Malinowski, B.; Popek, G.; Grześk, G. PCSK9 signaling pathways and their potential importance in clinical practice. EPMA J., 2017, 8(4), 391-402.
[http://dx.doi.org/10.1007/s13167-017-0106-6] [PMID: 29209441]
Graham, M.J.; Lemonidis, K.M.; Whipple, C.P.; Subramaniam, A.; Monia, B.P.; Crooke, S.T.; Crooke, R.M. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J. Lipid Res., 2007, 48(4), 763-767.
[http://dx.doi.org/10.1194/jlr.C600025-JLR200] [PMID: 17242417]
Bennett, C.F.; Swayze, E.E. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu. Rev. Pharmacol. Toxicol., 2010, 50, 259-293.
[http://dx.doi.org/10.1146/annurev.pharmtox.010909.105654] [PMID: 20055705]
Lindholm, M.W.; Elmén, J.; Fisker, N.; Hansen, H.F.; Persson, R.; Møller, M.R.; Rosenbohm, C.; Ørum, H.; Straarup, E.M.; Koch, T. PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates. Mol. Ther., 2012, 20(2), 376-381.
[http://dx.doi.org/10.1038/mt.2011.260] [PMID: 22108858]
Frank-Kamenetsky, M.; Grefhorst, A.; Anderson, N.N.; Racie, T.S.; Bramlage, B.; Akinc, A.; Butler, D.; Charisse, K.; Dorkin, R.; Fan, Y.; Gamba-Vitalo, C.; Hadwiger, P.; Jayaraman, M.; John, M.; Jayaprakash, K.N.; Maier, M.; Nechev, L.; Rajeev, K.G.; Read, T.; Röhl, I.; Soutschek, J.; Tan, P.; Wong, J.; Wang, G.; Zimmermann, T.; de Fougerolles, A.; Vornlocher, H.P.; Langer, R.; Anderson, D.G.; Manoharan, M.; Koteliansky, V.; Horton, J.D.; Fitzgerald, K. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc. Natl. Acad. Sci. USA, 2008, 105(33), 11915-11920.
[http://dx.doi.org/10.1073/pnas.0805434105] [PMID: 18695239]
Veedu, R.N.; Wengel, J. Locked nucleic acid as a novel class of therapeutic agents. RNA Biol., 2009, 6(3), 321-323.
[http://dx.doi.org/10.4161/rna.6.3.8807] [PMID: 19458498]
Gupta, N.; Fisker, N.; Asselin, M.C.; Lindholm, M.; Rosenbohm, C.; Ørum, H.; Elmén, J.; Seidah, N.G.; Straarup, E.M. A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo. PLoS One, 2010, 5(5)e10682
[http://dx.doi.org/10.1371/journal.pone.0010682] [PMID: 20498851]
Fitzgerald, K.; Frank-Kamenetsky, M.; Shulga-Morskaya, S.; Liebow, A.; Bettencourt, B.R.; Sutherland, J.E.; Hutabarat, R.M.; Clausen, V.A.; Karsten, V.; Cehelsky, J.; Nochur, S.V.; Kotelianski, V.; Horton, J.; Mant, T.; Chiesa, J.; Ritter, J.; Munisamy, M.; Vaishnaw, A.K.; Gollob, J.A.; Simon, A. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet, 2014, 383(9911), 60-68.
[http://dx.doi.org/10.1016/S0140-6736(13)61914-5] [PMID: 24094767]
Yamamoto, T.; Lu, C.; Ryan, R.O. A two-step binding model of PCSK9 interaction with the low density lipoprotein receptor. J. Biol. Chem., 2011, 286(7), 5464-5470.
[http://dx.doi.org/10.1074/jbc.M110.199042] [PMID: 21149300]
Maxwell, K.N.; Fisher, E.A.; Breslow, J.L. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc. Natl. Acad. Sci. USA, 2005, 102(6), 2069-2074.
[http://dx.doi.org/10.1073/pnas.0409736102] [PMID: 15677715]
a) Meister, G.; Tuschl, T. Mechanisms of gene silencing by double-stranded RNA. Nature, 2004, 431(7006), 343-349.
b) Vaishnaw, A.K.; Gollob, J.; Gamba-Vitalo, C.; Hutabarat, R.; Sah, D.; Meyers, R.; de Fougerolles, T.; Maraganore, J. A status report on RNAi therapeutics. Silence, 2010, 1(1), 14.
[PMID: 20615220]
Fitzgerald, K.; White, S.; Borodovsky, A.; Bettencourt, B.R.; Strahs, A.; Clausen, V.; Wijngaard, P.; Horton, J.D.; Taubel, J.; Brooks, A.; Fernando, C.; Kauffman, R.S.; Kallend, D.; Vaishnaw, A.; Simon, A. A highly durable RNAi therapeutic inhibitor of PCSK9. N. Engl. J. Med., 2017, 376(1), 41-51.
[http://dx.doi.org/10.1056/NEJMoa1609243] [PMID: 27959715]
Khvorova, A. Oligonucleotide Therapeutics - A new class of cholesterol-lowering drugs. N. Engl. J. Med., 2017, 376(1), 4-7.
[http://dx.doi.org/10.1056/NEJMp1614154] [PMID: 28052224]
Ray, K.K.; Landmesser, U.; Leiter, L.A.; Kallend, D.; Dufour, R.; Karakas, M.; Hall, T.; Troquay, R.P.; Turner, T.; Visseren, F.L.; Wijngaard, P.; Wright, R.S.; Kastelein, J.J. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N. Engl. J. Med., 2017, 376(15), 1430-1440.
[http://dx.doi.org/10.1056/NEJMoa1615758] [PMID: 28306389]
Sabatine, M.S.; Giugliano, R.P.; Keech, A.C.; Honarpour, N.; Wiviott, S.D.; Murphy, S.A.; Kuder, J.F.; Wang, H.; Liu, T.; Wasserman, S.M.; Sever, P.S.; Pedersen, T.R.; Committee, F.S. Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med., 2017, 376(18), 1713-1722.
[http://dx.doi.org/10.1056/NEJMoa1615664] [PMID: 28304224]
Raal, F.J.; Santos, R.D.; Blom, D.J.; Marais, A.D.; Charng, M.J.; Cromwell, W.C.; Lachmann, R.H.; Gaudet, D.; Tan, J.L.; Chasan-Taber, S.; Tribble, D.L.; Flaim, J.D.; Crooke, S.T. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet, 2010, 375(9719), 998-1006.
[http://dx.doi.org/10.1016/S0140-6736(10)60284-X] [PMID: 20227758]
Ray, K.K.; Stoekenbroek, R.M.; Kallend, D.; Leiter, L.A.; Landmesser, U.; Wright, R.S.; Wijngaard, P.; Kastelein, J.J.P. Effect of an siRNA therapeutic targeting PCSK9 on atherogenic lipoproteins. Circulation, 2018, 138(13), 1304-1316.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034710] [PMID: 29735484]
Flierl, U.; Nero, T.L.; Lim, B.; Arthur, J.F.; Yao, Y.; Jung, S.M.; Gitz, E.; Pollitt, A.Y.; Zaldivia, M.T.; Jandrot-Perrus, M.; Schäfer, A.; Nieswandt, B.; Andrews, R.K.; Parker, M.W.; Gardiner, E.E.; Peter, K. Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators. J. Exp. Med., 2015, 212(2), 129-137.
[http://dx.doi.org/10.1084/jem.20140391] [PMID: 25646267]
Petersen, D.N.; Hawkins, J.; Ruangsiriluk, W.; Stevens, K.A.; Maguire, B.A.; O’Connell, T.N.; Rocke, B.N.; Boehm, M.; Ruggeri, R.B.; Rolph, T.; Hepworth, D.; Loria, P.M.; Carpino, P.A. A Small-Molecule Anti-secretagogue of PCSK9 Targets the 80S Ribosome to Inhibit PCSK9 Protein Translation. Cell Chem. Biol., 2016, 23(11), 1362-1371.
[http://dx.doi.org/10.1016/j.chembiol.2016.08.016] [PMID: 27746128]
Lintner, N.G.; McClure, K.F.; Petersen, D.; Londregan, A.T.; Piotrowski, D.W.; Wei, L.; Xiao, J.; Bolt, M.; Loria, P.M.; Maguire, B.; Geoghegan, K.F.; Huang, A.; Rolph, T.; Liras, S.; Doudna, J.A.; Dullea, R.G.; Cate, J.H. Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. PLoS Biol., 2017, 15(3)e2001882
[http://dx.doi.org/10.1371/journal.pbio.2001882] [PMID: 28323820]
McClure, K.F.; Piotrowski, D.W.; Petersen, D.; Wei, L.; Xiao, J.; Londregan, A.T.; Kamlet, A.S.; Dechert-Schmitt, A.M.; Raymer, B.; Ruggeri, R.B.; Canterbury, D.; Limberakis, C.; Liras, S.; DaSilva-Jardine, P.; Dullea, R.G.; Loria, P.M.; Reidich, B.; Salatto, C.T.; Eng, H.; Kimoto, E.; Atkinson, K.; King-Ahmad, A.; Scott, D.; Beaumont, K.; Chabot, J.R.; Bolt, M.W.; Maresca, K.; Dahl, K.; Arakawa, R.; Takano, A.; Halldin, C. Liver-Targeted Small-Molecule Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9 Synthesis. Angew. Chem. Int. Ed. Engl., 2017, 56(51), 16218-16222.
[http://dx.doi.org/10.1002/anie.201708744] [PMID: 29073340]
Pfefferkorn, J.A. Strategies for the design of hepatoselective glucokinase activators to treat type 2 diabetes. Expert Opin. Drug Discov., 2013, 8(3), 319-330.
[http://dx.doi.org/10.1517/17460441.2013.748744] [PMID: 23289965]
Pettersen, D.; Fjellström, O. Small molecule modulators of PCSK9 - A literature and patent overview. Bioorg. Med. Chem. Lett., 2018, 28(7), 1155-1160.
[http://dx.doi.org/10.1016/j.bmcl.2018.02.046] [PMID: 29519739]
Baldwin, E.T.; Bourne, J.W.; Monroe, KD.; Reece, M.T.; Muehlemann, M.M.; Barta, T.E.; Nevalainen, V. Proprotein convertase subtilisin kexin type 9 (PCSK9) allosteric binding ligands to modulate serum low density lipoprotein (LDL) levels. US2016083425. 2016.
McNutt, M.C.; Kwon, H.J.; Chen, C.; Chen, J.R.; Horton, J.D.; Lagace, T.A. Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells. J. Biol. Chem., 2009, 284(16), 10561-10570.
[http://dx.doi.org/10.1074/jbc.M808802200] [PMID: 19224862]
Zhang, Y.; Zhou, L.; Kong-Beltran, M.; Li, W.; Moran, P.; Wang, J.; Quan, C.; Tom, J.; Kolumam, G.; Elliott, J.M.; Skelton, N.J.; Peterson, A.S.; Kirchhofer, D. Calcium-independent inhibition of PCSK9 by affinity-improved variants of the LDL receptor EGF(A) domain. J. Mol. Biol., 2012, 422(5), 685-696.
[http://dx.doi.org/10.1016/j.jmb.2012.06.018] [PMID: 22728257]
Schroeder, C.I.; Swedberg, J.E.; Withka, J.M.; Rosengren, K.J.; Akcan, M.; Clayton, D.J.; Daly, N.L.; Cheneval, O.; Borzilleri, K.A.; Griffor, M.; Stock, I.; Colless, B.; Walsh, P.; Sunderland, P.; Reyes, A.; Dullea, R.; Ammirati, M.; Liu, S.; McClure, K.F.; Tu, M.; Bhattacharya, S.K.; Liras, S.; Price, D.A.; Craik, D.J. Design and synthesis of truncated EGF-A peptides that restore LDL-R recycling in the presence of PCSK9 in vitro. Chem. Biol., 2014, 21(2), 284-294.
[http://dx.doi.org/10.1016/j.chembiol.2013.11.014] [PMID: 24440079]
Lammi, C.; Zanoni, C.; Aiello, G.; Arnoldi, A.; Grazioso, G. Lupin peptides modulate the protein-protein interaction of PCSK9 with the low density lipoprotein receptor in HepG2 cells. Sci. Rep., 2016, 6, 29931.
[http://dx.doi.org/10.1038/srep29931] [PMID: 27424515]
Stucchi, M.; Grazioso, G.; Lammi, C.; Manara, S.; Zanoni, C.; Arnoldi, A.; Lesma, G.; Silvani, A. Disrupting the PCSK9/LDLR protein-protein interaction by an imidazole-based minimalist peptidomimetic. Org. Biomol. Chem., 2016, 14(41), 9736-9740.
[http://dx.doi.org/10.1039/C6OB01642A] [PMID: 27722650]
Zhang, Y.; Eigenbrot, C.; Zhou, L.; Shia, S.; Li, W.; Quan, C.; Tom, J.; Moran, P.; Di Lello, P.; Skelton, N.J.; Kong-Beltran, M.; Peterson, A.; Kirchhofer, D. Identification of a small peptide that inhibits PCSK9 protein binding to the low density lipoprotein receptor. J. Biol. Chem., 2014, 289(2), 942-955.
[http://dx.doi.org/10.1074/jbc.M113.514067] [PMID: 24225950]
Zhang, Y.; Ultsch, M.; Skelton, N.J.; Burdick, D.J.; Beresini, M.H.; Li, W.; Kong-Beltran, M.; Peterson, A.; Quinn, J.; Chiu, C.; Wu, Y.; Shia, S.; Moran, P.; Di Lello, P.; Eigenbrot, C.; Kirchhofer, D. Discovery of a cryptic peptide-binding site on PCSK9 and design of antagonists. Nat. Struct. Mol. Biol., 2017, 24(10), 848-856.
[http://dx.doi.org/10.1038/nsmb.3453] [PMID: 28825733]
Londregan, A.T.; Wei, L.; Xiao, J.; Lintner, N.G.; Petersen, D.; Dullea, R.G.; McClure, K.F.; Bolt, M.W.; Warmus, J.S.; Coffey, S.B.; Limberakis, C.; Genovino, J.; Thuma, B.A.; Hesp, K.D.; Aspnes, G.E.; Reidich, B.; Salatto, C.T.; Chabot, J.R.; Cate, J.H.D.; Liras, S.; Piotrowski, D.W. Small molecule proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors: Hit to lead optimization of systemic agents. J. Med. Chem., 2018, 61(13), 5704-5718.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00650] [PMID: 29878763]
Lo Surdo, P.; Bottomley, M.J.; Calzetta, A.; Settembre, E.C.; Cirillo, A.; Pandit, S.; Ni, Y.G.; Hubbard, B.; Sitlani, A.; Carfí, A. Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH. EMBO Rep., 2011, 12(12), 1300-1305.
[http://dx.doi.org/10.1038/embor.2011.205] [PMID: 22081141]
Dias, C.S.; Shaywitz, A.J.; Wasserman, S.M.; Smith, B.P.; Gao, B.; Stolman, D.S.; Crispino, C.P.; Smirnakis, K.V.; Emery, M.G.; Colbert, A.; Gibbs, J.P.; Retter, M.W.; Cooke, B.P.; Uy, S.T.; Matson, M.; Stein, E.A. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J. Am. Coll. Cardiol., 2012, 60(19), 1888-1898.
[http://dx.doi.org/10.1016/j.jacc.2012.08.986] [PMID: 23083772]
Sullivan, D.; Olsson, A.G.; Scott, R.; Kim, J.B.; Xue, A.; Gebski, V.; Wasserman, S.M.; Stein, E.A. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA, 2012, 308(23), 2497-2506.
[http://dx.doi.org/10.1001/jama.2012.25790] [PMID: 23128163]
Koren, M.J.; Scott, R.; Kim, J.B.; Knusel, B.; Liu, T.; Lei, L.; Bolognese, M.; Wasserman, S.M. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet, 2012, 380(9858), 1995-2006.
[http://dx.doi.org/10.1016/S0140-6736(12)61771-1] [PMID: 23141812]
Giugliano, R.P.; Desai, N.R.; Kohli, P.; Rogers, W.J.; Somaratne, R.; Huang, F.; Liu, T.; Mohanavelu, S.; Hoffman, E.B.; McDonald, S.T.; Abrahamsen, T.E.; Wasserman, S.M.; Scott, R.; Sabatine, M.S. LAPLACE-TIMI 57 Investigators. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet, 2012, 380(9858), 2007-2017.
[http://dx.doi.org/10.1016/S0140-6736(12)61770-X] [PMID: 23141813]
Raal, F.; Scott, R.; Somaratne, R.; Bridges, I.; Li, G.; Wasserman, S.M.; Stein, E.A. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 inhibition in heterozygous familial hypercholesterolemia disorder (RUTHERFORD) randomized trial. Circulation, 2012, 126(20), 2408-2417.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.112.144055] [PMID: 23129602]
Blom, D.J.; Hala, T.; Bolognese, M.; Lillestol, M.J.; Toth, P.D.; Burgess, L.; Ceska, R.; Roth, E.; Koren, M.J.; Ballantyne, C.M.; Monsalvo, M.L.; Tsirtsonis, K.; Kim, J.B.; Scott, R.; Wasserman, S.M.; Stein, E.A.; Investigators, D. DESCARTES Investigators. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N. Engl. J. Med., 2014, 370(19), 1809-1819.
[http://dx.doi.org/10.1056/NEJMoa1316222] [PMID: 24678979]
Robinson, J.G.; Rosenson, R.S.; Farnier, M.; Chaudhari, U.; Sasiela, W.J.; Merlet, L.; Miller, K.; Kastelein, J.J. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: pooled data from randomized trials. J. Am. Coll. Cardiol., 2017, 69(5), 471-482.
[http://dx.doi.org/10.1016/j.jacc.2016.11.037] [PMID: 28153102]
Koren, M.J.; Lundqvist, P.; Bolognese, M.; Neutel, J.M.; Monsalvo, M.L.; Yang, J.; Kim, J.B.; Scott, R.; Wasserman, S.M.; Bays, H.; Investigators, M. MENDEL-2 Investigators. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J. Am. Coll. Cardiol., 2014, 63(23), 2531-2540.
[http://dx.doi.org/10.1016/j.jacc.2014.03.018] [PMID: 24691094]
Tabrizi, M.A.; Tseng, C.M.; Roskos, L.K. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov. Today, 2006, 11(1-2), 81-88.
[http://dx.doi.org/10.1016/S1359-6446(05)03638-X] [PMID: 16478695]
Waldmann, T.A.; Strober, W. Metabolism of immunoglobulins. Prog Allergy, 1969, 13, 1-110, Junghans, R. P.; Anderson, C. L. The protection receptor for IgG catabolism is the beta2-microglobulin-containing neonatal intestinal transport receptor. Proc. Natl. Acad. Sci. USA, 1996, 93(11), 5512-5516.
[PMID: 8643606]
Gibbs, J.P.; Doshi, S.; Kuchimanchi, M.; Grover, A.; Emery, M.G.; Dodds, M.G.; Gibbs, M.A.; Somaratne, R.; Wasserman, S.M.; Blom, D. Impact of target-mediated elimination on the dose and regimen of evolocumab, a human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9). J. Clin. Pharmacol., 2017, 57(5), 616-626.
[http://dx.doi.org/10.1002/jcph.840] [PMID: 27861991]
Gibbs, J.P.; Slatter, J.G.; Egbuna, O.; Geller, M.; Hamilton, L.; Dias, C.S.; Xu, R.Y.; Johnson, J.; Wasserman, S.M.; Emery, M.G. Evaluation of evolocumab (AMG 145), a fully human anti-PCSK9 IgG2 monoclonal antibody, in subjects with hepatic impairment. J. Clin. Pharmacol., 2017, 57(4), 513-523.
[http://dx.doi.org/10.1002/jcph.832] [PMID: 27667740]
Toth, P.P.; Descamps, O.; Genest, J.; Sattar, N.; Preiss, D.; Dent, R.; Djedjos, C.; Wu, Y.; Geller, M.; Uhart, M.; Somaratne, R.; Wasserman, S.M.; Investigators, P. PROFICIO investigators. Pooled safety analysis of evolocumab in over 6000 patients from double-blind and open-label extension studies. Circulation, 2017, 135(19), 1819-1831.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.025233] [PMID: 28249876]
Giugliano, R.P.; Mach, F.; Zavitz, K.; Kurtz, C.; Schneider, J.; Wang, H.; Keech, A.; Pedersen, T.R.; Sabatine, M.S.; Sever, P.S.; Honarpour, N.; Wasserman, S.M.; Ott, B.R. Design and rationale of the EBBINGHAUS trial: A phase 3, double-blind, placebo-controlled, multicenter study to assess the effect of evolocumab on cognitive function in patients with clinically evident cardiovascular disease and receiving statin background lipid-lowering therapy-A cognitive study of patients enrolled in the FOURIER trial. Clin. Cardiol., 2017, 40(2), 59-65.
[http://dx.doi.org/10.1002/clc.22678] [PMID: 28207168]
Blom, D.J.; Koren, M.J.; Roth, E.; Monsalvo, M.L.; Djedjos, C.S.; Nelson, P.; Elliott, M.; Wasserman, S.M.; Ballantyne, C.M.; Holman, R.R. Evaluation of the efficacy, safety and glycaemic effects of evolocumab (AMG 145) in hypercholesterolaemic patients stratified by glycaemic status and metabolic syndrome. Diabetes Obes. Metab., 2017, 19(1), 98-107.
[http://dx.doi.org/10.1111/dom.12788] [PMID: 27619750]
Stein, E.A.; Gipe, D.; Bergeron, J.; Gaudet, D.; Weiss, R.; Dufour, R.; Wu, R.; Pordy, R. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet, 2012, 380(9836), 29-36.
[http://dx.doi.org/10.1016/S0140-6736(12)60771-5] [PMID: 22633824]
Roth, E.M.; McKenney, J.M.; Hanotin, C.; Asset, G.; Stein, E.A. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N. Engl. J. Med., 2012, 367(20), 1891-1900.
[http://dx.doi.org/10.1056/NEJMoa1201832] [PMID: 23113833]
McKenney, J.M.; Koren, M.J.; Kereiakes, D.J.; Hanotin, C.; Ferrand, A.C.; Stein, E.A. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J. Am. Coll. Cardiol., 2012, 59(25), 2344-2353.
[http://dx.doi.org/10.1016/j.jacc.2012.03.007] [PMID: 22463922]
Roth, E.M.; Taskinen, M.R.; Ginsberg, H.N.; Kastelein, J.J.; Colhoun, H.M.; Robinson, J.G.; Merlet, L.; Pordy, R.; Baccara-Dinet, M.T. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int. J. Cardiol., 2014, 176(1), 55-61.
[http://dx.doi.org/10.1016/j.ijcard.2014.06.049] [PMID: 25037695]
Moriarty, P.M.; Jacobson, T.A.; Bruckert, E.; Thompson, P.D.; Guyton, J.R.; Baccara-Dinet, M.T.; Gipe, D. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J. Clin. Lipidol., 2014, 8(6), 554-561.
[http://dx.doi.org/10.1016/j.jacl.2014.09.007] [PMID: 25499937]
Robinson, J.G.; Farnier, M.; Krempf, M.; Bergeron, J.; Luc, G.; Averna, M.; Stroes, E.S.; Langslet, G.; Raal, F.J.; El Shahawy, M.; Koren, M.J.; Lepor, N.E.; Lorenzato, C.; Pordy, R.; Chaudhari, U.; Kastelein, J.J.; Investigators, O.L.T. ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med., 2015, 372(16), 1489-1499.
[http://dx.doi.org/10.1056/NEJMoa1501031] [PMID: 25773378]
Lunven, C.; Paehler, T.; Poitiers, F.; Brunet, A.; Rey, J.; Hanotin, C.; Sasiela, W.J. A randomized study of the relative pharmacokinetics, pharmacodynamics, and safety of alirocumab, a fully human monoclonal antibody to PCSK9, after single subcutaneous administration at three different injection sites in healthy subjects. Cardiovasc. Ther., 2014, 32(6), 297-301.
[http://dx.doi.org/10.1111/1755-5922.12093] [PMID: 25256660]
Jones, P.H.; Bays, H.E.; Chaudhari, U.; Pordy, R.; Lorenzato, C.; Miller, K.; Robinson, J.G. Safety of alirocumab (a PCSK9 monoclonal antibody) from 14 randomized trials. Am. J. Cardiol., 2016, 118(12), 1805-1811.
[http://dx.doi.org/10.1016/j.amjcard.2016.08.072] [PMID: 27729106]
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.; Du, Y.; Pordy, R.; Gipe, D.A.; Investigators, O.A. ODYSSEY ALTERNATIVE Investigators. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J. Clin. Lipidol., 2015, 9(6), 758-769.
[http://dx.doi.org/10.1016/j.jacl.2015.08.006] [PMID: 26687696]
Kastelein, J.J.; Ginsberg, H.N.; Langslet, G.; Hovingh, G.K.; Ceska, R.; Dufour, R.; Blom, D.; Civeira, F.; Krempf, M.; Lorenzato, C.; Zhao, J.; Pordy, R.; Baccara-Dinet, M.T.; Gipe, D.A.; Geiger, M.J.; Farnier, M. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur. Heart J., 2015, 36(43), 2996-3003.
[http://dx.doi.org/10.1093/eurheartj/ehv370] [PMID: 26330422]
a) Bays, H.; Gaudet, D.; Weiss, R.; Ruiz, J.L.; Watts, G.F.; Gouni-Berthold, I.; Robinson, J.; Zhao, J.; Hanotin, C.; Donahue, S. Alirocumab as Add-On to Atorvastatin Versus Other Lipid Treatment Strategies: ODYSSEY OPTIONS I Randomized Trial. J. Clin. Endocrinol. Metab., 2015, 100(8), 3140-3148.
b) Farnier, M.; Jones, P.; Severance, R.; Averna, M.; Steinhagen-Thiessen, E.; Colhoun, H.M.; Du, Y.; Hanotin, C.; Donahue, S. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial. Atherosclerosis, 2016, 244, 138-146.
c) Cannon, C.P.; Cariou, B.; Blom, D.; McKenney, J.M.; Lorenzato, C.; Pordy, R.; Chaudhari, U.; Colhoun, H.M.; Investigators, O.C.I. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur. Heart J., 2015, 36(19), 1186-1194.
[PMID: 25687353]
Verstockt, B.; Ferrante, M.; Vermeire, S.; Van Assche, G. New treatment options for inflammatory bowel diseases. J. Gastroenterol., 2018, 53(5), 585-590.
[http://dx.doi.org/10.1007/s00535-018-1449-z] [PMID: 29556726]
Yoo, E.M.; Wims, L.A.; Chan, L.A.; Morrison, S.L. Human IgG2 can form covalent dimers. J Immunol, 2003, 170(6), 3134-3138, Salfeld, J. G. Isotype selection in antibody engineering. Nat. Biotechnol., 2007, 25(12), 1369-1372.
[PMID: 18066027]
Jefferis, R. Antibody therapeutics: isotype and glycoform selection. Expert Opin. Biol. Ther., 2007, 7(9), 1401-1413.
[http://dx.doi.org/10.1517/14712598.7.9.1401] [PMID: 17727329]
Levisetti, M.; Joh, T.; Wan, H.; Liang, H.; Forgues, P.; Gumbiner, B.; Garzone, P.D. A phase I randomized study of a specifically engineered, pH-sensitive PCSK9 inhibitor RN317 (PF-05335810) in hypercholesterolemic subjects on statin therapy. Clin. Transl. Sci., 2017, 10(1), 3-11.
[http://dx.doi.org/10.1111/cts.12430] [PMID: 27860267]
Chaparro-Riggers, J.; Liang, H.; DeVay, R.M.; Bai, L.; Sutton, J.E.; Chen, W.; Geng, T.; Lindquist, K.; Casas, M.G.; Boustany, L.M.; Brown, C.L.; Chabot, J.; Gomes, B.; Garzone, P.; Rossi, A.; Strop, P.; Shelton, D.; Pons, J.; Rajpal, A. increasing serum half-life and extending cholesterol lowering in vivo by engineering antibody with pH-sensitive binding to PCSK9. J. Biol. Chem., 2012, 287(14), 11090-11097.
[http://dx.doi.org/10.1074/jbc.M111.319764] [PMID: 22294692]
Sjouke, B.; Kusters, D.M.; Kastelein, J.J.; Hovingh, G.K. Familial hypercholesterolemia: present and future management. Curr. Cardiol. Rep., 2011, 13(6), 527-536.
[http://dx.doi.org/10.1007/s11886-011-0219-9] [PMID: 21938413]
Page, M.M.; Stefanutti, C.; Sniderman, A.; Watts, G.F. Recent advances in the understanding and care of familial hypercholesterolaemia: significance of the biology and therapeutic regulation of proprotein convertase subtilisin/kexin type 9. Clin. Sci. (Lond.), 2015, 129(1), 63-79.
[http://dx.doi.org/10.1042/CS20140755] [PMID: 25881720]
a) Fernandez-Higuero, J.A.; Etxebarria, A.; Benito-Vicente, A.; Alves, A.C.; Arrondo, J.L.; Ostolaza, H.; Bourbon, M.; Martin, C. Structural analysis of APOB variants, p.(Arg3527Gln), p.(Arg1164Thr) and p.(Gln4494del), causing Familial Hypercholesterolaemia provides novel insights into variant pathogenicity. Sci. Rep., 2015, 5, 18184.
b) Di Bonito, P.; Valerio, G.; Grugni, G.; Licenziati, M.R.; Maffeis, C.; Manco, M.; Miraglia Del Giudice, E.; Pacifico, L.; Pellegrin, M.C.; Tomat, M.; Baroni, M.G. Comparison of non-HDL-cholesterol versus triglycerides-to-HDLcholesterol ratio in relation to cardiometabolic risk factors and preclinical organ damage in overweight/obese children: The CARITALY study. Nutr. Metab. Cardiovasc. Dis., 2015, 25(5), 489-494.
[PMID: 27193247]
Sjouke, B.; Hovingh, G.K.; Kastelein, J.J.; Stefanutti, C. Homozygous autosomal dominant hypercholesterolaemia: prevalence, diagnosis, and current and future treatment perspectives. Curr. Opin. Lipidol., 2015, 26(3), 200-209.
[http://dx.doi.org/10.1097/MOL.0000000000000179] [PMID: 25950706]
Huijgen, R.; Kindt, I.; Verhoeven, S.B.; Sijbrands, E.J.; Vissers, M.N.; Kastelein, J.J.; Hutten, B.A. Two years after molecular diagnosis of familial hypercholesterolemia: majority on cholesterol-lowering treatment but a minority reaches treatment goal. PLoS One, 2010, 5(2)e9220
[http://dx.doi.org/10.1371/journal.pone.0009220] [PMID: 20169164]
Fouchier, S.W.; Defesche, J.C.; Kastelein, J.J.; Sijbrands, E.J. Familial defective apolipoprotein B versus familial hypercholesterolemia: an assessment of risk. Semin. Vasc. Med., 2004, 4(3), 259-264.
[http://dx.doi.org/10.1055/s-2004-861493] [PMID: 15630635]
Mashima, R.; Ohira, M.; Okuyama, T.; Tatsumi, A. Quantification of the enzyme activities of iduronate-2-sulfatase, N-acetylgalactosamine-6-sulfatase and N-acetylgalactosamine-4-sulfatase using liquid chromatography-tandem mass spectrometry. Mol. Genet. Metab. Rep., 2017, 14, 36-40.
[http://dx.doi.org/10.1016/j.ymgmr.2017.12.001] [PMID: 29326871]
Corrigendum to:. Incremental prognostic utility of coronary CT angiography for asymptomatic patients based upon extent and severity of coronary artery calcium: results from the Coronary CT Angiography Evaluation For Clinical Outcomes International Multicenter (CONFIRM) study. Eur. Heart J., 2015, 36(8), 501-508.
Huijgen, R.; Fouchier, S.W.; Denoun, M.; Hutten, B.A.; Vissers, M.N.; Lambert, G.; Kastelein, J.J. Plasma levels of PCSK9 and phenotypic variability in familial hypercholesterolemia. J. Lipid Res., 2012, 53(5), 979-983.
[http://dx.doi.org/10.1194/jlr.P023994] [PMID: 22375030]
Yockman, J.W.; Kastenmeier, A.; Erickson, H.M.; Brumbach, J.G.; Whitten, M.G.; Albanil, A.; Li, D.Y.; Kim, S.W.; Bull, D.A. Novel polymer carriers and gene constructs for treatment of myocardial ischemia and infarction. J. Control. Release, 2008, 132(3), 260-266.
[http://dx.doi.org/10.1016/j.jconrel.2008.06.024] [PMID: 18662730]
Huijgen, R.; Hutten, B.A.; Kindt, I.; Vissers, M.N.; Kastelein, J.J. Discriminative ability of LDL-cholesterol to identify patients with familial hypercholesterolemia: a cross-sectional study in 26,406 individuals tested for genetic FH. Circ Cardiovasc Genet, 2012, 5(3), 354-359.
[http://dx.doi.org/10.1161/CIRCGENETICS.111.962456] [PMID: 22553281]
Catapano, A.L.; Graham, I.; De Backer, G.; Wiklund, O.; Chapman, M.J.; Drexel, H.; Hoes, A.W.; Jennings, C.S.; Landmesser, U.; Pedersen, T.R.; Reiner, Z.; Riccardi, G.; Taskinen, M.R.; Tokgozoglu, L.; Verschuren, W.M.M.; Vlachopoulos, C.; Wood, D.A.; Zamorano, J.L.; Cooney, M.T.; Group, E.S.C.S.D. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur. Heart. J., 2016, 37(39), 2999-3058. (b) Vallejo-Vaz, A. J.; Kondapally Seshasai, S. R.; Cole, D.; Hovingh, G. K.; Kastelein, J. J.; Mata, P.; Raal, F. J.; Santos, R. D.; Soran, H.; Watts, G. F.; Abifadel, M.; Aguilar-Salinas, C. A.; Akram, A.; Alnouri, F.; Alonso, R.; Al-Rasadi, K.; Banach, M.; Bogsrud, M. P.; Bourbon, M.; Bruckert, E.; Car, J.; Corral, P.; Descamps, O.; Dieplinger, H.; Durst, R.; Freiberger, T.; Gaspar, I. M.; Genest, J.; Harada-Shiba, M.; Jiang, L.; Kayikcioglu, M.; Lam, C. S.; Latkovskis, G.; Laufs, U.; Liberopoulos, E.; Nilsson, L.; Nordestgaard, B. G.; O’Donoghue, J. M.; Sahebkar, A.; Schunkert, H.; Shehab, A.; Stoll, M.; Su, T. C.; Susekov, A.; Widen, E.; Catapano, A. L.; Ray, K. K. Familial hypercholesterolaemia: A global call to arms. Atherosclerosis, 2015, 243(1), 257-259.
[PMID: 26408930]
Careskey, H.E.; Davis, R.A.; Alborn, W.E.; Troutt, J.S.; Cao, G.; Konrad, R.J. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J. Lipid Res., 2008, 49(2), 394-398.
[http://dx.doi.org/10.1194/jlr.M700437-JLR200] [PMID: 18033751]
Raal, F.J.; Stein, E.A.; Dufour, R.; Turner, T.; Civeira, F.; Burgess, L.; Langslet, G.; Scott, R.; Olsson, A.G.; Sullivan, D.; Hovingh, G.K.; Cariou, B.; Gouni-Berthold, I.; Somaratne, R.; Bridges, I.; Scott, R.; Wasserman, S.M.; Gaudet, D.; Investigators, R. RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet, 2015, 385(9965), 331-340.
[http://dx.doi.org/10.1016/S0140-6736(14)61399-4] [PMID: 25282519]
Raal, F.J.; Honarpour, N.; Blom, D.J.; Hovingh, G.K.; Xu, F.; Scott, R.; Wasserman, S.M.; Stein, E.A.; Investigators, T. TESLA Investigators. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet, 2015, 385(9965), 341-350.
[http://dx.doi.org/10.1016/S0140-6736(14)61374-X] [PMID: 25282520]
Watts, G.F.; Stefanutti, C. ODYSSEY ESCAPE: is PCSK9 inhibition the Trojan Horse for the use of lipoprotein apheresis in familial hypercholesterolaemia? Eur. Heart J., 2016, 37(48), 3596-3599.
[http://dx.doi.org/10.1093/eurheartj/ehw497] [PMID: 28087751]
Stewart, J.; Manmathan, G.; Wilkinson, P. Primary prevention of cardiovascular disease: A review of contemporary guidance and literature. JRSM Cardiovasc. Dis., 2017. 62048004016687211
[http://dx.doi.org/10.1177/2048004016687211] [PMID: 28286646]
Chapman, M.J.; Stock, J.K.; Ginsberg, H.N.; Forum, P. PCSK9 Forum. PCSK9 inhibitors and cardiovascular disease: heralding a new therapeutic era. Curr. Opin. Lipidol., 2015, 26(6), 511-520.
[http://dx.doi.org/10.1097/MOL.0000000000000239] [PMID: 26780005]
Wilson, P.W.; D’Agostino, R.B.; Sullivan, L.; Parise, H.; Kannel, W.B. Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch. Intern. Med., 2002, 162(16), 1867-1872. (b) McGee, D. L.; Diverse Populations, C. Body mass index and mortality: a meta-analysis based on person-level data from twenty-six observational studies. Ann. Epidemiol., 2005, 15(2), 87-97. (c) Yusuf, S.; Hawken, S.; Ounpuu, S.; Dans, T.; Avezum, A.; Lanas, F.; McQueen, M.; Budaj, A.; Pais, P.; Varigos, J.; Lisheng, L.; Investigators, I. S. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet, 2004, 364(9438), 937-952. (d) Flint, A. J.; Rimm, E. B. Commentary: Obesity and cardiovascular disease risk among the young and old--is BMI the wrong benchmark? Int. J. Epidemiol.,2006, 35(1), 187-189. (e) Valavanis, I. K.; Mougiakakou, S. G.; Grimaldi, K. A.; Nikita, K. S. A multifactorial analysis of obesity as CVD risk factor: use of neural network based methods in a nutrigenetics context. BMC Bioinformatics, 2010, 11, 453. (f) Almost, J.; Doran, D.; Ogilvie, L.; Miller, C.; Kennedy, S.; Timmings, C.; Rose, D. N.; Squires, M.; Lee, C. T.; Bookey-Bassett, S. Exploring work-life issues in provincial corrections settings. J. Forensic Nurs., 2013, 9(1), 3-13.
[PMID: 24158097]
a) Krauss, R.M.; Winston, M.; Fletcher, B.J.; Grundy, S.M. Obesity: impact on cardiovascular disease. Circulation, 1998, 98(14), 1472-1476.
b) Hubert, H.B.; Feinleib, M.; McNamara, P.M.; Castelli, W.P. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation, 1983, 67(5), 968-977.
c) Phillips, C.M.; Tierney, A.C.; Perez-Martinez, P.; Defoort, C.; Blaak, E.E.; Gjelstad, I.M.; Lopez-Miranda, J.; Kiec-Klimczak, M.; Malczewska-Malec, M.; Drevon, C.A.; Hall, W.; Lovegrove, J.A.; Karlstrom, B.; Riserus, U.; Roche, H.M. Obesity and body fat classification in the metabolic syndrome: impact on cardiometabolic risk metabotype. Obesity (Silver Spring), 2013, 21(1), E154-E161.
[PMID: 23505198]
a) Van Gaal, L.F.; Mertens, I.L.; De Block, C.E. Mechanisms linking obesity with cardiovascular disease. Nature, 2006, 444(7121), 875-880.
b) Howard, B.V.; Ruotolo, G.; Robbins, D.C. Obesity and dyslipidemia. Endocrinol. Metab. Clin. North Am., 2003, 32(4), 855-867.
[PMID: 14711065]
a) Rizzo, M.; Kotur-Stevuljevic, J.; Berneis, K.; Spinas, G.; Rini, G.B.; Jelic-Ivanovic, Z.; Spasojevic-Kalimanovska, V.; Vekic, J. Atherogenic dyslipidemia and oxidative stress: a new look. Transl. Res., 2009, 153(5), 217-223.
b) Vinik, A.I. The metabolic basis of atherogenic dyslipidemia. Clin. Cornerstone, 2005, 7(2-3), 27-35.
c) Nikolic, D.; Katsiki, N.; Montalto, G.; Isenovic, E.R.; Mikhailidis, D.P.; Rizzo, M. Lipoprotein subfractions in metabolic syndrome and obesity: clinical significance and therapeutic approaches. Nutrients, 2013, 5(3), 928-948.
[PMID: 23507795]
a) Lopaschuk, G.D.; Folmes, C.D.; Stanley, W.C. Cardiac energy metabolism in obesity. Circ. Res., 2007, 101(4), 335-347.
b) Szczepaniak, L.S.; Dobbins, R.L.; Metzger, G.J.; Sartoni-D’Ambrosia, G.; Arbique, D.; Vongpatanasin, W.; Unger, R.; Victor, R.G. Myocardial triglycerides and systolic function in humans: in vivo evaluation by localized proton spectroscopy and cardiac imaging. Magn. Reson. Med., 2003, 49(3), 417-423.
[PMID: 12594743]
Rider, O.J.; Cox, P.; Tyler, D.; Clarke, K.; Neubauer, S. Myocardial substrate metabolism in obesity. Int. J. Obes., 2013, 37(7), 972-979.
[http://dx.doi.org/10.1038/ijo.2012.170] [PMID: 23069666]
Musunuru, K. Atherogenic dyslipidemia: cardiovascular risk and dietary intervention. Lipids, 2010, 45(10), 907-914.
[http://dx.doi.org/10.1007/s11745-010-3408-1] [PMID: 20524075]
Urban, D.; Pöss, J.; Böhm, M.; Laufs, U. Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. J. Am. Coll. Cardiol., 2013, 62(16), 1401-1408.
[http://dx.doi.org/10.1016/j.jacc.2013.07.056] [PMID: 23973703]
Denis, M.; Marcinkiewicz, J.; Zaid, A.; Gauthier, D.; Poirier, S.; Lazure, C.; Seidah, N.G.; Prat, A. Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation, 2012, 125(7), 894-901.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.111.057406] [PMID: 22261195]
Maxwell, K.N.; Soccio, R.E.; Duncan, E.M.; Sehayek, E.; Breslow, J.L. Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J. Lipid Res., 2003, 44(11), 2109-2119.
[http://dx.doi.org/10.1194/jlr.M300203-JLR200] [PMID: 12897189]
Saheki, T.; Iijima, M.; Li, M.X.; Kobayashi, K.; Horiuchi, M.; Ushikai, M.; Okumura, F.; Meng, X.J.; Inoue, I.; Tajima, A.; Moriyama, M.; Eto, K.; Kadowaki, T.; Sinasac, D.S.; Tsui, L.C.; Tsuji, M.; Okano, A.; Kobayashi, T. Citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice recapitulate features of human citrin deficiency. J. Biol. Chem., 2007, 282(34), 25041-25052.
[http://dx.doi.org/10.1074/jbc.M702031200] [PMID: 17591776]
Brown, M.S.; Goldstein, J.L. Biomedicine. Lowering LDL--not only how low, but how long? Science, 2006, 311(5768), 1721-1723.
[http://dx.doi.org/10.1126/science.1125884] [PMID: 16556829]
Feingold, K.R.; Moser, A.H.; Shigenaga, J.K.; Patzek, S.M.; Grunfeld, C. Inflammation stimulates the expression of PCSK9. Biochem. Biophys. Res. Commun., 2008, 374(2), 341-344.
[http://dx.doi.org/10.1016/j.bbrc.2008.07.023] [PMID: 18638454]
Ranheim, T.; Mattingsdal, M.; Lindvall, J.M.; Holla, O.L.; Berge, K.E.; Kulseth, M.A.; Leren, T.P. Genome-wide expression analysis of cells expressing gain of function mutant D374Y-PCSK9. J. Cell. Physiol., 2008, 217(2), 459-467.
[http://dx.doi.org/10.1002/jcp.21519] [PMID: 18570182]
Tang, Z.; Jiang, L.; Peng, J.; Ren, Z.; Wei, D.; Wu, C.; Pan, L.; Jiang, Z.; Liu, L. PCSK9 siRNA suppresses the inflammatory response induced by oxLDL through inhibition of NF-κB activation in THP-1-derived macrophages. Int. J. Mol. Med., 2012, 30(4), 931-938.
[http://dx.doi.org/10.3892/ijmm.2012.1072] [PMID: 22825241]
Wu, C.Y.; Tang, Z.H.; Jiang, L.; Li, X.F.; Jiang, Z.S.; Liu, L.S. PCSK9 siRNA inhibits HUVEC apoptosis induced by ox-LDL via Bcl/Bax-caspase9-caspase3 pathway. Mol. Cell. Biochem., 2012, 359(1-2), 347-358.
[http://dx.doi.org/10.1007/s11010-011-1028-6] [PMID: 21847580]
a) Sahebkar, A.; Watts, G.F. New therapies targeting apoB metabolism for high-risk patients with inherited dyslipidaemias: what can the clinician expect? Cardiovasc. Drugs Ther., 2013, 27(6), 559-567.
b) Raal, F.J.; Giugliano, R.P.; Sabatine, M.S.; Koren, M.J.; Langslet, G.; Bays, H.; Blom, D.; Eriksson, M.; Dent, R.; Wasserman, S.M.; Huang, F.; Xue, A.; Albizem, M.; Scott, R.; Stein, E.A. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J. Am. Coll. Cardiol., 2014, 63(13), 1278-1288.
[PMID: 24509273]
Rousselet, E.; Marcinkiewicz, J.; Kriz, J.; Zhou, A.; Hatten, M.E.; Prat, A.; Seidah, N.G. PCSK9 reduces the protein levels of the LDL receptor in mouse brain during development and after ischemic stroke. J. Lipid Res., 2011, 52(7), 1383-1391.
[http://dx.doi.org/10.1194/jlr.M014118] [PMID: 21518694]
Poirier, S.; Prat, A.; Marcinkiewicz, E.; Paquin, J.; Chitramuthu, B.P.; Baranowski, D.; Cadieux, B.; Bennett, H.P.; Seidah, N.G. Implication of the proprotein convertase NARC-1/PCSK9 in the development of the nervous system. J. Neurochem., 2006, 98(3), 838-850.
[http://dx.doi.org/10.1111/j.1471-4159.2006.03928.x] [PMID: 16893422]
Lan, H.; Pang, L.; Smith, M.M.; Levitan, D.; Ding, W.; Liu, L.; Shan, L.; Shah, V.V.; Laverty, M.; Arreaza, G.; Zhang, Q.; Murgolo, N.J.; Hernandez, M.; Greene, J.R.; Gustafson, E.L.; Bayne, M.L.; Davis, H.R.; Hedrick, J.A. Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects gene expression pathways beyond cholesterol metabolism in liver cells. J. Cell. Physiol., 2010, 224(1), 273-281.
[http://dx.doi.org/10.1002/jcp.22130] [PMID: 20333646]
Wu, Q.; Tang, Z.H.; Peng, J.; Liao, L.; Pan, L.H.; Wu, C.Y.; Jiang, Z.S.; Wang, G.X.; Liu, L.S. The dual behavior of PCSK9 in the regulation of apoptosis is crucial in Alzheimer’s disease progression (Review). Biomed. Rep., 2014, 2(2), 167-171.
[http://dx.doi.org/10.3892/br.2013.213] [PMID: 24649090]
Piao, M.X.; Bai, J.W.; Zhang, P.F.; Zhang, Y.Z. PCSK9 regulates apoptosis in human neuroglioma u251 cells via mitochondrial signaling pathways. Int. J. Clin. Exp. Pathol., 2015, 8(3), 2787-2794.
[PMID: 26045785]
Demidyuk, I.V.; Shubin, A.V.; Gasanov, E.V.; Kurinov, A.M.; Demkin, V.V.; Vinogradova, T.V.; Zinovyeva, M.V.; Sass, A.V.; Zborovskaya, I.B.; Kostrov, S.V. Alterations in gene expression of proprotein convertases in human lung cancer have a limited number of scenarios. PLoS One, 2013, 8(2)e55752
[http://dx.doi.org/10.1371/journal.pone.0055752] [PMID: 23409034]
Rokkas, T.; Sechopoulos, P.; Pistiolas, D.; Kothonas, F.; Margantinis, G.; Koukoulis, G. Population differences concerning TNF-α gene polymorphisms in gastric carcinogenesis based on meta-analysis. Ann. Gastroenterol., 2014, 27(2), 139-148.
[PMID: 24733020]
Li, S.; Guo, Y.L.; Xu, R.X.; Zhang, Y.; Zhu, C.G.; Sun, J.; Qing, P.; Wu, N.Q.; Jiang, L.X.; Li, J.J. Association of plasma PCSK9 levels with white blood cell count and its subsets in patients with stable coronary artery disease. Atherosclerosis, 2014, 234(2), 441-445.
[http://dx.doi.org/10.1016/j.atherosclerosis.2014.04.001] [PMID: 24769476]
Ruscica, M.; Ricci, C.; Macchi, C.; Magni, P.; Cristofani, R.; Liu, J.; Corsini, A.; Ferri, N. Suppressor of cytokine signaling-3 (SOCS-3) induces proprotein convertase subtilisin kexin type 9 (PCSK9) expression in hepatic HepG2 cell line. J. Biol. Chem., 2016, 291(7), 3508-3519.
[http://dx.doi.org/10.1074/jbc.M115.664706] [PMID: 26668321]
Giunzioni, I.; Tavori, H.; Covarrubias, R.; Major, A.S.; Ding, L.; Zhang, Y.; DeVay, R.M.; Hong, L.; Fan, D.; Predazzi, I.M.; Rashid, S.; Linton, M.F.; Fazio, S. Local effects of human PCSK9 on the atherosclerotic lesion. J. Pathol., 2016, 238(1), 52-62.
[http://dx.doi.org/10.1002/path.4630] [PMID: 26333678]
Sharma, K. IL-18 attenuates experimental choroidal neovascularization as a potential therapy for wet age-related macular degeneration. Sci. Transl. Med., 2014, 6(230), ra44.
[http://dx.doi.org/10.5214/ans.0972.7531.210407] [PMID: 25452676]
Everett, B.M.; Mora, S.; Glynn, R.J.; MacFadyen, J.; Ridker, P.M. Safety profile of subjects treated to very low low-density lipoprotein cholesterol levels (<30 mg/dl) with rosuvastatin 20 mg daily (from JUPITER). Am. J. Cardiol., 2014, 114(11), 1682-1689.
[http://dx.doi.org/10.1016/j.amjcard.2014.08.041] [PMID: 25439449]
Schmidt, A.F.; Swerdlow, D.I.; Holmes, M.V.; Patel, R.S.; Fairhurst-Hunter, Z.; Lyall, D.M.; Hartwig, F.P.; Horta, B.L.; Hyppönen, E.; Power, C.; Moldovan, M.; van Iperen, E.; Hovingh, G.K.; Demuth, I.; Norman, K.; Steinhagen-Thiessen, E.; Demuth, J.; Bertram, L.; Liu, T.; Coassin, S.; Willeit, J.; Kiechl, S.; Willeit, K.; Mason, D.; Wright, J.; Morris, R.; Wanamethee, G.; Whincup, P.; Ben-Shlomo, Y.; McLachlan, S.; Price, J.F.; Kivimaki, M.; Welch, C.; Sanchez-Galvez, A.; Marques-Vidal, P.; Nicolaides, A.; Panayiotou, A.G.; Onland-Moret, N.C.; van der Schouw, Y.T.; Matullo, G.; Fiorito, G.; Guarrera, S.; Sacerdote, C.; Wareham, N.J.; Langenberg, C.; Scott, R.; Luan, J.; Bobak, M.; Malyutina, S.; Pająk, A.; Kubinova, R.; Tamosiunas, A.; Pikhart, H.; Husemoen, L.L.; Grarup, N.; Pedersen, O.; Hansen, T.; Linneberg, A.; Simonsen, K.S.; Cooper, J.; Humphries, S.E.; Brilliant, M.; Kitchner, T.; Hakonarson, H.; Carrell, D.S.; McCarty, C.A.; Kirchner, H.L.; Larson, E.B.; Crosslin, D.R.; de Andrade, M.; Roden, D.M.; Denny, J.C.; Carty, C.; Hancock, S.; Attia, J.; Holliday, E.; O’Donnell, M.; Yusuf, S.; Chong, M.; Pare, G.; van der Harst, P.; Said, M.A.; Eppinga, R.N.; Verweij, N.; Snieder, H.; Christen, T.; Mook-Kanamori, D.O.; Gustafsson, S.; Lind, L.; Ingelsson, E.; Pazoki, R.; Franco, O.; Hofman, A.; Uitterlinden, A.; Dehghan, A.; Teumer, A.; Baumeister, S.; Dörr, M.; Lerch, M.M.; Völker, U.; Völzke, H.; Ward, J.; Pell, J.P.; Smith, D.J.; Meade, T.; Maitland-van der Zee, A.H.; Baranova, E.V.; Young, R.; Ford, I.; Campbell, A.; Padmanabhan, S.; Bots, M.L.; Grobbee, D.E.; Froguel, P.; Thuillier, D.; Balkau, B.; Bonnefond, A.; Cariou, B.; Smart, M.; Bao, Y.; Kumari, M.; Mahajan, A.; Ridker, P.M.; Chasman, D.I.; Reiner, A.P.; Lange, L.A.; Ritchie, M.D.; Asselbergs, F.W.; Casas, J.P.; Keating, B.J.; Preiss, D.; Hingorani, A.D.; Sattar, N. LifeLines Cohort study group UCLEB consortium. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol., 2017, 5(2), 97-105.
[http://dx.doi.org/10.1016/S2213-8587(16)30396-5] [PMID: 27908689]
Ference, B.A.; Robinson, J.G.; Brook, R.D.; Catapano, A.L.; Chapman, M.J.; Neff, D.R.; Voros, S.; Giugliano, R.P.; Davey Smith, G.; Fazio, S.; Sabatine, M.S. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N. Engl. J. Med., 2016, 375(22), 2144-2153.
[http://dx.doi.org/10.1056/NEJMoa1604304] [PMID: 27959767]
Lotta, L.A.; Sharp, S.J.; Burgess, S.; Perry, J.R.B.; Stewart, I.D.; Willems, S.M.; Luan, J.; Ardanaz, E.; Arriola, L.; Balkau, B.; Boeing, H.; Deloukas, P.; Forouhi, N.G.; Franks, P.W.; Grioni, S.; Kaaks, R.; Key, T.J.; Navarro, C.; Nilsson, P.M.; Overvad, K.; Palli, D.; Panico, S.; Quirós, J.R.; Riboli, E.; Rolandsson, O.; Sacerdote, C.; Salamanca, E.C.; Slimani, N.; Spijkerman, A.M.; Tjonneland, A.; Tumino, R. van der A, D.L.; van der Schouw, Y.T.; McCarthy, M.I.; Barroso, I.; O’Rahilly, S.; Savage, D.B.; Sattar, N.; Langenberg, C.; Scott, R.A.; Wareham, N.J. Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis. JAMA, 2016, 316(13), 1383-1391.
[http://dx.doi.org/10.1001/jama.2016.14568] [PMID: 27701660]
Miao, J.; Manthena, P.V.; Haas, M.E.; Ling, A.V.; Shin, D.J.; Graham, M.J.; Crooke, R.M.; Liu, J.; Biddinger, S.B. Role of insulin in the regulation of proprotein convertase subtilisin/kexin type 9. Arterioscler. Thromb. Vasc. Biol., 2015, 35(7), 1589-1596.
[http://dx.doi.org/10.1161/ATVBAHA.115.305688] [PMID: 26023080]
Ai, D.; Chen, C.; Han, S.; Ganda, A.; Murphy, A.J.; Haeusler, R.; Thorp, E.; Accili, D.; Horton, J.D.; Tall, A.R. Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. J. Clin. Invest., 2012, 122(4), 1262-1270.
[http://dx.doi.org/10.1172/JCI61919] [PMID: 22426206]
Burkart, K.M.; Manichaikul, A.; Wilk, J.B.; Ahmed, F.S.; Burke, G.L.; Enright, P.; Hansel, N.N.; Haynes, D.; Heckbert, S.R.; Hoffman, E.A.; Kaufman, J.D.; Kurai, J.; Loehr, L.; London, S.J.; Meng, Y.; O’Connor, G.T.; Oelsner, E.; Petrini, M.; Pottinger, T.D.; Powell, C.A.; Redline, S.; Rotter, J.I.; Smith, L.J.; Soler Artigas, M.; Tobin, M.D.; Tsai, M.Y.; Watson, K.; White, W.; Young, T.R.; Rich, S.S.; Barr, R.G. APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema. Eur. Respir. J., 2014, 43(4), 1003-1017.
[http://dx.doi.org/10.1183/09031936.00147612] [PMID: 23900982]
Persson, L.; Gälman, C.; Angelin, B.; Rudling, M. Importance of proprotein convertase subtilisin/kexin type 9 in the hormonal and dietary regulation of rat liver low-density lipoprotein receptors. Endocrinology, 2009, 150(3), 1140-1146.
[http://dx.doi.org/10.1210/en.2008-1281] [PMID: 19008317]
Lakoski, S.G.; Lagace, T.A.; Cohen, J.C.; Horton, J.D.; Hobbs, H.H. Genetic and metabolic determinants of plasma PCSK9 levels. J. Clin. Endocrinol. Metab., 2009, 94(7), 2537-2543.
[http://dx.doi.org/10.1210/jc.2009-0141] [PMID: 19351729]
Arrieta, A.; Page, T.F.; Veledar, E.; Nasir, K. Economic evaluation of PCSK9 inhibitors in reducing cardiovascular risk from health system and private payer perspectives. PLoS One, 2017, 12(1)e0169761
[http://dx.doi.org/10.1371/journal.pone.0169761] [PMID: 28081164]
Tice, J.A.; Kazi, D.S.; Pearson, S.D. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for treatment of high cholesterol levels: effectiveness and value. JAMA Intern Med, 2016, 176(1), 107-108. (b) Kazi, D. S.; Moran, A. E.; Bibbins-Domingo, K. Cost-effectiveness of PCSK9 inhibitor therapy-reply. JAMA, 2016, 316(20), 2152.
Arrieta, A.; Hong, J.C.; Khera, R.; Virani, S.S.; Krumholz, H.M.; Nasir, K. Updated Cost-effectiveness assessments of PCSK9 inhibitors from the perspectives of the health system and private payers: insights derived from the FOURIER trial. JAMA Cardiol., 2017, 2(12), 1369-1374.
[http://dx.doi.org/10.1001/jamacardio.2017.3655] [PMID: 29049467]

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Year: 2019
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DOI: 10.2174/1568026619666190809094203
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