Dyslipidaemias and Cardiovascular Disease: Focus on the Role of PCSK9 Inhibitors

Chen, Z.; Peto, R.; Collins, R.; MacMahon, S.; Lu, J.; Li, W. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. BMJ, 1991, 303(6797), 276-282.
[http://dx.doi.org/10.1136/bmj.303.6797.276] [PMID: 1888927]

Stamler, J.; Vaccaro, O.; Neaton, J.D.; Wentworth, D.; Group, M.R.F.I.T.R. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes Care, 1993, 16(2), 434-444.
[http://dx.doi.org/10.2337/diacare.16.2.434] [PMID: 8432214]

Austin, M.A.; Hutter, C.M.; Zimmern, R.L.; Humphries, S.E. Familial hypercholesterolemia and coronary heart disease: a HuGE association review. Am. J. Epidemiol., 2004, 160(5), 421-429.
[http://dx.doi.org/10.1093/aje/kwh237] [PMID: 15321838]

Ference, B.A.; Yoo, W.; Alesh, I.; Mahajan, N.; Mirowska, K.K.; Mewada, A.; Kahn, J.; Afonso, L.; Williams, K.A., Sr; Flack, J.M. Effect of long-term exposure to lower low density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J. Am. Coll. Cardiol., 2012, 60(25), 2631-2639.
[http://dx.doi.org/10.1016/j.jacc.2012.09.017] [PMID: 23083789]

Kazi, D.S.; Penko, J.M.; Bibbins-Domingo, K. Statins for primary prevention of cardiovascular disease: review of evidence and recommendations for clinical practice. Med. Clin. North Am., 2017, 101(4), 689-699.
[http://dx.doi.org/10.1016/j.mcna.2017.03.001] [PMID: 28577620]

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, Ž.; Riccardi, G.; Taskinen, M.R.; Tokgozoglu, L.; Verschuren, W.M.M.; Vlachopoulos, C.; Wood, D.A.; Zamorano, J.L.; Cooney, M.T. ESC Scientific Document Group.. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur. Heart J., 2016, 37(39), 2999-3058.
[http://dx.doi.org/10.1093/eurheartj/ehw272] [PMID: 27567407]

Law, M.R.; Wald, N.J.; Rudnicka, A.R. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta analysis. BMJ, 2003, 326(7404), 1423.
[http://dx.doi.org/10.1136/bmj.326.7404.1423] [PMID: 12829554]

National Clinical Guideline Centre (UK) Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease, National Institute for Health and Care Excellence (UK). 2014.
[PMID: 25340243]

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’ (CTT) Collaborators.. 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.
[http://dx.doi.org/10.1016/S0140-6736(05)67394-1] [PMID: 16214597]

Fulcher, J.; O’Connell, R.; Voysey, M.; Emberson, J.; Blackwell, L.; Mihaylova, B.; Simes, J.; Collins, R.; Kirby, A.; Colhoun, H.; Braunwald, E.; La Rosa, J.; Pedersen, T.R.; Tonkin, A.; Davis, B.; Sleight, P.; Franzosi, M.G.; Baigent, C.; Keech, A. Cholesterol Treatment Trialists’ (CTT) Collaboration.. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet, 2015, 385(9976), 1397-1405.
[http://dx.doi.org/10.1016/S0140-6736(14)61368-4] [PMID: 25579834]

Anderson, T.J.; Grégoire, J.; Pearson, G.J.; Barry, A.R.; Couture, P.; Dawes, M.; Francis, G.A.; Genest, J., Jr; Grover, S.; Gupta, M.; Hegele, R.A.; Lau, D.C.; Leiter, L.A.; Lonn, E.; Mancini, G.B.; McPherson, R.; Ngui, D.; Poirier, P.; Sievenpiper, J.L.; Stone, J.A.; Thanassoulis, G.; Ward, R. 2016 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult. Can. J. Cardiol., 2016, 32(11), 1263-1282.
[http://dx.doi.org/10.1016/j.cjca.2016.07.510] [PMID: 27712954]

Jacobson, T.A.; Ito, M.K.; Maki, K.C.; Orringer, C.E.; Bays, H.E.; Jones, P.H.; McKenney, J.M.; Grundy, S.M.; Gill, E.A.; Wild, R.A.; Wilson, D.P.; Brown, W.V. National lipid association recommendations for patient-centered management of dyslipidemia: part 1-full report. J. Clin. Lipidol., 2015, 9(2), 129-169.
[http://dx.doi.org/10.1016/j.jacl.2015.02.003] [PMID: 25911072]

Lloyd-Jones, D.M.; Morris, P.B.; Ballantyne, C.M.; Birtcher, K.K.; Daly, D.D., Jr; DePalma, S.M.; Minissian, M.B.; Orringer, C.E.; Smith, S.C., Jr; Committee, W. Writing Committee.. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk. J. Am. Coll. Cardiol., 2016, 68(1), 92-125.
[http://dx.doi.org/10.1016/j.jacc.2016.03.519] [PMID: 27046161]

Rabar, S.; Harker, M.; O'flynn, N.; Wierzbicki, A. S. Guideline Development Group. Lipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE guidance BMJ,, 2014, 349, g4356.
[http://dx.doi.org/10.1136/bmj.g4356] [PMID: 25035388]

Boekholdt, S.M.; Hovingh, G.K.; Mora, S.; Arsenault, B.J.; Amarenco, P.; Pedersen, T.R.; LaRosa, J.C.; Waters, D.D.; DeMicco, D.A.; Simes, R.J.; Keech, A.C.; Colquhoun, D.; Hitman, G.A.; Betteridge, D.J.; Clearfield, M.B.; Downs, J.R.; Colhoun, H.M.; Gotto, A.M., Jr; Ridker, P.M.; Grundy, S.M.; Kastelein, J.J. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J. Am. Coll. Cardiol., 2014, 64(5), 485-494.
[http://dx.doi.org/10.1016/j.jacc.2014.02.615] [PMID: 25082583]

Goodman, S.G.; Langer, A.; Bastien, N.R.; McPherson, R.; Francis, G.A.; Genest, J.J., Jr; Leiter, L.A.; Investigators, D.C. DYSIS Canadian Investigators.. Prevalence of dyslipidemia in statin-treated patients in Canada: results of the dyslipidemia international study (DYSIS). Can. J. Cardiol., 2010, 26(9), e330-e335.
[http://dx.doi.org/10.1016/S0828-282X(10)70454-2] [PMID: 21076724]

Kotseva, K.; Wood, D.; De Bacquer, D.; De Backer, G.; Rydén, L.; Jennings, C.; Gyberg, V.; Amouyel, P.; Bruthans, J.; Castro Conde, A.; Cífková, R.; Deckers, J.W.; De Sutter, J.; Dilic, M.; Dolzhenko, M.; Erglis, A.; Fras, Z.; Gaita, D.; Gotcheva, N.; Goudevenos, J.; Heuschmann, P.; Laucevicius, A.; Lehto, S.; Lovic, D.; Miličić, D.; Moore, D.; Nicolaides, E.; Oganov, R.; Pajak, A.; Pogosova, N.; Reiner, Z.; Stagmo, M.; Störk, S.; Tokgözoğlu, L.; Vulic, D. EUROASPIRE Investigators.. EUROASPIRE IV: A European society of cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries. Eur. J. Prev. Cardiol., 2016, 23(6), 636-648.
[http://dx.doi.org/10.1177/2047487315569401] [PMID: 25687109]

Hajhosseiny, R.; Sabir, I.; Khavandi, K.; Wierzbicki, A.S. The ebbs and flows in the development of cholesterol lowering drugs: prospects for the future. Clin. Pharmacol. Ther., 2014, 96(1), 64-73.
[http://dx.doi.org/10.1038/clpt.2014.76] [PMID: 24699033]

Preiss, D.; Sattar, N. Statins and the risk of new-onset diabetes: a review of recent evidence. Curr. Opin. Lipidol., 2011, 22(6), 460-466.
[http://dx.doi.org/10.1097/MOL.0b013e32834b4994] [PMID: 21897230]

Preiss, D.; Baigent, C. Cardiovascular disease: PCSK9 inhibition: a new player in cholesterol-lowering therapies? Nat. Rev. Nephrol., 2017, 13(8), 450-451.
[http://dx.doi.org/10.1038/nrneph.2017.94] [PMID: 28669994]

Stroes, E.S.; Thompson, P.D.; Corsini, A.; Vladutiu, G.D.; Raal, F.J.; Ray, K.K.; Roden, M.; Stein, E.; Tokgözoğlu, L.; Nordestgaard, B.G.; Bruckert, E.; De Backer, G.; Krauss, R.M.; Laufs, U.; Santos, R.D.; Hegele, R.A.; Hovingh, G.K.; Leiter, L.A.; Mach, F.; März, W.; Newman, C.B.; Wiklund, O.; Jacobson, T.A.; Catapano, A.L.; Chapman, M.J.; Ginsberg, H.N. European Atherosclerosis Society Consensus Panel.. Statin-associated muscle symptoms: impact on statin therapy- European atherosclerosis society consensus panel statement on assessment, aetiology and management. Eur. Heart J., 2015, 36(17), 1012-1022.
[http://dx.doi.org/10.1093/eurheartj/ehv043] [PMID: 25694464]

Sampson, U.K.; Fazio, S.; Linton, M.F. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr. Atheroscler. Rep., 2012, 14(1), 1-10.
[http://dx.doi.org/10.1007/s11883-011-0219-7] [PMID: 22102062]

Cannon, C.P. IMPROVE-IT trial: a comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes after acute coronary syndromes. Circulation, 2014, 130(23), 2109.

Bohula, E.A.; Morrow, D.A.; Giugliano, R.P.; Blazing, M.A.; He, P.; Park, J.G.; Murphy, S.A.; White, J.A.; Kesaniemi, Y.A.; Pedersen, T.R.; Brady, A.J.; Mitchel, Y.; Cannon, C.P.; Braunwald, E. Atherothrombotic risk stratification and ezetimibe for secondary prevention. J. Am. Coll. Cardiol., 2017, 69(8), 911-921.
[http://dx.doi.org/10.1016/j.jacc.2016.11.070] [PMID: 28231942]

Rader, D.J.; Kastelein, J.J. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation, 2014, 129(9), 1022-1032.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.001292] [PMID: 24589695]

US Food and Drug Administration, 2015.Available at:, www.fda.gov/ NewsEvents/ Newsroom/ PressAnnouncements/ ucm460082.htm

US Food and Drug Administration. FDA approves Praluent to treat certain patients with high cholesterol: first in a new class of injectable cholesterol-lowering drugs. Press Release , 2015.Available at:. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm455883.htm

Seidah, N.G.; Benjannet, S.; Wickham, L.; Marcinkiewicz, J.; Jasmin, S.B.; Stifani, S.; Basak, A.; Prat, A.; Chrétien, 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]

Seidah, N.G.; Prat, A. Precursor convertases in the secretory pathway, cytosol and extracellular milieu. Essays Biochem., 2002, 38, 79-94.
[http://dx.doi.org/10.1042/bse0380079] [PMID: 12463163]

Benjannet, S.; Rhainds, D.; Essalmani, R.; Mayne, J.; Wickham, L.; Jin, W.; Asselin, M-C.; Hamelin, J.; Varret, M.; Allard, D.; Trillard, M.; Abifadel, M.; Tebon, A.; Attie, A.D.; Rader, D.J.; Boileau, C.; Brissette, L.; Chrétien, M.; Prat, A.; Seidah, N.G. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J. Biol. Chem., 2004, 279(47), 48865-48875.
[http://dx.doi.org/10.1074/jbc.M409699200] [PMID: 15358785]

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.
[http://dx.doi.org/10.1038/nsmb1235] [PMID: 17435765]

Du, F.; Hui, Y.; Zhang, M.; Linton, M.F.; Fazio, S.; Fan, D. Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein. J. Biol. Chem., 2011, 286(50), 43054-43061.
[http://dx.doi.org/10.1074/jbc.M111.273474] [PMID: 22027821]

Bottomley, M.J.; Cirillo, A.; Orsatti, L.; Ruggeri, L.; Fisher, T.S.; Santoro, J.C.; Cummings, R.T.; Cubbon, R.M.; Lo Surdo, P.; Calzetta, A.; Noto, A.; Baysarowich, J.; Mattu, M.; Talamo, F.; De Francesco, R.; Sparrow, C.P.; Sitlani, A.; Carfí, A. Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants. J. Biol. Chem., 2009, 284(2), 1313-1323.
[http://dx.doi.org/10.1074/jbc.M808363200] [PMID: 19001363]

Chen, Y.; Wang, H.; Yu, L.; Yu, X.; Qian, Y.W.; Cao, G.; Wang, J. Role of ubiquitination in PCSK9-mediated low-density lipoprotein receptor degradation. Biochem. Biophys. Res. Commun., 2011, 415(3), 515-518.
[http://dx.doi.org/10.1016/j.bbrc.2011.10.110] [PMID: 22074827]

Zhang, D-W.; Lagace, T.A.; Garuti, R.; Zhao, Z.; McDonald, M.; Horton, J.D.; Cohen, J.C.; Hobbs, H.H. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J. Biol. Chem., 2007, 282(25), 18602-18612.
[http://dx.doi.org/10.1074/jbc.M702027200] [PMID: 17452316]

Park, S.W.; Moon, Y.A.; Horton, J.D. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J. Biol. Chem., 2004, 279(48), 50630-50638.
[http://dx.doi.org/10.1074/jbc.M410077200] [PMID: 15385538]

Qian, Y.W.; Schmidt, R.J.; Zhang, Y.; Chu, S.; Lin, A.; Wang, H.; Wang, X.; Beyer, T.P.; Bensch, W.R.; Li, W.; Ehsani, M.E.; Lu, D.; Konrad, R.J.; Eacho, P.I.; Moller, D.E.; Karathanasis, S.K.; Cao, G. Secreted PCSK9 downregulates low density lipoprotein receptor through receptor mediated endocytosis. J. Lipid Res., 2007, 48(7), 1488-1498.
[http://dx.doi.org/10.1194/jlr.M700071-JLR200] [PMID: 17449864]

Saavedra, Y.G.L.; Day, R.; Seidah, N.G. The M2 module of the Cys-His-rich domain (CHRD) of PCSK9 protein is needed for the extracellular low-density lipoprotein receptor (LDLR) degradation pathway. J. Biol. Chem., 2012, 287(52), 43492-43501.
[http://dx.doi.org/10.1074/jbc.M112.394023] [PMID: 23105118]

Maxwell, K.N.; Breslow, J.L. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc. Natl. Acad. Sci. USA, 2004, 101(18), 7100-7105.
[http://dx.doi.org/10.1073/pnas.0402133101] [PMID: 15118091]

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]

Tavori, H.; Fan, D.; Blakemore, J.L.; Yancey, P.G.; Ding, L.; Linton, M.F.; Fazio, S. Serum proprotein convertase subtilisin/ kexin type 9 and cell surface low-density lipoprotein receptor: evidence for a reciprocal regulation. Circulation, 2013, 127(24), 2403-2413.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.001592] [PMID: 23690465]

Abifadel, M.; Elbitar, S.; El Khoury, P.; Ghaleb, Y.; Chémaly, M.; Moussalli, M.L.; Rabès, J.P.; Varret, M.; Boileau, C. Living the PCSK9 adventure: from the identification of a new gene in familial hypercholesterolemia towards a potential new class of anticholesterol drugs. Curr. Atheroscler. Rep., 2014, 16(9), 439.
[http://dx.doi.org/10.1007/s11883-014-0439-8] [PMID: 25052769]

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]

Horton, J.D.; Shah, N.A.; Warrington, J.A.; Anderson, N.N.; Park, S.W.; Brown, M.S.; Goldstein, J.L. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc. Natl. Acad. Sci. USA, 2003, 100(21), 12027-12032.
[http://dx.doi.org/10.1073/pnas.1534923100] [PMID: 14512514]

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]

Mohammadi, A.; Shabani, M.; Naseri, F.; Hosseni, B.; Soltanmohammadi, E.; Piran, S.; Najafi, M. Circulating PCSK9 Over SREBP-2 expression affects serum ldl and cholesterol levels. Adv. Clin. Exp. Med., 2017.
[http://dx.doi.org/10.17219/acem/62836] [PMID: 28691419 ]

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 HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters. J. Lipid Res., 2010, 51(6), 1486-1495.
[http://dx.doi.org/10.1194/jlr.M003566] [PMID: 20048381]

Shende, V.R.; Wu, M.; Singh, A.B.; Dong, B.; Kan, C.F.K.; Liu, J. Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1α in normolipidemic mice. J. Lipid Res., 2015, 56(4), 801-809.
[http://dx.doi.org/10.1194/jlr.M052969] [PMID: 25652089]

Berthold, H.K.; Seidah, N.G.; Benjannet, S.; Gouni-Berthold, I. Evidence from a randomized trial that simvastatin, but not ezetimibe, upregulates circulating PCSK9 levels. PLoS One, 2013, 8(3)e60095
[http://dx.doi.org/10.1371/journal.pone.0060095] [PMID: 23544125]

Awan, Z.; Seidah, N.G.; MacFadyen, J.G.; Benjannet, S.; Chasman, D.I.; Ridker, P.M.; Genest, J. Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial. Clin. Chem., 2012, 58(1), 183-189.
[http://dx.doi.org/10.1373/clinchem.2011.172932] [PMID: 22065156]

Grefhorst, A.; McNutt, M.C.; Lagace, T.A.; Horton, J.D. Plasma PCSK9 preferentially reduces liver LDL receptors in mice. J. Lipid Res., 2008, 49(6), 1303-1311.
[http://dx.doi.org/10.1194/jlr.M800027-JLR200] [PMID: 18354138]

Liu, M.; Wu, G.; Baysarowich, J.; Kavana, M.; Addona, G.H.; Bierilo, K.K.; Mudgett, J.S.; Pavlovic, G.; Sitlani, A.; Renger, J.J.; Hubbard, B.K.; Fisher, T.S.; Zerbinatti, C.V. PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain. J. Lipid Res., 2010, 51(9), 2611-2618.
[http://dx.doi.org/10.1194/jlr.M006635] [PMID: 20453200]

Schmidt, R.J.; Beyer, T.P.; Bensch, W.R.; Qian, Y.W.; Lin, A.; Kowala, M.; Alborn, W.E.; Konrad, R.J.; Cao, G. Secreted proprotein convertase subtilisin/kexin type 9 reduces both hepatic and extrahepatic low-density lipoprotein receptors in vivo. Biochem. Biophys. Res. Commun., 2008, 370(4), 634-640.
[http://dx.doi.org/10.1016/j.bbrc.2008.04.004] [PMID: 18406350]

Persson, L.; Cao, G.; Ståhle, L.; Sjöberg, B.G.; Troutt, J.S.; Konrad, R.J.; Gälman, C.; Wallén, H.; Eriksson, M.; Hafström, I.; Lind, S.; Dahlin, M.; Amark, P.; Angelin, B.; Rudling, M. Circulating proprotein convertase subtilisin kexin type 9 has a diurnal rhythm synchronous with cholesterol synthesis and is reduced by fasting in humans. Arterioscler. Thromb. Vasc. Biol., 2010, 30(12), 2666-2672.
[http://dx.doi.org/10.1161/ATVBAHA.110.214130] [PMID: 20884874]

Cui, Q.; Ju, X.; Yang, T.; Zhang, M.; Tang, W.; Chen, Q.; Hu, Y.; Haas, J.V.; Troutt, J.S.; Pickard, R.T.; Darling, R.; Konrad, R.J.; Zhou, H.; Cao, G. Serum PCSK9 is associated with multiple metabolic factors in a large Han Chinese population. Atherosclerosis, 2010, 213(2), 632-636.
[http://dx.doi.org/10.1016/j.atherosclerosis.2010.09.027] [PMID: 21040917]

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]

Gustafsen, C.; Kjolby, M.; Nyegaard, M.; Mattheisen, M.; Lundhede, J.; Buttenschøn, H.; Mors, O.; Bentzon, J.F.; Madsen, P.; Nykjaer, A.; Glerup, S. The hypercholesterolemia- risk gene SORT1 facilitates PCSK9 secretion. Cell Metab., 2014, 19(2), 310-318.
[http://dx.doi.org/10.1016/j.cmet.2013.12.006] [PMID: 24506872]

Kjolby, M.; Nielsen, M.S.; Petersen, C.M. Sortilin, encoded by the cardiovascular risk gene SORT1, and its suggested functions in cardiovascular disease. Curr. Atheroscler. Rep., 2015, 17(4), 496.
[http://dx.doi.org/10.1007/s11883-015-0496-7] [PMID: 25702058]

Buttenschøn, H.N.; Demontis, D.; Kaas, M.; Elfving, B.; Mølgaard, S.; Gustafsen, C.; Kaerlev, L.; Petersen, C.M.; Børglum, A.D.; Mors, O.; Glerup, S. Increased serum levels of sortilin are associated with depression and correlated with BDNF and VEGF. Transl. Psychiatry, 2015, 5(11) e677
[http://dx.doi.org/10.1038/tp.2015.167] [PMID: 26556286]

Leren, T.P. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin. Genet., 2004, 65(5), 419-422.
[http://dx.doi.org/10.1111/j.0009-9163.2004.0238.x] [PMID: 15099351]

Naoumova, R.P.; Tosi, I.; Patel, D.; Neuwirth, C.; Horswell, S.D.; Marais, A.D.; van Heyningen, C.; Soutar, A.K. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler. Thromb. Vasc. Biol., 2005, 25(12), 2654-2660.
[http://dx.doi.org/10.1161/01.ATV.0000190668.94752.ab] [PMID: 16224054]

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.
[http://dx.doi.org/10.1007/s00439-003-1071-9] [PMID: 14727179]

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]

Al-Mashhadi, R. H.; Sørensen, C. B.; Kragh, P. M.; Christoffersen, C.; Mortensen, M. B.; Tolbod, L. P.; Thim, T.; Du, Y.; Li, J.; Liu, Y. Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. Sci. Transl. Med, 2013 , 5(166), 166ra1.
[http://dx.doi.org/10.1126/scitranslmed.3004853] [PMID: 23283366]

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]

Kent, S.T.; Rosenson, R.S.; Avery, C.L.; Chen, Y.D.I.; Correa, A.; Cummings, S.R.; Cupples, L.A.; Cushman, M.; Evans, D.S.; Gudnason, V. PCSK9 Loss-of-Function variants, low-density lipoprotein cholesterol, and risk of coronary heart disease and Stroke : data from 9 studies of blacks and whites. Circ. Cardiovasc. Genet., 2017, 10(4), e001632.
[http://dx.doi.org/10.1161/CIRCGENETICS.116.001632] [PMID: 28768753]

Cohen, J.; Pertsemlidis, A.; Kotowski, I.K.; Graham, R.; Garcia, C.K.; Hobbs, H.H. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet., 2005, 37(2), 161-165.
[http://dx.doi.org/10.1038/ng1509] [PMID: 15654334]

Zhao, Z.; Tuakli-Wosornu, Y.; Lagace, T.A.; Kinch, L.; Grishin, N.V.; Horton, J.D.; Cohen, J.C.; Hobbs, H.H. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am. J. Hum. Genet., 2006, 79(3), 514-523.
[http://dx.doi.org/10.1086/507488] [PMID: 16909389]

Alghamdi, R.H.; O’Reilly, P.; Lu, C.; Gomes, J.; Lagace, T.A.; Basak, A. LDL-R promoting activity of peptides derived from human PCSK9 catalytic domain (153-421): design, synthesis and biochemical evaluation. Eur. J. Med. Chem., 2015, 92, 890-907.
[http://dx.doi.org/10.1016/j.ejmech.2015.01.022] [PMID: 25679794]

McNutt, M.C.; Lagace, T.A.; Horton, J.D. Catalytic activity is not required for secreted PCSK9 to reduce low density lipoprotein receptors in HepG2 cells. J. Biol. Chem., 2007, 282(29), 20799-20803.
[http://dx.doi.org/10.1074/jbc.C700095200] [PMID: 17537735]

Palmer-Smith, H.; Basak, A. Regulatory effects of peptides from the pro and catalytic domains of proprotein convertase subtilisin/kexin 9 (PCSK9) on low-density lipoprotein receptor (LDL-R). Curr. Med. Chem., 2010, 17(20), 2168-2182.
[http://dx.doi.org/10.2174/092986710791299948] [PMID: 20423303]

Mitchell, T.; Chao, G.; Sitkoff, D.; Lo, F.; Monshizadegan, H.; Meyers, D.; Low, S.; Russo, K.; DiBella, R.; Denhez, F.; Gao, M.; Myers, J.; Duke, G.; Witmer, M.; Miao, B.; Ho, S.P.; Khan, J.; Parker, R.A. Pharmacologic profile of the Adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering. J. Pharmacol. Exp. Ther., 2014, 350(2), 412-424.
[http://dx.doi.org/10.1124/jpet.114.214221] [PMID: 24917546]

Cameron, J.; Ranheim, T.; Kulseth, M.A.; Leren, T.P.; Berge, K.E. Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis, 2008, 201(2), 266-273.
[http://dx.doi.org/10.1016/j.atherosclerosis.2008.02.004] [PMID: 18355829]

Dong, B.; Li, H.; Singh, A.B.; Cao, A.; Liu, J. Inhibition of PCSK9 transcription by berberine involves down-regulation of hepatic HNF1α protein expression through the ubiquitin proteasome degradation pathway. J. Biol. Chem., 2015, 290(7), 4047-4058.
[http://dx.doi.org/10.1074/jbc.M114.597229] [PMID: 25540198]

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]

Sehgal, A.; Vaishnaw, A.; Fitzgerald, K. Liver as a target for oligonucleotide therapeutics. J. Hepatol., 2013, 59(6), 1354-1359.
[http://dx.doi.org/10.1016/j.jhep.2013.05.045] [PMID: 23770039]

Wang, X.; Raghavan, A.; Chen, T.; Qiao, L.; Zhang, Y.; Ding, Q.; Musunuru, K. CRISPR-Cas9 Targeting of pcsk9 in human hepatocytes in vivo-brief report. Arterioscler. Thromb. Vasc. Biol., 2016, 36(5), 783-786.
[http://dx.doi.org/10.1161/ATVBAHA.116.307227] [PMID: 26941020]

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]

van Poelgeest, E.P.; Hodges, M.R.; Moerland, M.; Tessier, Y.; Levin, A.A.; Persson, R.; Lindholm, M.W.; Dumong Erichsen, K.; Ørum, H.; Cohen, A.F.; Burggraaf, J. Antisense-mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9): a first-in-human randomized, placebo-controlled trial. Br. J. Clin. Pharmacol., 2015, 80(6), 1350-1361.
[http://dx.doi.org/10.1111/bcp.12738] [PMID: 26261033]

Fitzgerald, K.; Simon, A.; White, S.; Borodovsky, A.; Patel, N.; Bettencourt, B.; Clausen, V.; Horton, J. D.; Wijngaard, P.; Kauffman, R. ALN-PCSsc, an RNAi investigational agent that inhibits PCSK9 with potential for effective quarterly or possibly bi-annual dosing: results of a single-blind, placebo-controlled, Phase I single-ascending dose (SAD) and multi-dose (MD) trial in adults with elevated LDL-C, on and off statins. Latebreaking Clinical Trials, 2015, 4

Kastelein, J.J.; Nissen, S.E.; Rader, D.J.; Hovingh, G.K.; Wang, M.D.; Shen, T.; Krueger, K.A. Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled Phase 2 study. Eur. Heart J., 2016, 37(17), 1360-1369.
[http://dx.doi.org/10.1093/eurheartj/ehv707] [PMID: 26757788]

Foltz, I.N.; Karow, M.; Wasserman, S.M. Evolution and emergence of therapeutic monoclonal antibodies: what cardiologists need to know. Circulation, 2013, 127(22), 2222-2230.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002033] [PMID: 23733968]

Catapano, A.L.; Papadopoulos, N. The safety of therapeutic monoclonal antibodies: implications for cardiovascular disease and targeting the PCSK9 pathway. Atherosclerosis, 2013, 228(1), 18-28.
[http://dx.doi.org/10.1016/j.atherosclerosis.2013.01.044] [PMID: 23466067]

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]

Roth, E.M.; Diller, P. Alirocumab for hyperlipidemia: physiology of PCSK9 inhibition, pharmacodynamics and Phase I and II clinical trial results of a PCSK9 monoclonal antibody. Future Cardiol., 2014, 10(2), 183-199.
[http://dx.doi.org/10.2217/fca.13.107] [PMID: 24762246]

Emery, M.; Gibbs, J.; Slatter, J.; Hamilton, L.; Wasserman, S.; Geller, M.; Dias, C. Evolocumab pharmacokinetics and its effects on LDL-C and PCSK9 lowering in subjects with mild or moderate hepatic impairment. Clin. Pharmacol. Ther., 2015, 97, S69.

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]

Pfizer Inc. Discontinues Global Development of Bococizumab, Its Investigational PCSK9 Inhibitor, 2016.Available at:, http://www.pfizer.com/news/pressrelease/press-releasedetail/pfizer_discontinues_global_development_of_bococizumab_its_investigational_pcsk9_in

Carthew, R.W.; Sontheimer, E.J. origins and mechanisms of miRNAs and siRNAs. Cell, 2009, 136(4), 642-655.
[http://dx.doi.org/10.1016/j.cell.2009.01.035] [PMID: 19239886]

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]

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]

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]

Landlinger, C.; Pouwer, M.G.; Juno, C.; van der Hoorn, J.W.A.; Pieterman, E.J.; Jukema, J.W.; Staffler, G.; Princen, H.M.G.; Galabova, G. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice. Eur. Heart J., 2017, 38(32), 2499-2507.
[http://dx.doi.org/10.1093/eurheartj/ehx260] [PMID: 28637178]

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]

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]

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]

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]

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]

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]

Hirayama, A.; Honarpour, N.; Yoshida, M.; Yamashita, S.; Huang, F.; Wasserman, S.M.; Teramoto, T. Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk-primary results from the phase 2 YUKAWA study. Circ. J., 2014, 78(5), 1073-1082.
[http://dx.doi.org/10.1253/circj.CJ-14-0130] [PMID: 24662398]

Stein, E.A.; Giugliano, R.P.; Koren, M.J.; Raal, F.J.; Roth, E.M.; Weiss, R.; Sullivan, D.; Wasserman, S.M.; Somaratne, R.; Kim, J.B.; Yang, J.; Liu, T.; Albizem, M.; Scott, R.; Sabatine, M.S. PROFICIO Investigators.. Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials. Eur. Heart J., 2014, 35(33), 2249-2259.
[http://dx.doi.org/10.1093/eurheartj/ehu085] [PMID: 24598985]

Koren, M.J.; Giugliano, R.P.; Raal, F.J.; Sullivan, D.; Bolognese, M.; Langslet, G.; Civeira, F.; Somaratne, R.; Nelson, P.; Liu, T.; Scott, R.; Wasserman, S.M.; Sabatine, M.S. OSLER Investigators. Efficacy and safety of longerterm administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the openlabel study of long-term evaluation against LDL-C (OSLER) randomized trial Circulation, 2013, 129(2), 234-243.
[http://dx.doi.org/10.1161/circulationaha.113.007012v] [PMID: 24255061]

Raal, F.; Honarpour, N.; Blom, D.; Hovingh, G.; Xu, F.; Scott, R.; Wasserman, S.; Stein, E. Trial evaluating evolocumab, a PCSK9 antibody, in patients with homozygous FH (TESLA): Results of the randomized, double-blind, placebo-controlled trial. Atherosclerosis, 2014, 235(2), e12.
[http://dx.doi.org/10.1016/j.atherosclerosis.2014.05.004]

Kiyosue, A.; Honarpour, N.; Kurtz, C.; Xue, A.; Wasserman, S.M.; Hirayama, A. A phase 3 study of evolocumab (AMG 145) in statin-treated Japanese patients at high cardiovascular risk. Am. J. Cardiol., 2016, 117(1), 40-47.
[http://dx.doi.org/10.1016/j.amjcard.2015.10.021] [PMID: 26547291]

Robinson, J.G.; Nedergaard, B.S.; Rogers, W.J.; Fialkow, J.; Neutel, J.M.; Ramstad, D.; Somaratne, R.; Legg, J.C.; Nelson, P.; Scott, R.; Wasserman, S.M.; Weiss, R. LAPLACE-2 Investigators.. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA, 2014, 311(18), 1870-1882.
[http://dx.doi.org/10.1001/jama.2014.4030] [PMID: 24825642]

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. 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]

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. 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]

Stroes, E.; Colquhoun, D.; Sullivan, D.; Civeira, F.; Rosenson, R.S.; Watts, G.F.; Bruckert, E.; Cho, L.; Dent, R.; Knusel, B.; Xue, A.; Scott, R.; Wasserman, S.M.; Rocco, M. GAUSS-2 Investigators.. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J. Am. Coll. Cardiol., 2014, 63(23), 2541-2548.
[http://dx.doi.org/10.1016/j.jacc.2014.03.019] [PMID: 24694531]

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. FOURIER Steering Committee and 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.; 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]

Raal, F.J.; Hovingh, G.K.; Blom, D.; Santos, R.D.; Harada-Shiba, M.; Bruckert, E.; Couture, P.; Soran, H.; Watts, G.F.; Kurtz, C.; Honarpour, N.; Tang, L.; Kasichayanula, S.; Wasserman, S.M.; Stein, E.A. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open label TAUSSIG study. Lancet Diabetes Endocrinol., 2017, 5(4), 280-290.
[http://dx.doi.org/10.1016/S2213-8587(17)30044-X] [PMID: 28215937]

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. 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]

Stein, E.A.; Koren, M.; Honarpour, N.; Kurtz, C.; Yang, J.; Wasserman, S.; Raal, F. Clinical equivalence of evolocumab 140 mg every two weeks and 420 mg monthly dosing regimens: a pooled analysis of 3146 patients in phase 3 studies. J. Am. Coll. Cardiol., 2015, 65(10), A1368.
[http://dx.doi.org/10.1016/S0735-1097(15)61368-7]

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]

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.; Taskinen, M.R.; Ginsberg, H.; Kastelein, J.; Colhoun, H.M.; Merlet, L.; Pordy, R.; Baccara-Dinet, M.T. A 24-week study of alirocumab as monotherapy versus ezetimibe: the first Phase 3 data of a proprotein convertase subtilisin/kexin type 9 inhibitor. J. Am. Coll. Cardiol., 2014, 63(12), A1370.
[http://dx.doi.org/10.1016/S0735-1097(14)61370-X]

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. 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]

Stroes, E.; Guyton, J.R.; Lepor, N.; Civeira, F.; Gaudet, D.; Watts, G.F.; Baccara-Dinet, M.T.; Lecorps, G.; Manvelian, G.; Farnier, M. ODYSSEY CHOICE II Investigators. Efficacy and safety of alirocumab 150 mg every 4 weeks in patients with hypercholesterolemia not on statin therapy: the ODYSSEY CHOICE II study. J. Am. Heart Assoc., 2016, 5(9), e003421.
[http://dx.doi.org/10.1161/JAHA.116.003421] [PMID: 27625344]

Colhoun, H.M.; Robinson, J.G.; Farnier, M.; Cariou, B.; Blom, D.; Kereiakes, D.J.; Lorenzato, C.; Pordy, R.; Chaudhari, U. Efficacy and safety of alirocumab, a fully human PCSK9 monoclonal antibody, in high cardiovascular risk patients with poorly controlled hypercholesterolemia on maximally tolerated doses of statins: rationale and design of the ODYSSEY COMBO I and II trials. BMC Cardiovasc. Disord., 2014, 14(1), 121.
[http://dx.doi.org/10.1186/1471-2261-14-121] [PMID: 25240705]

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.
[http://dx.doi.org/10.1210/jc.2015-1520] [PMID: 26030325]

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.
[http://dx.doi.org/10.1016/j.atherosclerosis.2015.11.010] [PMID: 26638010]

Teramoto, T.; Kobayashi, M.; Tasaki, H.; Yagyu, H.; Higashikata, T.; Takagi, Y.; Uno, K.; Baccara-Dinet, M.T.; Nohara, A. efficacy and safety of alirocumab in Japanese patients with heterozygous familial hypercholesterolemia or at high cardiovascular risk with hypercholesterolemia not adequately controlled with statins　- ODYSSEY JAPAN randomized controlled trial. Circ. J., 2016, 80(9), 1980-1987.
[http://dx.doi.org/10.1253/circj.CJ-16-0387] [PMID: 27452202]

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. 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]

Roth, E.M.; Moriarty, P.M.; Bergeron, J.; Langslet, G.; Manvelian, G.; Zhao, J.; Baccara-Dinet, M.T.; Rader, D.J. ODYSSEY CHOICE I investigators.. A phase III randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I. Atherosclerosis, 2016, 254, 254-262.
[http://dx.doi.org/10.1016/j.atherosclerosis.2016.08.043] [PMID: 27639753]

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]

Ginsberg, H.N.; Rader, D.J.; Raal, F.J.; Guyton, J.R.; Lorenzato, C.; Pordy, R.; Baccara-Dinet, M.T.; Stroes, E. ODYSSEY HIGH FH: efficacy and safety of alirocumab in patients with severe heterozygous familial hypercholesterolemia. Circulation, 2014, 130(23), 2119.

Moriarty, P.M.; Parhofer, K.G.; Babirak, S.P.; Cornier, M.A.; Duell, P.B.; Hohenstein, B.; Leebmann, J.; Ramlow, W.; Schettler, V.; Simha, V.; Steinhagen-Thiessen, E.; Thompson, P.D.; Vogt, A.; von Stritzky, B.; Du, Y.; Manvelian, G. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. Eur. Heart J., 2016, 37(48), 3588-3595.
[http://dx.doi.org/10.1093/eurheartj/ehw388] [PMID: 27572070]

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]

Cannon, C.P.; Cariou, B.; Blom, D.; McKenney, J.M.; Lorenzato, C.; Pordy, R.; Chaudhari, U.; Colhoun, H.M. ODYSSEY COMBO II Investigators.. 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.
[http://dx.doi.org/10.1093/eurheartj/ehv028] [PMID: 25687353]

Kereiakes, D.J.; Robinson, J.G.; Cannon, C.P.; Lorenzato, C.; Pordy, R.; Chaudhari, U.; Colhoun, H.M. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am. Heart J., 2015, 169(6), 906-915. e13.
[http://dx.doi.org/10.1016/j.ahj.2015.03.004] [PMID: 26027630]

Müller-Wieland, D.; Leiter, L.A.; Cariou, B.; Letierce, A.; Colhoun, H.M.; Del Prato, S.; Henry, R.R.; Tinahones, F.J.; Aurand, L.; Maroni, J.; Ray, K.K.; Bujas-Bobanovic, M. Design and rationale of the ODYSSEY DM-DYSLIPIDEMIA trial: lipid-lowering efficacy and safety of alirocumab in individuals with type 2 diabetes and mixed dyslipidaemia at high cardiovascular risk. Cardiovasc. Diabetol., 2017, 16(1), 70.
[http://dx.doi.org/10.1186/s12933-017-0552-4] [PMID: 28545518]

Leiter, L.A.; Cariou, B.; Müller-Wieland, D.; Colhoun, H.M.; Del Prato, S.; Tinahones, F.J.; Ray, K.K.; Bujas- Bobanovic, M.; Domenger, C.; Mandel, J.; Samuel, R.; Henry, R.R. Efficacy and safety of alirocumab in insulintreated individuals with type 1 or type 2 diabetes and high cardiovascular risk: The ODYSSEY DM-INSULIN randomized trial. Diabetes Obes. Metab., 2017, 19(12), 1781- 1792.
[http://dx.doi.org/10.1111/dom.13114] [PMID: 28905478]

Roth, E.M.; McKenney, J.M. ODYSSEY MONO: effect of alirocumab 75 mg subcutaneously every 2 weeks as monotherapy versus ezetimibe over 24 weeks. Future Cardiol., 2015, 11(1), 27-37.
[http://dx.doi.org/10.2217/fca.14.82] [PMID: 25606700]

van der Tuin, S.J.; Kühnast, S.; Berbée, J.F.; Verschuren, L.; Pieterman, E.J.; Havekes, L.M.; van der Hoorn, J.W.; Rensen, P.C.; Jukema, J.W.; Princen, H.M.; Willems van Dijk, K.; Wang, Y. Anacetrapib reduces (V)LDL cholesterol by inhibition of CETP activity and reduction of plasma PCSK9. J. Lipid Res., 2015, 56(11), 2085-2093.
[http://dx.doi.org/10.1194/jlr.M057794] [PMID: 26342106]

Miyosawa, K.; Watanabe, Y.; Murakami, K.; Murakami, T.; Shibata, H.; Iwashita, M.; Yamazaki, H.; Yamazaki, K.; Ohgiya, T.; Shibuya, K.; Mizuno, K.; Tanabe, S.; Singh, S.A.; Aikawa, M. New CETP inhibitor K-312 reduces PCSK9 expression: a potential effect on LDL cholesterol metabolism. Am. J. Physiol. Endocrinol. Metab., 2015, 309(2), E177-E190.
[http://dx.doi.org/10.1152/ajpendo.00528.2014] [PMID: 26015437]

Gaudet, D.; Kereiakes, D.J.; McKenney, J.M.; Roth, E.M.; Hanotin, C.; Gipe, D.; Du, Y.; Ferrand, A-C.; Ginsberg, H.N.; Stein, E.A. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am. J. Cardiol., 2014, 114(5), 711-715.
[http://dx.doi.org/10.1016/j.amjcard.2014.05.060] [PMID: 25060413]

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.
[http://dx.doi.org/10.1016/j.jacc.2014.01.006] [PMID: 24509273]

Romagnuolo, R.; Scipione, C.A.; Boffa, M.B.; Marcovina, S.M.; Seidah, N.G.; Koschinsky, M.L. Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor. J. Biol. Chem., 2015, 290(18), 11649-11662.
[http://dx.doi.org/10.1074/jbc.M114.611988] [PMID: 25778403]

Koschinsky, M.; Gemin, M.; Scipione, C.; Boffa, M.; Seidah, N.; Romagnuolo, R. Evaluating the roles of PCSK9 and specific receptors in lipoprotein (a) catabolism. J. Clin. Lipidol., 2016, 3(10), 720-721.
[http://dx.doi.org/10.1016/j.jacl.2016.03.099]

Kurt, B.; Soufi, M.; Sattler, A.; Schaefer, J.R. Lipoprotein(a)-clinical aspects and future challenges. Clin. Res. Cardiol. Suppl., 2015, 10(1), 26-32.
[http://dx.doi.org/10.1007/s11789-015-0075-z] [PMID: 25732622]

Lambert, G.; Thedrez, A.; Croyal, M.; Ramin-Mangata, S.; Couret, D.; Diotel, N.; Nobécourt-Dupuy, E.; Krempf, M.; LeBail, J.C.; Poirier, B.; Blankenstein, J.; Villard, E.F.; Guillot, E. The complexity of lipoprotein (a) lowering by PCSK9 monoclonal antibodies. Clin. Sci. (Lond.), 2017, 131(4), 261-268.
[http://dx.doi.org/10.1042/CS20160403] [PMID: 28108631]

Walley, K.R.; Thain, K.R.; Russell, J.A.; Reilly, M.P.; Meyer, N.J.; Ferguson, J. F.; Christie, J.D.; Nakada, T.-a.; Fjell, C.D.; Thair, S.A. PCSK9 is a critical regulator of the innate immune response and septic shock outcome Sci. Transl. Med., 2014, 6(258), 258ra143.
[http://dx.doi.org/10.1126/scitranslmed.3008782] [PMID: 25320235]

Topchiy, E.; Cirstea, M.; Kong, H.J.; Boyd, J.H.; Wang, Y.; Russell, J.A.; Walley, K.R. Lipopolysaccharide is cleared from the circulation by hepatocytes via the low density lipoprotein receptor. PLoS One, 2016, 11(5)e0155030
[http://dx.doi.org/10.1371/journal.pone.0155030] [PMID: 27171436]

Tang, Z.H.; Peng, J.; Ren, Z.; Yang, J.; Li, T.T.; Li, T.H.; Wang, Z.; Wei, D.H.; Liu, L.S.; Zheng, X.L.; Jiang, Z.S. New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway. Atherosclerosis, 2017, 262, 113-122.
[http://dx.doi.org/10.1016/j.atherosclerosis.2017.04.023] [PMID: 28535426]

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]

Cheng, J.M.; Oemrawsingh, R.M.; Garcia-Garcia, H.M.; Boersma, E.; van Geuns, R-J.; Serruys, P.W.; Kardys, I.; Akkerhuis, K.M. PCSK9 in relation to coronary plaque inflammation: Results of the ATHEROREMO-IVUS study. Atherosclerosis, 2016, 248, 117-122.
[http://dx.doi.org/10.1016/j.atherosclerosis.2016.03.010] [PMID: 27015246]

Ridker, P.M.; Rifai, N.; Bradwin, G.; Rose, L. Plasma proprotein convertase subtilisin/kexin type 9 levels and the risk of first cardiovascular events. Eur. Heart J., 2016, 37(6), 554-560.
[http://dx.doi.org/10.1093/eurheartj/ehv568] [PMID: 26508163]

Vlachopoulos, C.; Terentes-Printzios, D.; Georgiopoulos, G.; Skoumas, I.; Koutagiar, I.; Ioakeimidis, N.; Stefanadis, C.; Tousoulis, D. Prediction of cardiovascular events with levels of proprotein convertase subtilisin/kexin type 9: a systematic review and meta-analysis. Atherosclerosis, 2016, 252, 50-60.
[http://dx.doi.org/10.1016/j.atherosclerosis.2016.07.922] [PMID: 27501130]

Chan, D.C.; Pang, J.; McQuillan, B.M.; Hung, J.; Beilby, J.P.; Barrett, P.H.R.; Watts, G.F. Plasma proprotein convertase subtilisin kexin type 9 as a predictor of carotid atherosclerosis in asymptomatic adults. Heart Lung Circ., 2016, 25(5), 520-525.
[http://dx.doi.org/10.1016/j.hlc.2015.10.017] [PMID: 26706651]

Alonso, R.; Mata, P.; Muñiz, O.; Fuentes-Jimenez, F.; Díaz, J.L.; Zambón, D.; Tomás, M.; Martin, C.; Moyon, T.; Croyal, M.; Thedrez, A.; Lambert, G. PCSK9 and lipoprotein (a) levels are two predictors of coronary artery calcification in asymptomatic patients with familial hypercholesterolemia. Atherosclerosis, 2016, 254, 249-253.
[http://dx.doi.org/10.1016/j.atherosclerosis.2016.08.038] [PMID: 27594539]

Xie, W.; Liu, J.; Wang, W.; Wang, M.; Qi, Y.; Zhao, F.; Sun, J.; Liu, J.; Li, Y.; Zhao, D. Association between plasma PCSK9 levels and 10-year progression of carotid atherosclerosis beyond LDL-C: a cohort study. Int. J. Cardiol., 2016, 215, 293-298.
[http://dx.doi.org/10.1016/j.ijcard.2016.04.103] [PMID: 27128549]

Nissen, S.E.; Nicholls, S.J.; Sipahi, I.; Libby, P.; Raichlen, J.S.; Ballantyne, C.M.; Davignon, J.; Erbel, R.; Fruchart, J.C.; Tardif, J.C.; Schoenhagen, P.; Crowe, T.; Cain, V.; Wolski, K.; Goormastic, M.; Tuzcu, E.M. ASTEROID Investigators.. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA, 2006, 295(13), 1556-1565.
[http://dx.doi.org/10.1001/jama.295.13.jpc60002] [PMID: 16533939]

Nicholls, S.J.; Ballantyne, C.M.; Barter, P.J.; Chapman, M.J.; Erbel, R.M.; Libby, P.; Raichlen, J.S.; Uno, K.; Borgman, M.; Wolski, K.; Nissen, S.E. Effect of two intensive statin regimens on progression of coronary disease. N. Engl. J. Med., 2011, 365(22), 2078-2087.
[http://dx.doi.org/10.1056/NEJMoa1110874] [PMID: 22085316]

Nicholls, S.J.; Puri, R.; Anderson, T.; Ballantyne, C.M.; Cho, L.; Kastelein, J.J.; Koenig, W.; Somaratne, R.; Kassahun, H.; Yang, J.; Wasserman, S.M.; Scott, R.; Ungi, I.; Podolec, J.; Ophuis, A.O.; Cornel, J.H.; Borgman, M.; Brennan, D.M.; Nissen, S.E. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA, 2016, 316(22), 2373-2384.
[http://dx.doi.org/10.1001/jama.2016.16951] [PMID: 27846344]

Navarese, E.P.; Kołodziejczak, M.; Kereiakes, D.J.; Tantry, U.S.; O’connor, C.; Gurbel, P.A. Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies for acute coronary syndrome: a narrative review role of PCSK9 inhibition in ACS. Ann. Intern. Med., 2016, 164(9), 600-607.
[http://dx.doi.org/10.7326/M15-2994] [PMID: 26999484]

Gencer, B.; Montecucco, F.; Nanchen, D.; Carbone, F.; Klingenberg, R.; Vuilleumier, N.; Aghlmandi, S.; Heg, D.; Räber, L.; Auer, R.; Jüni, P.; Windecker, S.; Lüscher, T.F.; Matter, C.M.; Rodondi, N.; Mach, F. Prognostic value of PCSK9 levels in patients with acute coronary syndromes. Eur. Heart J., 2016, 37(6), 546-553.
[http://dx.doi.org/10.1093/eurheartj/ehv637] [PMID: 26655339]

Zhu, Y.M.; Anderson, T.J.; Sikdar, K.; Fung, M.; McQueen, M.J.; Lonn, E.M.; Verma, S. Association of proprotein convertase subtilisin/kexin type 9 (PCSK9) with cardiovascular risk in primary prevention. Arterioscler. Thromb. Vasc. Biol., 2015, 35(10), 2254-2259.
[http://dx.doi.org/10.1161/atvbaha.115.306172] [PMID: 26293463]

Leander, K.; Mälarstig, A.; Van’t Hooft, F.M.; Hyde, C.; Hellénius, M-L.; Troutt, J.S.; Konrad, R.J.; Öhrvik, J.; Hamsten, A.; de Faire, U. Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) predicts future risk of cardiovascular events independently of established risk factors. Circulation, 2016, 133(13), 1230-1239.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.115.018531] [PMID: 26896437]

Werner, C.; Hoffmann, M.M.; Winkler, K.; Böhm, M.; Laufs, U. Risk prediction with proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients with stable coronary disease on statin treatment. Vascul. Pharmacol., 2014, 62(2), 94-102.
[http://dx.doi.org/10.1016/j.vph.2014.03.004] [PMID: 24685817]

Li, S.; Li, J.J. PCSK9: a key factor modulating atherosclerosis. J. Atheroscler. Thromb., 2015, 22(3), 221-230.
[http://dx.doi.org/10.5551/jat.27615] [PMID: 25410128]

Sabatine, M.S.; Leiter, L.A.; Wiviott, S.D.; Giugliano, R.P.; Deedwania, P.; De Ferrari, G.M.; Murphy, S.A.; Kuder, J.F.; Gouni-Berthold, I.; Lewis, B.S.; Handelsman, Y.; Pineda, A.L.; Honarpour, N.; Keech, A.C.; Sever, P.S.; Pedersen, T.R. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol., 2017, 5(12), 941-950.
[http://dx.doi.org/10.1016/S2213-8587(17)30313-3] [PMID: 28927706]

Bonaca, M. P.; Nault, P.; Giugliano, R. P.; Keech, A. C.; Pineda, A. L.; Kanevsky, E.; Kuder, J.; Murphy, S. A.; Jukema, J. W.; Lewis, B. S. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk). Circulation, 2018, 137(4), 338-350.
[http://dx.doi.org/10.1161/circulationaha.117.032235] [PMID: 29133605]

Mihaylova, B.; Emberson, J.; Blackwell, L.; Keech, A.; Simes, J.; Barnes, E.H.; Voysey, M.; Gray, A.; Collins, R.; Baigent, C. Cholesterol Treatment Trialists’ (CTT) Collaborators.. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet, 2012, 380(9841), 581-590.
[http://dx.doi.org/10.1016/S0140-6736(12)60367-5] [PMID: 22607822]

Ray, K.K.; Ginsberg, H.N.; Davidson, M.H.; Pordy, R.; Bessac, L.; Minini, P.; Eckel, R.H.; Cannon, C.P. reductions in atherogenic lipids and Major cardiovascular events. Circulation, 2016, 134(24), 1931-1943.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.024604] [PMID: 27777279]

Schwartz, G.G.; Steg, P.G.; Szarek, M.; Bhatt, D.L.; Bittner, V.A.; Diaz, R.; Edelberg, J.M.; Goodman, S.G.; Hanotin, C.; Harrington, R.A.; Jukema, J.W.; Lecorps, G.; Mahaffey, K.W.; Moryusef, A.; Pordy, R.; Quintero, K.; Roe, M.T.; Sasiela, W.J.; Tamby, J.F.; Tricoci, P.; White, H.D.; Zeiher, A.M. ODYSSEY OUTCOMES Committees and Investigators.. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N. Engl. J. Med., 2018, 379(22), 2097-2107.
[http://dx.doi.org/10.1056/NEJMoa1801174] [PMID: 30403574]

Ridker, P.M.; Revkin, J.; Amarenco, P.; Brunell, R.; Curto, M.; Civeira, F.; Flather, M.; Glynn, R.J.; Gregoire, J.; Jukema, J.W.; Karpov, Y.; Kastelein, J.J.P.; Koenig, W.; Lorenzatti, A.; Manga, P.; Masiukiewicz, U.; Miller, M.; Mosterd, A.; Murin, J.; Nicolau, J.C.; Nissen, S.; Ponikowski, P.; Santos, R.D.; Schwartz, P.F.; Soran, H.; White, H.; Wright, R.S.; Vrablik, M.; Yunis, C.; Shear, C.L.; Tardif, J.C. SPIRE Cardiovascular Outcome Investigators.. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N. Engl. J. Med., 2017, 376(16), 1527-1539.
[http://dx.doi.org/10.1056/NEJMoa1701488] [PMID: 28304242]

Ridker, P.M.; Tardif, J.C.; Amarenco, P.; Duggan, W.; Glynn, R.J.; Jukema, J.W.; Kastelein, J.J.P.; Kim, A.M.; Koenig, W.; Nissen, S.; Revkin, J.; Rose, L.M.; Santos, R.D.; Schwartz, P.F.; Shear, C.L.; Yunis, C. SPIRE Investigators.. Lipid-reduction variability and antidrug-antibody formation with bococizumab. N. Engl. J. Med., 2017, 376(16), 1517-1526.
[http://dx.doi.org/10.1056/NEJMoa1614062] [PMID: 28304227]

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]

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. 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. No Evidence of Cognitive Issues When Evolocumab Added to Statin Therapy , 2017. Available at:. http://www.acc.org/about-acc/press-releases /2017/ 03/17/11/11/sat-8am-no-evidence-of-cognitive-issues-whenevolocumab- added-to-statin-therapy2017

Dent, R.; Joshi, R.; Stephen Djedjos, C.; Legg, J.; Elliott, M.; Geller, M.; Meyer, D.; Somaratne, R.; Recknor, C.; Weiss, R. Evolocumab lowers LDL-C safely and effectively when self-administered in the at-home setting. Springerplus, 2016, 5(1), 300.
[http://dx.doi.org/10.1186/s40064-016-1892-3] [PMID: 27066336]

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]

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]

Cenedella, R.J. Cholesterol and cataracts. Surv. Ophthalmol., 1996, 40(4), 320-337.
[http://dx.doi.org/10.1016/S0039-6257(96)82007-8] [PMID: 8658343]

Kostis, J.; Dobrzynski, J.; Kostis, W.; Sargsyan, D. 5967 Effect of the magnitude of LDL lowering on the incidence of cataract among patients treated with statins or PCSK9 antibodies. Eur. Heart J., 2017, 38(Suppl. 1), ehx493.5967.
[http://dx.doi.org/10.1093/eurheartj/ehx493.5967 ]

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]

Fernández-Ruiz, I. Diabetes: PCSK9 inhibition is not associated with new-onset diabetes. Nat. Rev. Cardiol., 2016, 13(10), 568-569.
[http://dx.doi.org/10.1038/nrcardio.2016.132] [PMID: 27510548]

Koren, M.J.; Sabatine, M.S.; Giugliano, R.P.; Langslet, G.; Wiviott, S.D.; Kassahun, H.; Ruzza, A.; Ma, Y.; Somaratne, R.; Raal, F.J. Long-term Low-Density Lipoprotein Cholesterol-Lowering Efficacy, Persistence, and Safety of Evolocumab in Treatment of Hypercholesterolemia: Results Up to 4 Years From the Open-Label OSLER-1 Extension Study. JAMA Cardiol., 2017, 2(6), 598-607.
[http://dx.doi.org/10.1001/jamacardio.2017.0747] [PMID: 28291870]

Leiter, L.A.; Teoh, H.; Kallend, D.; Wright, R.S.; Landmesser, U.; Wijngaard, P.L.J.; Kastelein, J.J.P.; Ray, K.K. Inclisiran lowers LDL-C and PCSK9 irrespective of diabetes status: the ORION-1 randomized clinical trial. Diabetes Care, 2018, 42(1), 173-176.
[http://dx.doi.org/10.2337/dc18-1491] [PMID: 30487231]

Leiter, L.; Teoh, H.; Kallend, D.; Wright, R.S.; Landmesser, U.; Wijngaard, P.L.; Kastelein, J.J.; Ray, K.K. Inclisiran lowers LDL-C and PCSK9 irrespective of diabetes status without worsening glycemia, Am. Diabetes. Assoc., 2018, 67(Suppl. 1), 337-OR.
[http://dx.doi.org/10.2337/db18-337-OR]