Lipid lowering with PCSK9 inhibitors

Journal name:
Nature Reviews Cardiology
Volume:
11,
Pages:
563–575
Year published:
DOI:
doi:10.1038/nrcardio.2014.84
Published online

Abstract

Statins are the most-effective therapy currently available for lowering the LDL-cholesterol (LDL-C) level and preventing cardiovascular events. Additional therapies are necessary for patients who cannot reach the target LDL-C level when taking the maximum-tolerated dose of a statin. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme with an important role in lipoprotein metabolism. Rare gain-of-function mutations in PCSK9 lead to a high LDL-C level and premature coronary heart disease, whereas loss-of-function variants lead to a low LDL-C level and a reduced incidence of coronary heart disease. Furthermore, the PCSK9 level is increased with statin therapy through negative feedback, which promotes LDL-receptor degradation and decreases the efficacy of LDL-C lowering with statins. PCSK9 inhibition is, therefore, a rational therapeutic target, and several approaches are being pursued. In phase I, II, and III trials, inhibition of PCSK9 with monoclonal antibodies has produced an additional 50–60% decrease in the LDL-C level when used in combination with statin therapy, compared with statin monotherapy. In short-term trials, PCSK9 inhibitors were well tolerated and had a low incidence of adverse effects. Ongoing phase III trials will provide information about the long-term safety of these drugs, and their efficacy in preventing cardiovascular events.

At a glance

Figures

  1. LDL-cholesterol metabolism in the presence or absence of PCSK9.
    Figure 1: LDL-cholesterol metabolism in the presence or absence of PCSK9.

    a | PCSK9 is synthesized in the liver as an inactive enzyme precursor that contains a triad of residues required for catalytic activity. PCSK9 circulates in the plasma as a phosphoprotein and, after having been secreted, can immediately bind to, and be endocytosed with, surrounding LDL receptors. The complex of the PCSK9 molecule and the LDL receptor is internalized and undergoes degradation in endosomal and lysosomal compartments, with few receptors recycled to the cell surface. This leads to a decreased number of LDL receptors on the surface of cells. b | Human monoclonal antibodies can bind to PCSK9 adjacent to the region that is required for interaction with LDL receptors. PCSK9 is, therefore, prevented from binding to LDL receptors. After endocytosis, the LDL receptor is recycled back to the surface of the cell, with few receptors degraded in the lysosome. Abbreviation: PCSK9, proprotein convertase subtilisin/kexin type 9.

  2. Ongoing phase III clinical trials of PCSK9 inhibitors.
    Figure 2: Ongoing phase III clinical trials of PCSK9 inhibitors.

    Phase III trials designed to evaluate the long-term safety and tolerability of a | alirocumab, b | evolocumab, and c | bococizumab, and their efficacy in reducing the rate of cardiovascular events in various populations of patients. Abbreviations: FH, familial hypercholesterolaemia; IVUS, intravascular ultrasonography; MACE, major adverse cardiac events; OLE, open-label extension; PCSK9, proprotein convertase subtilisin/kexin type 9.

References

  1. Agarwal, S. K. et al. Sources of variability in measurements of cardiac troponin T in a community-based sample: the atherosclerosis risk in communities study. Clin. Chem. 57, 891897 (2011).
  2. Boekholdt, S. M. et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA 307, 13021309 (2012).
  3. Sniderman, A. D. et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ. Cardiovasc. Qual. Outcomes 4, 337345 (2011).
  4. Genser, B. & Marz, W. Low density lipoprotein cholesterol, statins and cardiovascular events: a meta-analysis. Clin. Res. Cardiol. 95, 393404 (2006).
  5. Baigent, C. et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366, 12671278 (2005).
  6. Cannon, C. P. et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med. 350, 14951504 (2004).
  7. Avis, H. J. et al. Efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia. J. Am. Coll. Cardiol. 55, 11211126 (2010).
  8. Toth, P. P., Harper, C. R. & Jacobson, T. A. Clinical characterization and molecular mechanisms of statin myopathy. Expert Rev. Cardiovasc. Ther. 6, 955969 (2008).
  9. Preiss, D. et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 305, 25562564 (2011).
  10. Preiss, D. & Sattar, N. Statins and the risk of new-onset diabetes: a review of recent evidence. Curr. Opin. Lipidol. 22, 460466 (2011).
  11. Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154156 (2003).
  12. Abifadel, M. et al. Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum. Mutat. 30, 520529 (2009).
  13. Maxwell, K. N. & Breslow, J. L. Proprotein convertase subtilisin kexin 9: the third locus implicated in autosomal dominant hypercholesterolemia. Curr. Opin. Lipidol. 16, 167172 (2005).
  14. Jensen, H. K. The molecular genetic basis and diagnosis of familial hypercholesterolemia in Denmark. Dan. Med. Bull. 49, 318345 (2002).
  15. Humphries, S. E. et al. Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. J. Med. Genet. 43, 943949 (2006).
  16. Humphries, S. E. et al. Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing. J. Mol. Med. (Berl.) 84, 203214 (2006).
  17. Cariou, B. et al. PCSK9 dominant negative mutant results in increased LDL catabolic rate and familial hypobetalipoproteinemia. Arterioscler. Thromb. Vasc. Biol. 29, 21912197 (2009).
  18. Fasano, T. et al. A novel loss of function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol. Arterioscler. Thromb. Vasc. Biol. 27, 677681 (2007).
  19. 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. 354, 12641272 (2006).
  20. Benn, M., Nordestgaard, B. G., Grande, P., Schnohr, P. & Tybjaerg-Hansen, A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J. Am. Coll. Cardiol. 55, 28332842 (2010).
  21. Hooper, A. J., Marais, A. D., Tanyanyiwa, D. M. & Burnett, J. R. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 193, 445448 (2007).
  22. Zhao, Z. et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am. J. Hum. Genet. 79, 514523 (2006).
  23. Anand, S. S. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. Vasc. Med. 8, 289290 (2003).
  24. Brown, M. S. & Goldstein, J. L. Biomedicine: lowering LDL—not only how low, but how long? Science 311, 17211723 (2006).
  25. Folsom, A. R., Peacock, J. M. & Boerwinkle, E. Variation in PCSK9, low LDL cholesterol, and risk of peripheral arterial disease. Atherosclerosis 202, 211215 (2009).
  26. Huang, C. C. et al. Longitudinal association of PCSK9 sequence variations with low-density lipoprotein cholesterol levels: the Coronary Artery Risk Development in Young Adults Study. Circ. Cardiovasc. Genet. 2, 354361 (2009).
  27. Horton, J. D., Cohen, J. C. & Hobbs, H. H. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem. Sci. 32, 7177 (2007).
  28. Chen, S. N. et al. A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis. J. Am. Coll. Cardiol. 45, 16111619 (2005).
  29. Brown, W. V., Breslow, J. & Ballantyne, C. Clinical use of genetic typing in human lipid disorders. J. Clin. Lipidol. 6, 199207 (2012).
  30. Benjannet, S. et al. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J. Biol. Chem. 279, 4886548875 (2004).
  31. Zaid, A. et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. Hepatology 48, 646654 (2008).
  32. Persson, L. et al. 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. 30, 26662672 (2010).
  33. Cui, Q. et al. Serum PCSK9 is associated with multiple metabolic factors in a large Han Chinese population. Atherosclerosis 213, 632636 (2010).
  34. Seidah, N. G. et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc. Natl Acad. Sci. USA 100, 928933 (2003).
  35. Cunningham, D. et al. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat. Struct. Mol. Biol. 14, 413419 (2007).
  36. Cariou, B., Le May, C. & Costet, P. Clinical aspects of PCSK9. Atherosclerosis 216, 258265 (2011).
  37. Tibolla, G., Norata, G. D., Artali, R., Meneghetti, F. & Catapano, A. L. Proprotein convertase subtilisin/kexin type 9 (PCSK9): from structure-function relation to therapeutic inhibition. Nutr. Metab. Cardiovasc. Dis. 21, 835843 (2011).
  38. Lagace, T. A. et al. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J. Clin. Invest. 116, 29953005 (2006).
  39. Schmidt, R. J. et al. Secreted proprotein convertase subtilisin/kexin type 9 reduces both hepatic and extrahepatic low-density lipoprotein receptors in vivo. Biochem. Biophys. Res. Commun. 370, 634640 (2008).
  40. Zhang, D. W. et al. 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. 282, 1860218612 (2007).
  41. Poirier, S. et al. The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J. Biol. Chem. 283, 23632372 (2008).
  42. 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 102, 20692074 (2005).
  43. Rashid, S. et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc. Natl Acad. Sci. USA 102, 53745379 (2005).
  44. Alborn, W. E. et al. Serum proprotein convertase subtilisin kexin type 9 is correlated directly with serum LDL cholesterol. Clin. Chem. 53, 18141819 (2007).
  45. Careskey, H. E. et al. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J. Lipid Res. 49, 394398 (2008).
  46. Welder, G. et al. High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol. J. Lipid Res. 51, 27142721 (2010).
  47. Brown, M. S. & Goldstein, J. L. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc. Natl Acad. Sci. USA 96, 1104111048 (1999).
  48. Dubuc, G. et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 24, 14541459 (2004).
  49. Nohturfft, A., DeBose-Boyd, R. A., Scheek, S., Goldstein, J. L. & Brown, M. S. Sterols regulate cycling of SREBP cleavage-activating protein (SCAP) between endoplasmic reticulum and Golgi. Proc. Natl Acad. Sci. USA 96, 1123511240 (1999).
  50. Berge, K. E., Ose, L. & Leren, T. P. Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arterioscler. Thromb. Vasc. Biol. 26, 10941100 (2006).
  51. Brautbar, A. & Ballantyne, C. M. Pharmacological strategies for lowering LDL cholesterol: statins and beyond. Nat. Rev. Cardiol. 8, 253265 (2011).
  52. Gupta, N. et al. A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo. PLoS ONE 5, e10682 (2010).
  53. Graham, M. J. et al. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J. Lipid Res. 48, 763767 (2007).
  54. Lindholm, M. W. et al. PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates. Mol. Ther. 20, 376381 (2012).
  55. Do, R. Q., Vogel, R. A. & Schwartz, G. G. PCSK9 inhibitors: potential in cardiovascular therapeutics. Curr. Cardiol. Rep. 15, 345 (2013).
  56. US National Library of Medicine. ClinicalTrials.gov [online], (2011).
  57. Frank-Kamenetsky, M. et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc. Natl Acad. Sci. USA 105, 1191511920 (2008).
  58. Stein, E. A. & Swergold, G. D. Potential of proprotein convertase subtilisin/kexin type 9 based therapeutics. Curr. Atheroscler. Rep. 15, 310 (2013).
  59. Chan, J. C. et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc. Natl Acad. Sci. USA 106, 98209825 (2009).
  60. Gumbiner, B. et al. The effects of multiple dose administration of RN316 (PF-04950615), a humanized IgG2a monoclonal antibody binding proprotein convertase subtilisin kexin type 9, in hypercholesterolemic subjects [abstract 13524]. Circulation 126, 27762799 (2012).
  61. Zhang, L. et al. An anti-PCSK9 antibody reduces LDL-cholesterol on top of a statin and suppresses hepatocyte SREBP-regulated genes. Int. J. Biol. Sci. 8, 310327 (2012).
  62. Ni, Y. G. et al. A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces LDL cholesterol in vivo. J. Lipid Res. 52, 7886 (2011).
  63. Fitzgerald, K. et al. 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 383, 6068 (2014).
  64. Stein, E. A. et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med. 366, 11081118 (2012).
  65. Dias, C. S. et al. 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. 60, 18881898 (2012).
  66. US National Library of Medicine. ClinicalTrials.gov [online], (2012).
  67. US National Library of Medicine. ClinicalTrials.gov [online], (2010).
  68. US National Library of Medicine. ClinicalTrials.gov [online], (2011).
  69. US National Library of Medicine. ClinicalTrials.gov [online], (2012).
  70. US National Library of Medicine. ClinicalTrials.gov [online], (2012).
  71. US National Library of Medicine. ClinicalTrials.gov [online], (2013).
  72. US National Library of Medicine. ClinicalTrials.gov [online], (2013).
  73. US National Library of Medicine. ClinicalTrials.gov [online], (2013).
  74. Gumbiner, B. et al. The effects of single dose administration of RN316 (PF-04950615), a humanized IgG2a monoclonal antibody binding proprotein convertase subtilisin kexin type 9, in hypercholesterolemic subjects treated with and without atorvastatin [abstract]. Circulation 126, A13322 (2012).
  75. US National Library of Medicine. ClinicalTrials.gov [online], (2014).
  76. McKenney, J. M. et al. 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. 59, 23442353 (2012).
  77. 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. 367, 18911900 (2012).
  78. Stein, E. A. et al. 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 380, 2936 (2012).
  79. Stein, E. A. et al. One year open-label treatment with alirocumab 150 mg every two weeks in heterozygous familial hypercholesterolemic patients [abstract 1183-134]. Presented at ACC Scientific Sessions (2014).
  80. Giugliano, R. P. et al. 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 380, 20072017 (2012).
  81. Koren, M. J. et al. 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 380, 19952006 (2012).
  82. Raal, F. et al. 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 126, 24082417 (2012).
  83. Sullivan, D. et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 308, 24972506 (2012).
  84. Xu, R. et al. Effects of evolocumab on lipoprotein particles and subclasses in hypercholesterolemic and heterozygous familial hypercholesterolemia subjects on statin therapy [abstract 1183-134]. Presented at ACC Scientific Sessions (2014).
  85. Gumbiner, B. Effects of 12 weeks of treatment with RN316 (PF-04950615), a humanized IgG2a monoclonal antibody binding proprotein convertase subtilisin kexin type 9, in hypercholesterolemic subjects on high and maximal dose statins. Presented at AHA Scientific Sessions 2012.
  86. Ballantyne, C. M. et al. Efficacy and safety of bococizumab (RN316/PF-04950615), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 in statin-treated hypercholesterolemic subjects: results from a randomized, placebo-controlled, dose-ranging study (NCT: 01592240) [abstract 1183-129]. Presented at ACC Scientific Sessions 2014.
  87. US National Library of Medicine. ClinicalTrials.gov [online], (2013).
  88. US National Library of Medicine. ClinicalTrials.gov [online], (2013).
  89. Desai, N. R. et al. AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy: an analysis from the LDL-C Assessment with Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined with Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial. Circulation 128, 962969 (2013).
  90. Roth, E. M. et al. A 24-week study of alirocumab as monotherapy versus ezetimibe: the first phase 3 data of a proprotein convertase subtilisin/kexin type 9 inhibitor [abstract 1183-125]. Presented at ACC Scientific Sessions (2014).
  91. US National Library of Medicine. ClinicalTrials.gov [online], (2013).
  92. US National Library of Medicine. ClinicalTrials.gov [online], (2013).
  93. US National Library of Medicine. ClinicalTrials.gov [online], (2013).
  94. US National Library of Medicine. ClinicalTrials.gov [online], (2013).
  95. US National Library of Medicine. ClinicalTrials.gov [online], (2014).
  96. US National Library of Medicine. ClinicalTrials.gov [online], (2014).
  97. US National Library of Medicine. ClinicalTrials.gov [online], (2013).
  98. US National Library of Medicine. ClinicalTrials.gov [online], (2013).
  99. US National Library of Medicine. ClinicalTrials.gov [online], (2013).
  100. US National Library of Medicine. ClinicalTrials.gov [online], (2013).
  101. US National Library of Medicine. ClinicalTrials.gov [online], (2014).
  102. Koren, M. J. et al. Anti-PCSK9 monotherapy for hypercholesterolemia—the MENDEL-2 randomized, controlled phase 3 clinical trial of evolocumab. J. Am. Coll. Cardiol. http://dx.doi.org/10.1016/j.jacc.2014.03.018.
  103. Stroes, E. et al. 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. http://dx.doi.org/10.1016/j.jacc.2014.03.019.
  104. Blom, D. J. et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N. Engl. J. Med. 370, 18091819 (2014).
  105. Robinson, J. G. et al. The LAPLACE-2 trial: a phase 3, double-blind, randomized, placebo and ezetimibe controlled, multicenter study to evaluate safety, tolerability and efficacy of evolocumab (AMG 145) in combination with statin therapy in subjects with primary hypercholesterolemia and mixed dyslipidemia. Presented at ACC Scientific Sessions (2014).
  106. Raal, F. et al. The addition of evolocumab (AMG 145) allows the majority of heterozygous familial hypercholesterolemic patients to achieve low-density lipoprotein cholesterol goals—results from the phase 3 randomized, double-blind, placebo-controlled study [abstract 400-005]. Presented at ACC Scientific Sessions (2014).
  107. US National Library of Medicine. ClinicalTrials.gov [online], (2014).
  108. US National Library of Medicine. ClinicalTrials.gov [online], (2014).
  109. US National Library of Medicine. ClinicalTrials.gov [online], (2014).
  110. US National Library of Medicine. ClinicalTrials.gov [online], (2014).
  111. US National Library of Medicine. ClinicalTrials.gov [online], (2014).
  112. US National Library of Medicine. ClinicalTrials.gov [online], (2014).
  113. US National Library of Medicine. ClinicalTrials.gov [online], (2014).
  114. US National Library of Medicine. ClinicalTrials.gov [online], (2014).
  115. US National Library of Medicine. ClinicalTrials.gov [online], (2014).
  116. US National Library of Medicine. ClinicalTrials.gov [online], (2014).
  117. US National Library of Medicine. ClinicalTrials.gov [online], (2014).
  118. Stone, N. J. et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. http://dx.doi.org/10.1016/j.jacc.2013.11.002.
  119. Pasternak, R. C. et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J. Am. Coll. Cardiol. 40, 567572 (2002).
  120. Larosa, J. C., Pedersen, T. R., Somaratne, R. & Wasserman, S. M. Safety and effect of very low levels of low-density lipoprotein cholesterol on cardiovascular events. Am. J. Cardiol. 111, 12211229 (2013).
  121. Hsia, J., MacFadyen, J. G., Monyak, J. & Ridker, P. M. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). J. Am. Coll. Cardiol. 57, 16661675 (2011).
  122. Martin, S. S. et al. Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J. Am. Coll. Cardiol. 62, 732739 (2013).
  123. Sibal, L., Neely, R. D., Jones, A. & Home, P. D. Friedewald equation underestimates low-density lipoprotein cholesterol at low concentrations in young people with and without type 1 diabetes. Diabet. Med. 27, 3745 (2010).
  124. Scharnagl, H., Nauck, M., Wieland, H. & Marz, W. The Friedewald formula underestimates LDL cholesterol at low concentrations. Clin. Chem. Lab. Med. 39, 426431 (2001).
  125. McKinney, J. S. & Kostis, W. J. Statin therapy and the risk of intracerebral hemorrhage: a meta-analysis of 31 randomized controlled trials. Stroke 43, 21492156 (2012).
  126. Lewington, S. et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 370, 18291839 (2007).
  127. Amarenco, P. et al. High-dose atorvastatin after stroke or transient ischemic attack. N. Engl. J. Med. 355, 549559 (2006).
  128. Jones, A. R. & Shusta, E. V. in Therapeutic Monoclonal Antibodies: From Bench to Clinic (ed. An, Z.) 483502 (John Wiley & Sons, 2009).
  129. McGuinness, B. et al. Statins for the treatment of dementia. Cochrane Database of Systematic Reviews, Issue 8, Art. No.: CD007514. http://dx.doi.org/10.1002/14651858.CD007514.pub2.
  130. McGuinness, B. et al. Cochrane review on 'Statins for the treatment of dementia'. Int. J. Geriatr. Psychiatry 28, 119126 (2013).
  131. Heikkila, P., Kahri, A. I., Ehnholm, C. & Kovanen, P. T. The effect of low- and high-density lipoprotein cholesterol on steroid hormone production and ACTH-induced differentiation of rat adrenocortical cells in primary culture. Cell Tissue Res. 256, 487494 (1989).
  132. Heikkila, P., Kahri, A. I., Kovanen, P. T. & Ehnholm, C. Effects of mevinolin, an inhibitor of cholesterol synthesis, on the morphology and function of differentiating and differentiated rat adrenocortical cells in primary culture. Cell Tissue Res. 261, 125132 (1990).
  133. Roubtsova, A. et al. Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. Arterioscler. Thromb. Vasc. Biol. 31, 785791 (2011).
  134. Mbikay, M. et al. PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett. 584, 701706 (2010).
  135. Labonte, P. et al. PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression. Hepatology 50, 1724 (2009).
  136. Ranheim, T. et al. Genome-wide expression analysis of cells expressing gain of function mutant D374Y-PCSK9. J. Cell. Physiol. 217, 459467 (2008).
  137. Lan, H. et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects gene expression pathways beyond cholesterol metabolism in liver cells. J. Cell. Physiol. 224, 273281 (2010).

Download references

Author information

Affiliations

  1. Sections of Cardiovascular Research and Cardiology, Department of Medicine, Baylor College of Medicine, 6565 Fannin Street, MS A601, Houston, TX 77030, USA.

    • Razvan T. Dadu &
    • Christie M. Ballantyne

Contributions

Both authors researched data for the article, discussed its content, wrote the manuscript, and reviewed/edited the article before submission.

Competing interests statement

C.M.B. is a consultant for: Abbott, Aegerion, Amarin, Amgen, Arena, Cerenis, Esperion, Genentech, Genzyme, Kowa, Merck, Novartis, Omthera, Pfizer, Regeneron, Resverlogix, Roche, and Sanofi-Synthelabo; and a member of the speakers' bureau for Abbott. C.M.B.'s institution has received grants or research support from: Abbott, Amarin, Amgen, Eli Lilly, Genentech, GlaxoSmithKline, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi-Synthelabo, and Takeda, and from the AHA and the NIH. R.T.D. declares no competing interests.

Corresponding author

Correspondence to:

Author details

  • Razvan T. Dadu

    Razvan T. Dadu MD, PhD is currently a cardiology fellow at Baylor College of Medicine, TX, USA. He received his Doctor of Medicine and Doctor of Philosophy degrees from Iuliu Hatieganu University of Medicine and Pharmacy in Romania. His PhD project was developed in collaboration with Yale University in CT, USA. After his internal medicine residency, Dr Dadu completed a Lipid and Atherosclerosis fellowship at Baylor College of Medicine. During the fellowship, his research was focused on atherosclerosis and biomarkers in cardiovascular disease and was conducted under the mentorship of Dr Christie Ballantyne. Dr Dadu is certified in clinical lipidology.

  • Christie M. Ballantyne

    Christie M. Ballantyne MD is director of the Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center; chief of the sections of Cardiovascular Research and Cardiology, Department of Medicine, Baylor College of Medicine; director of the Maria and Alando J. Ballantyne, MD, Atherosclerosis Laboratory; Professor of Medicine, Molecular and Human Genetics, and Molecular Physiology and Biophysics, with a joint appointment in Pediatrics, Baylor College of Medicine; and co-director of the Lipid Metabolism and Atherosclerosis Clinic, Houston Methodist Hospital, Houston, TX, USA. He received his Doctor of Medicine from Baylor College of Medicine, and his postgraduate training included an internal medicine residency at the University of Texas Southwestern Medical School, a cardiology fellowship at Baylor College of Medicine, and an American Heart Association Fellowship at the Institute for Molecular Genetics at Baylor. Dr Ballantyne's research interests include preventive cardiology, lipids, metabolic syndrome, atherosclerosis, genetics, and coronary artery disease.

Additional data