Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Lipid lowering with PCSK9 inhibitors

Key Points

  • Although statins are the primary drug therapy for high LDL-cholesterol (LDL-C) level, statins are inadequate for many individuals because of limitations in tolerability or efficacy

  • Proprotein convertase subtilisin/kexin type 9 (PCSK9), an important enzyme in lipid metabolism, is a promising therapeutic target to lower the LDL-C level

  • Phase II trials of inhibition with anti-PCSK9 antibodies have shown promising lipid-lowering effects and short-term tolerability

  • Phase III trials of PCSK9 inhibitors are providing evidence on the benefit of additional LDL-C lowering in high-risk patients whose LDL-C level remains elevated despite statin therapy

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: LDL-cholesterol metabolism in the presence or absence of PCSK9.
Figure 2: Ongoing phase III clinical trials of PCSK9 inhibitors.

Similar content being viewed by others

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, 891–897 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 1302–1309 (2012).

    Article  CAS  PubMed  Google Scholar 

  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, 337–345 (2011).

    Article  PubMed  Google Scholar 

  4. Genser, B. & Marz, W. Low density lipoprotein cholesterol, statins and cardiovascular events: a meta-analysis. Clin. Res. Cardiol. 95, 393–404 (2006).

    Article  CAS  PubMed  Google Scholar 

  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, 1267–1278 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Cannon, C. P. et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med. 350, 1495–1504 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Avis, H. J. et al. Efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia. J. Am. Coll. Cardiol. 55, 1121–1126 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Toth, P. P., Harper, C. R. & Jacobson, T. A. Clinical characterization and molecular mechanisms of statin myopathy. Expert Rev. Cardiovasc. Ther. 6, 955–969 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Preiss, D. et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 305, 2556–2564 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Preiss, D. & Sattar, N. Statins and the risk of new-onset diabetes: a review of recent evidence. Curr. Opin. Lipidol. 22, 460–466 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154–156 (2003).

    Article  CAS  PubMed  Google Scholar 

  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, 520–529 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Maxwell, K. N. & Breslow, J. L. Proprotein convertase subtilisin kexin 9: the third locus implicated in autosomal dominant hypercholesterolemia. Curr. Opin. Lipidol. 16, 167–172 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Jensen, H. K. The molecular genetic basis and diagnosis of familial hypercholesterolemia in Denmark. Dan. Med. Bull. 49, 318–345 (2002).

    CAS  PubMed  Google Scholar 

  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, 943–949 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 203–214 (2006).

    Article  CAS  Google Scholar 

  17. Cariou, B. et al. PCSK9 dominant negative mutant results in increased LDL catabolic rate and familial hypobetalipoproteinemia. Arterioscler. Thromb. Vasc. Biol. 29, 2191–2197 (2009).

    Article  CAS  PubMed  Google Scholar 

  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, 677–681 (2007).

    Article  CAS  PubMed  Google Scholar 

  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, 1264–1272 (2006).

    Article  CAS  PubMed  Google Scholar 

  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, 2833–2842 (2010).

    Article  CAS  PubMed  Google Scholar 

  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, 445–448 (2007).

    Article  CAS  PubMed  Google Scholar 

  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, 514–523 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 289–290 (2003).

    Article  PubMed  Google Scholar 

  24. Brown, M. S. & Goldstein, J. L. Biomedicine: lowering LDL—not only how low, but how long? Science 311, 1721–1723 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Folsom, A. R., Peacock, J. M. & Boerwinkle, E. Variation in PCSK9, low LDL cholesterol, and risk of peripheral arterial disease. Atherosclerosis 202, 211–215 (2009).

    Article  CAS  PubMed  Google Scholar 

  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, 354–361 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Horton, J. D., Cohen, J. C. & Hobbs, H. H. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem. Sci. 32, 71–77 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 1611–1619 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Brown, W. V., Breslow, J. & Ballantyne, C. Clinical use of genetic typing in human lipid disorders. J. Clin. Lipidol. 6, 199–207 (2012).

    Article  PubMed  Google Scholar 

  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, 48865–48875 (2004).

    Article  CAS  PubMed  Google Scholar 

  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, 646–654 (2008).

    Article  CAS  PubMed  Google Scholar 

  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, 2666–2672 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Cui, Q. et al. Serum PCSK9 is associated with multiple metabolic factors in a large Han Chinese population. Atherosclerosis 213, 632–636 (2010).

    Article  CAS  PubMed  Google Scholar 

  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, 928–933 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cunningham, D. et al. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat. Struct. Mol. Biol. 14, 413–419 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Cariou, B., Le May, C. & Costet, P. Clinical aspects of PCSK9. Atherosclerosis 216, 258–265 (2011).

    Article  CAS  PubMed  Google Scholar 

  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, 835–843 (2011).

    Article  CAS  PubMed  Google Scholar 

  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, 2995–3005 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 634–640 (2008).

    Article  CAS  PubMed  Google Scholar 

  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, 18602–18612 (2007).

    Article  CAS  PubMed  Google Scholar 

  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, 2363–2372 (2008).

    Article  CAS  PubMed  Google Scholar 

  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, 2069–2074 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rashid, S. et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc. Natl Acad. Sci. USA 102, 5374–5379 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Alborn, W. E. et al. Serum proprotein convertase subtilisin kexin type 9 is correlated directly with serum LDL cholesterol. Clin. Chem. 53, 1814–1819 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Careskey, H. E. et al. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J. Lipid Res. 49, 394–398 (2008).

    Article  CAS  PubMed  Google Scholar 

  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, 2714–2721 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 11041–11048 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 1454–1459 (2004).

    Article  CAS  PubMed  Google Scholar 

  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, 11235–11240 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 1094–1100 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Brautbar, A. & Ballantyne, C. M. Pharmacological strategies for lowering LDL cholesterol: statins and beyond. Nat. Rev. Cardiol. 8, 253–265 (2011).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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, 763–767 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Lindholm, M. W. et al. PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates. Mol. Ther. 20, 376–381 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Do, R. Q., Vogel, R. A. & Schwartz, G. G. PCSK9 inhibitors: potential in cardiovascular therapeutics. Curr. Cardiol. Rep. 15, 345 (2013).

    Article  PubMed  Google Scholar 

  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, 11915–11920 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Stein, E. A. & Swergold, G. D. Potential of proprotein convertase subtilisin/kexin type 9 based therapeutics. Curr. Atheroscler. Rep. 15, 310 (2013).

    Article  PubMed  CAS  Google Scholar 

  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, 9820–9825 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 2776–2799 (2012).

    Article  Google Scholar 

  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, 310–327 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 78–86 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 60–68 (2014).

  64. Stein, E. A. et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med. 366, 1108–1118 (2012).

    Article  CAS  PubMed  Google Scholar 

  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, 1888–1898 (2012).

    Article  CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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, 2344–2353 (2012).

    Article  CAS  PubMed  Google Scholar 

  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, 1891–1900 (2012).

    Article  CAS  PubMed  Google Scholar 

  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, 29–36 (2012).

    Article  CAS  PubMed  Google Scholar 

  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, 2007–2017 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 1995–2006 (2012).

    Article  CAS  PubMed  Google Scholar 

  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, 2408–2417 (2012).

    Article  CAS  PubMed  Google Scholar 

  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, 2497–2506 (2012).

    Article  CAS  PubMed  Google Scholar 

  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, 962–969 (2013).

    Article  CAS  PubMed  Google Scholar 

  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, 1809–1819 (2014).

    Article  CAS  PubMed  Google Scholar 

  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, 567–572 (2002).

    Article  PubMed  Google Scholar 

  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, 1221–1229 (2013).

    Article  CAS  PubMed  Google Scholar 

  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, 1666–1675 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. Martin, S. S. et al. Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J. Am. Coll. Cardiol. 62, 732–739 (2013).

    Article  CAS  PubMed  Google Scholar 

  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, 37–45 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. Scharnagl, H., Nauck, M., Wieland, H. & Marz, W. The Friedewald formula underestimates LDL cholesterol at low concentrations. Clin. Chem. Lab. Med. 39, 426–431 (2001).

    Article  CAS  PubMed  Google Scholar 

  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, 2149–2156 (2012).

    Article  CAS  PubMed  Google Scholar 

  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, 1829–1839 (2007).

    Article  PubMed  CAS  Google Scholar 

  127. Amarenco, P. et al. High-dose atorvastatin after stroke or transient ischemic attack. N. Engl. J. Med. 355, 549–559 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Jones, A. R. & Shusta, E. V. in Therapeutic Monoclonal Antibodies: From Bench to Clinic (ed. An, Z.) 483–502 (John Wiley & Sons, 2009).

    Book  Google Scholar 

  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, 119–126 (2013).

    Article  PubMed  Google Scholar 

  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, 487–494 (1989).

    Article  CAS  PubMed  Google Scholar 

  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, 125–132 (1990).

    Article  CAS  PubMed  Google Scholar 

  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, 785–791 (2011).

    Article  CAS  PubMed  Google Scholar 

  134. Mbikay, M. et al. PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett. 584, 701–706 (2010).

    Article  CAS  PubMed  Google Scholar 

  135. Labonte, P. et al. PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression. Hepatology 50, 17–24 (2009).

    Article  CAS  PubMed  Google Scholar 

  136. Ranheim, T. et al. Genome-wide expression analysis of cells expressing gain of function mutant D374Y-PCSK9. J. Cell. Physiol. 217, 459–467 (2008).

    Article  CAS  PubMed  Google Scholar 

  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, 273–281 (2010).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

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

Corresponding author

Correspondence to Christie M. Ballantyne.

Ethics declarations

Competing interests

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.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dadu, R., Ballantyne, C. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol 11, 563–575 (2014). https://doi.org/10.1038/nrcardio.2014.84

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrcardio.2014.84

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing