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PCSK9 Inhibition: Discovery, Current Evidence, and Potential Effects on LDL-C and Lp(a)

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Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that binds to low-density lipoprotein receptors (LDL-Rs), leading to their accelerated degradation and increased low-density lipoprotein cholesterol (LDL-C) levels. Therefore, PCSK9 levels play a critical role in cholesterol metabolism by reducing LDL-R levels and thus increasing levels of plasma LDL-C. Recently, investigational agents inhibiting PCSK9 have been shown to lower LDL-C and also, potentially, an important secondary target, lipoprotein(a). Therefore, several pharmaceutical companies have initiated drug-development programs that target PCSK9 and are built on a solid foundation of basic science, genetic studies, and epidemiological observations. PCSK9 inhibition with monoclonal antibodies demonstrated LDL-C lowering of up to 57 % when the PCSK9 antibodies are used as monotherapy and up to 73 % when added to background lipid-lowering therapy. In addition, long-term cardiovascular outcome studies are currently under way to confirm the longer term safety and efficacy of PCSK9 inhibitors and to determine whether PCSK9 inhibition lowers the incidence of major cardiovascular events. PCSK9 inhibitors may provide safe and effective lipid-lowering therapy, especially for patients with inadequate LDL-C lowering on lipid-lowering treatments, those who are statin intolerant or have contraindications to statin therapy, and those with hereditary hypercholesterolemia/familial hypercholesterolemia and severely elevated LDL-C.

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References

  1. Anderson KM, Castelli WP, Levy D. Cholesterol and mortality. 30 years of follow-up from the Framingham study. J Am Med Assoc. 1987;257:2176–80.

    Article  CAS  Google Scholar 

  2. Stamler J, Stamler R, Neaton JD, et al. Low risk-factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy: findings for 5 large cohorts of young adult and middle-aged men and women. JAMA. 1999;282:2012–8.

    Article  CAS  PubMed  Google Scholar 

  3. Kavey R-EW, Daniels SR, Lauer RM, Atkins DL, Hayman LL, Taubert K. American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Circulation. 2003;107:1562–6.

    Article  PubMed  Google Scholar 

  4. Pagidipati NJ, Gaziano TA. Estimating deaths from cardiovascular disease: a review of global methodologies of mortality measurement. Circulation. 2013;127:749–56.

    Article  PubMed Central  PubMed  Google Scholar 

  5. LaRosa JC. Reduction of serum LDL-C levels: a relationship to clinical benefits. Am J Cardiovasc Drugs. 2003;3:271–81.

    Article  CAS  PubMed  Google Scholar 

  6. Forrester JS, Bairey-Merz CN, Kaul S. The aggressive low density lipoprotein lowering controversy. J Am Coll Cardiol. 2000;36:1419–25.

    Article  CAS  PubMed  Google Scholar 

  7. 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;380:581–90.

    Article  Google Scholar 

  8. Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29:431–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Willeit P, Kiechl S, Kronenberg F, et al. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck study. J Am Coll Cardiol. 2014;64:851–60.

    Article  PubMed  Google Scholar 

  10. Nordestgaard BG, Chapman MJ, Ray K, for European Atherosclerosis Society Consensus Panel, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31:2844–53.

  11. Rader DJ, Kastelein JJP. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation. 2014;129:1022–32.

    Article  PubMed  Google Scholar 

  12. Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci. 2007;32:71–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A. 2003;100:928–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Seidah NG, Awan Z, Chrétien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res. 2014;114:1022–36.

    Article  CAS  PubMed  Google Scholar 

  15. Catapano AL, Papadopoulos N. The safety of therapeutic monoclonal antibodies: implications for cardiovascular disease and targeting the PCSK9 pathway. Atherosclerosis. 2013;228:18–28.

    Article  CAS  PubMed  Google Scholar 

  16. Abifadel M, Varret M, Rabès J-P, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–6.

    Article  CAS  PubMed  Google Scholar 

  17. Abifadel M, Rabès J-P, Devillers M, et al. Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum Mutat. 2009;30:520–9.

    Article  CAS  PubMed  Google Scholar 

  18. Humphries SE, Whittall RA, Hubbart CS, for Simon Broome Familial Hyperlipidaemia Register Group and Scientific Steering Committee, 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. 2006;43:943–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Naoumova RP, Tosi I, Patel D, et al. 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;25:2654–60.

    Article  CAS  PubMed  Google Scholar 

  20. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37:161–5.

    Article  CAS  PubMed  Google Scholar 

  21. Cohen JC, Boerwinkle E, Mosley Jr TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–72.

    Article  CAS  PubMed  Google Scholar 

  22. Cohen JC. Emerging LDL, therapies: using human genetics to discover new therapeutic targets for plasma lipids. J Clin Lipidol. 2013;7:S1–5.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet. 2006;79:514–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. European Association for Cardiovascular Prevention & Rehabilitation. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769–818.

    Article  Google Scholar 

  25. O’Keefe Jr JH, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004;43:2142–6.

    Article  PubMed  Google Scholar 

  26. Stone NJ, Robinson JG, Lichtenstein AH, 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. Circulation. 2014;129:S1–S45.

    Article  PubMed  Google Scholar 

  27. Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2004;24:1454–9.

    Article  CAS  PubMed  Google Scholar 

  28. ATP III. Final report. VI: Drug therapy. Circulation. 2002;106:3303–25.

  29. Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol. 2014;64:485–94.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Ben-Yehuda O, DeMaria AN. LDL-cholesterol targets after the ACC/AHA 2013 guidelines: evidence that lower is better? J Am Coll Cardiol. 2014;64:495–7.

    Article  PubMed  Google Scholar 

  31. Dragan S, Serban M-C, Banach M. Proprotein convertase subtilisin/kexin 9 inhibitors: an emerging lipid-lowering therapy? J Cardiovasc Pharmacol Ther. 2015;20:157–68.

  32. Blom DJ, Hala T, Bolognese M, for DESCARTES Investigators, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370:1809–19.

    Article  CAS  PubMed  Google Scholar 

  33. Giugliano RP, Desai NR, Kohli P, for LAPLACE-TIMI 57 Investigators, 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. 2012;380:2007–17.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Koren MJ, Giugliano RP, Raal FJ, for OSLER Investigators, et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation. 2014;129:234–43.

    Article  CAS  PubMed  Google Scholar 

  35. Koren MJ, Lundqvist P, Bolognese M, for MENDEL-2 Investigators, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2531–40.

    Article  CAS  PubMed  Google Scholar 

  36. Koren MJ, Scott R, Kim JB, 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. 2012;380:1995–2006.

    Article  CAS  PubMed  Google Scholar 

  37. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand A-C, Stein EA. 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;59:2344–53.

    Article  CAS  PubMed  Google Scholar 

  38. Raal F, Scott R, Somaratne R, 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. 2012;126:2408–17.

    Article  CAS  PubMed  Google Scholar 

  39. Robinson JG, Nedergaard BS, Rogers WJ, for LAPLACE-2 Investigators, et al. 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;311:1870–82.

    Article  PubMed  Google Scholar 

  40. Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012;367:1891–900.

    Article  CAS  PubMed  Google Scholar 

  41. Stein EA, Bergeron J, Gaudet D, et al. One year open-label treatment with alirocumab 150 mg every two weeks in heterozygous familial hypercholesterolemic patients [abstract]. J Am Coll Cardiol. 2014;63:A1371.

    Article  Google Scholar 

  42. Stein EA, Gipe D, Bergeron J, 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. 2012;380:29–36.

    Article  CAS  PubMed  Google Scholar 

  43. Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation. 2013;128:2113–20.

    Article  CAS  PubMed  Google Scholar 

  44. Stroes E, Colquhoun D, Sullivan D, for GAUSS-2 Investigators, 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. 2014;63:2541–8.

    Article  CAS  PubMed  Google Scholar 

  45. Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012;308:2497–506.

    Article  CAS  PubMed  Google Scholar 

  46. Moriarty PM, Jacobson TA, Bruckert E, et al. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: Design and rationale of ODYSSEY ALTERNATIVE, a randomized Phase 3 trial. J Clin Lipidol. 2014;8:554–61.

    Article  PubMed  Google Scholar 

  47. Colhoun HM, Robinson JG, Farnier M, et al. 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;14:121.

    Article  PubMed Central  PubMed  Google Scholar 

  48. Robinson JG, Colhoun HM, Bays HE, et al. Efficacy and safety of alirocumab as add-on therapy in high-cardiovascular-risk patients with hypercholesterolemia not adequately controlled with atorvastatin (20 or 40 mg) or rosuvastatin (10 or 20 mg): design and rationale of the ODYSSEY OPTIONS studies. Clin Cardiol. 2014;37:597–604.

    Article  PubMed Central  PubMed  Google Scholar 

  49. Sabatine MS, Giugliano RP, Wiviott SD, for Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500–9.

  50. Cannon CP, Cariou B, Blom D, for the ODYSSEY COMBO II Investigators, et al. 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):1186–94.

  51. Robinson JG, Farnier M, Krempf M, for ODYSSEY LONG TERM Investigators, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–99.

  52. Roth EM, Taskinen M-R, Ginsberg HN, et al. 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;176:55–61.

    Article  PubMed  Google Scholar 

  53. Farnier M. PCSK9: from discovery to therapeutic applications. Arch Cardiovasc Dis. 2014;107:58–66.

    Article  PubMed  Google Scholar 

  54. Sahebkar A, Watts GF. New LDL-cholesterol lowering therapies: pharmacology, clinical trials, and relevance to acute coronary syndromes. Clin Ther. 2013;35:1082–98.

    Article  CAS  PubMed  Google Scholar 

  55. Robinson J, Farnier M, Chaudhari U, et al. Adverse events in patients with low-density lipoprotein cholesterol levels <25 or <15 mg/dL on at least two consecutive visits in fourteen randomized, controlled, clinical trials of alirocumab [abstract]. J Am Coll Cardiol. 2015;65:A1350.

    Article  Google Scholar 

  56. Kereiakes DJ, Robinson JG, Cannon CP, et al. 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):906–15.

  57. Bays H, Farnier M, Gaudet D, et al. Efficacy and safety of combining alirocumab with atorvastatin or rosuvastatin versus statin intensification or adding ezetimibe in high cardiovascular risk patients: ODYSSEY OPTIONS I and II [abstract]. Circulation. 2014;130:2118–9.

    Google Scholar 

  58. Kastelein JJP, Robinson JG, Farnier M, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovasc Drugs Ther. 2014;28:281–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia on maximally tolerated doses of statins: the ODYSSEY COMBO I study [abstract]. Circulation. 2014;130:2119–20.

    Google Scholar 

  60. Moriarty PM, Thompson PD, Cannon CP, et al. ODYSSEY ALTERNATIVE: efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody, alirocumab, versus ezetimibe, in patients with statin intolerance as defined by a placebo run-in and statin rechallenge arm [abstract]. Circulation. 2014;130:2108–9.

    Google Scholar 

  61. Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY Outcomes trial. Am Heart J. 2014;168:682–9.

    Article  CAS  PubMed  Google Scholar 

  62. Ginsberg HN, Rader DJ, Raal FJ, et al. ODYSSEY HIGH FH: efficacy and safety of alirocumab in patients with severe heterozygous familial hypercholesterolemia [abstract]. Circulation. 2014;130:2119.

    Google Scholar 

  63. Jones PH, Bays H, Chaudhari U, et al. Pooled safety and adverse events in nine randomized, placebo-controlled, phase 2 and 3 clinical trials of alirocumab [abstract]. J Am Coll Cardiol. 2015;65:A1363.

    Article  Google Scholar 

  64. Raal FJ, Honarpour N, Blom DJ, for TESLA Investigators, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:341–50.

  65. Raal FJ, Stein EA, Dufour R, for RUTHEFORD-2 Investigators, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:331–40.

  66. Desai NR, Giugliano RP, Zhou J, et al. AMG 145, a monoclonal antibody against PCSK9, facilitates achievement of national cholesterol education program–adult treatment panel III low-density lipoprotein cholesterol goals among high-risk patients: an analysis from the LAPLACE-TIMI 57 trial (LDL-C Assessment with PCSK9 monoclonaL Antibody Inhibition Combined With Statin thErapy–Thrombolysis In Myocardial infarction 57). J Am Coll Cardiol. 2014;63:430–3.

    Article  CAS  PubMed  Google Scholar 

  67. Kohli P, Desai NR, Giugliano RP, et al. Design and rationale of the LAPLACE-TIMI 57 trial: a phase II, double-blind, placebo-controlled study of the efficacy and tolerability of a monoclonal antibody inhibitor of PCSK9 in subjects with hypercholesterolemia on background statin therapy. Clin Cardiol. 2012;35:385–91.

    Article  PubMed Central  PubMed  Google Scholar 

  68. Koren M, Rosenson R, Khan B, et al. LDL cholesterol reduction in elderly patients with the pcsk9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of 1779 patients in phase 2, 3 and open label extension studies [abstract]. J Am Coll Cardiol. 2015;65:A1366.

    Article  Google Scholar 

  69. Toth PP, Sattar N, Genest J, et al. A comprehensive safety analysis of 6026 patients from phase 2 and 3 short and long term clinical trials with evolocumab (AMG 145) [abstract]. J Am Coll Cardiol. 2015;65:A1351.

    Article  Google Scholar 

  70. Ballantyne CM, Neutel J, Cropp A, et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am J Cardiol. 2015;115:1212–21.

  71. Alonso R, Andres E, Mata N, for SAFEHEART Investigators, et al. Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation. J Am Coll Cardiol. 2014;63:1982–9.

    Article  CAS  PubMed  Google Scholar 

  72. Emerging Risk Factors Collaboration. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302:412–23.

    Article  Google Scholar 

  73. Kamstrup PR, Tybjærg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301:2331–9.

  74. Deo RC, Wilson JG, Xing C, et al. Single-nucleotide polymorphisms in LPA explain most of the ancestry-specific variation in Lp(a) levels in African Americans. PLoS One. 2011;6:e14581.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Enkhmaa B, Anuurad E, Zhang W, Berglund L. Significant associations between lipoprotein(a) and corrected apolipoprotein B-100 levels in African-Americans. Atherosclerosis. 2014;235:223–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Virani SS, Brautbar A, Davis BC, et al. Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2012;125:241–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Gaudet D, Kereiakes DJ, McKenney JM, et al. 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;114:711–5.

    Article  CAS  PubMed  Google Scholar 

  78. Raal FJ, Giugliano RP, Sabatine MS, et al. 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;63:1278–88.

    Article  CAS  PubMed  Google Scholar 

  79. HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203–12.

    Article  Google Scholar 

  80. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, 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. 2014;383:60–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Stein EA, Kasichayanula S, Turner T, et al. LDL cholesterol reduction with BMS-962476, an adnectin inhibitor of PCSK9: results of a single ascending dose study [abstract]. J Am Coll Cardiol. 2014;63:A1372.

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Acknowledgments

Editorial support for this manuscript was provided by MicroMass Communications, Inc, with funding from Regeneron Pharmaceuticals, Inc, Tarrytown, NY, and Sanofi US, Bridgewater, NJ.

Sources of support

Support for this educational article was provided by Regeneron Pharmaceuticals, Inc, and Sanofi US.

Conflict of interest

KCF is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, and Sanofi US. SAN has nothing to disclose.

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  1. Tulane Heart and Vascular Institute, Tulane University School of Medicine, 1430 Tulane Avenue, #8548, New Orleans, LA, 70112, USA

    Keith C. Ferdinand

  2. Department of Clinical Research and Leadership, School of Medicine and Health Sciences, The George Washington University, Washington, DC, 20037, USA

    Samar A. Nasser

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Ferdinand, K.C., Nasser, S.A. PCSK9 Inhibition: Discovery, Current Evidence, and Potential Effects on LDL-C and Lp(a). Cardiovasc Drugs Ther 29, 295–308 (2015). https://doi.org/10.1007/s10557-015-6588-3

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