Skip to main content

Advertisement

SpringerLink
Log in

PCSK9 Inhibitors: Treating the Right Patients in Daily Practice

  • Lipid Abnormalities and Cardiovascular Prevention (G De Backer, Section Editor)
  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) have emerged as a novel approach to low-density lipoprotein cholesterol (LDL-C) lowering. The potential role of PCSK9 inhibitors in clinical practice will be reviewed.

Recent Findings

Clinical trials have demonstrated that PCSK9 inhibitors produce robust LDL-C lowering when administered either as monotherapy or in combination with statins. This provides the opportunity to achieve effective lipid lowering in familial hypercholesterolemia, patients with either established atherosclerotic cardiovascular disease or high risk primary prevention and an important opportunity to treat patients with statin intolerance. The findings from plaque imaging and patients with established atherosclerotic cardiovascular disease suggest that PCSK9 inhibition has favorable outcomes beyond improving lipid profiles, which has the opportunity to expand their use.

Summary

PCSK9 inhibitors represent a new approach to achieving effective cardiovascular risk reduction in a broader number of patients. How these agents will be taken up in clinical practice remains to be determined.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–81. doi:10.1016/s0140-6736(10)61350-5.

    Article  CAS  PubMed  Google Scholar 

  2. Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci U S A. 2004;101(18):7100–5. doi:10.1073/pnas.0402133101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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(2):161–5. doi:10.1038/ng1509.

    Article  CAS  PubMed  Google Scholar 

  4. Careskey HE, Davis RA, Alborn WE, Troutt JS, Cao G, Konrad RJ. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J Lipid Res. 2008;49(2):394–8. doi:10.1194/jlr.M700437-JLR200.

    Article  CAS  PubMed  Google Scholar 

  5. Lambert G, Ancellin N, Charlton F, Comas D, Pilot J, Keech A, et al. Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment. Clin Chem. 2008;54(6):1038–45. doi:10.1373/clinchem.2007.099747.

    Article  CAS  PubMed  Google Scholar 

  6. Nilsson LM, Abrahamsson A, Sahlin S, Gustafsson U, Angelin B, Parini P, et al. Bile acids and lipoprotein metabolism: effects of cholestyramine and chenodeoxycholic acid on human hepatic mRNA expression. Biochem Biophys Res Commun. 2007;357(3):707–11. doi:10.1016/j.bbrc.2007.03.196.

    Article  CAS  PubMed  Google Scholar 

  7. Troutt JS, Alborn WE, Cao G, Konrad RJ. Fenofibrate treatment increases human serum proprotein convertase subtilisin kexin type 9 levels. J Lipid Res. 2010;51(2):345–51. doi:10.1194/jlr.M000620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chan JC, Piper DE, Cao Q, Liu D, King C, Wang W, et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci U S A. 2009;106(24):9820–5. doi:10.1073/pnas.0903849106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, et al. 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. doi:10.1093/eurheartj/ehv370.

    PubMed  PubMed Central  Google Scholar 

  10. Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):331–40. doi:10.1016/s0140-6736(14)61399-4.

    Article  CAS  PubMed  Google Scholar 

  11. Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):341–50. doi:10.1016/s0140-6736(14)61374-x.

    Article  CAS  PubMed  Google Scholar 

  12. Ahmad Z. Statin intolerance. Am J Cardiol. 2014;113(10):1765–71. doi:10.1016/j.amjcard.2014.02.033.

    Article  CAS  PubMed  Google Scholar 

  13. Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, et al. 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):758–69. doi:10.1016/j.jacl.2015.08.006.

    Article  PubMed  Google Scholar 

  14. Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF, 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(23):2541–8. doi:10.1016/j.jacc.2014.03.019.

    Article  CAS  PubMed  Google Scholar 

  15. •• Nissen SE, Dent-Acosta RE, Rosenson RS, Stroes E, Sattar N, Preiss D, et al. Comparison of PCSK9 inhibitor evolocumab vs ezetimibe in statin-intolerant patients: design of the goal achievement after utilizing an anti-PCSK9 antibody in statin-intolerant subjects 3 (GAUSS-3) Trial. Clin Cardiol. 2016;39(3):137–44. doi:10.1002/clc.22518. This study provides evidence that a PCSK9 inhibitor produces greater LDL-C lowering than do ezetimibe in a statin-intolerant population, with no difference between groups regarding muscle symptoms.

    Article  PubMed  Google Scholar 

  16. •• Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA. 2016;316(22):2373–84. doi:10.1001/jama.2016.16951. This study demonstrated that PCSK9 inhibitor use is associated with significant regression of coronary atherosclerosis and plaque regression on intravascular ultrasound imaging.

    Article  CAS  PubMed  Google Scholar 

  17. •• Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017; doi:10.1056/NEJMoa1615664. This study provides evidence that use of a PCSK9 inhibitor in patients with a history of myocardial infarction, ischemic stroke, or peripheral arterial disease saw not only a reduction in LDL-C but reduction in composite endpoint cardiovascular death, myocardial infarction, and stroke.

  18. Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017; doi:10.1056/NEJMoa1701488.

  19. Ridker PM, Tardif JC, Amarenco P, Duggan W, Glynn RJ, Jukema JW, et al. Lipid-reduction variability and antidrug-antibody formation with bococizumab. N Engl J Med. 2017; doi:10.1056/NEJMoa1614062.

  20. Schwartz GG, Bessac L, Berdan LG, Bhatt DL, Bittner V, Diaz R, 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(5):682–9. doi:10.1016/j.ahj.2014.07.028.

    Article  CAS  PubMed  Google Scholar 

  21. Giugliano RP, Mach F, Zavitz K, Kurtz C, Schneider J, Wang H, et al. Design and rationale of the EBBINGHAUS trial: a phase 3, double-blind, placebo-controlled, multicenter study to assess the effect of evolocumab on cognitive function in patients with clinically evident cardiovascular disease and receiving statin background lipid-lowering therapy—a cognitive study of patients enrolled in the FOURIER trial. Clin Cardiol. 2017;40(2):59–65. doi:10.1002/clc.22678.

    Article  PubMed  Google Scholar 

  22. Giugliano RP, Desai NR, Kohli P, Rogers WJ, Somaratne R, Huang F 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(9858):2007-17. doi:10.1016/s0140-6736(12)61770-x.

  23. Koren MJ, Scott R, Kim JB, Knusel B, Liu T, Lei L 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(9858):1995-2006. doi:10.1016/s0140-6736(12)61771-1.

  24. Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, Gebski V 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(23):2497-506. doi:10.1001/jama.2012.25790.

  25. 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(19):2113-20. doi:10.1161/circulationaha.113.004678.

  26. Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM et al. Low-density lipoprotein cholesterollowering 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):2408-17. doi:10.1161/circulationaha.112.144055.

  27. 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(20):1891-900. doi:10.1056/NEJMoa1201832.

  28. Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R 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(9836):29-36. doi:10.1016/s0140-6736(12)60771-5.

  29. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, 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(25):2344-53. doi:10.1016/j.jacc.2012.03.007.

  30. Koren MJ, Lundqvist P, Bolognese M, Neutel JM, Monsalvo ML, Yang J et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2531-40. doi:10.1016/j.jacc.2014.03.018.

  31. Koren MJ, Giugliano RP, Raal FJ, Sullivan D, Bolognese M, Langslet G 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(2):234-43. doi:10.1161/circulationaha.113.007012.

  32. Robinson JG, Nedergaard BS, Rogers WJ, Fialkow J, Neutel JM, Ramstad D 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(18):1870-82. doi:10.1001/jama.2014.4030.

  33. Blom DJ, Djedjos CS, Monsalvo ML, Bridges I, Wasserman SM, Scott R et al. Effects of evolocumab on vitamin E and steroid hormone levels: results from the 52-week, phase 3, double-blind, randomized, placebo-controlled DESCARTES study. Circ Res. 2015;117(8):731-41. doi:10.1161/circresaha.115.307071.

  34. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489-99. doi:10.1056/NEJMoa1501031.

  35. Stroes E, Guyton JR, Lepor N, Civeira F, Gaudet D, Watts GF et al. 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). doi:10.1161/jaha.116.003421.

  36. Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R 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. doi:10.1093/eurheartj/ehv028.

  37. Kastelein JJ, Robinson JG, Farnier M, Krempf M, Langslet G, Lorenzato C 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(3):281-9. doi:10.1007/s10557-014-6523-z.

  38. Roth EM, Taskinen MR, Ginsberg HN, Kastelein JJ, Colhoun HM, Robinson JG 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(1):55-61. doi:10.1016/j.ijcard.2014.06.049.

Download references

Author information

Authors and Affiliations

  1. South Australian Health and Medical Research Institute, University of Adelaide, PO Box 11060, Adelaide, SA, 5001, Australia

    Peta King & Stephen J. Nicholls

Authors
  1. Peta King
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen J. Nicholls
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen J. Nicholls.

Ethics declarations

Conflict of Interest

Peta King declares that she has no conflict of interest.

Stephen J. Nicholls reports grants from AstraZeneca, Amgen, Eli Lilly, Cerenis, Novartis, Resverlogix, Anthera, LipoScience, InfraReDx, and Sanofi-Regeneron and personal fees from AstraZeneca, Amgen, Boehringer Ingelheim, CSL Behring, Eli Lilly, Novartis, Merck, Takeda, Roche, Pfizer, and Sanofi-Regeneron.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Lipid Abnormalities and Cardiovascular Prevention

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

King, P., Nicholls, S.J. PCSK9 Inhibitors: Treating the Right Patients in Daily Practice. Curr Cardiol Rep 19, 66 (2017). https://doi.org/10.1007/s11886-017-0882-6

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11886-017-0882-6

Keywords

Search

Navigation