Evolocumab: Considerations for the Management of Hyperlipidemia

  • Barbara S. Wiggins
  • Jeffrey Senfield
  • Helina Kassahun
  • Armando Lira
  • Ransi Somaratne
Statin Drugs (B. Wiggins, Section Editor)
  • 290 Downloads
Part of the following topical collections:
  1. Topical Collection on Statin Drugs

Abstract

Purpose of Review

To review the efficacy, safety, pharmacology, and pharmacokinetics of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.

Recent Findings

PCSK9 inhibitors are a class of lipid-lowering agents that significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in patients with atherosclerotic cardiovascular disease and hyperlipidemia. Evolocumab is a monoclonal antibody that inhibits PCSK9 and has been evaluated in phase II and III studies as monotherapy, in combination with statins and other lipid-lowering therapies, in patients who are statin intolerant, and in patients with heterozygous and homozygous familial hypercholesterolemia. Data from these studies show that evolocumab significantly reduces LDL-C levels. Treatment with evolocumab also significantly improves levels of other lipid parameters (e.g., apolipoproteins A1 and B, lipoprotein(a), non–high-density lipoprotein cholesterol, and triglycerides). Recent results indicate that LDL-C reduction with evolocumab significantly reduces the risk of cardiovascular events and is also associated with atherosclerotic plaque regression. From a safety standpoint, rates of adverse events (AEs), serious AEs, and AEs leading to discontinuation were similar between evolocumab and controls in clinical trials, and no increase in AEs was observed when evolocumab was used in combination with statins.

Summary

Patients with elevated LDL-C benefit from evolocumab treatment, suggesting that evolocumab could help meet an unmet medical need in high-risk patient populations with atherosclerotic cardiovascular disease and hyperlipidemia that are unable to reduce LDL-C levels sufficiently with statin therapy alone.

Keywords

Low-density lipoprotein cholesterol PCSK9 Statins Evolocumab 

Notes

Acknowledgments

The authors acknowledge Meghan Johnson, PhD, of Complete Healthcare Communications, LLC, whose work was funded by Amgen, and Annalise M. Nawrocki, PhD, of Amgen Inc., for writing and editorial assistance.

Compliance with Ethical Standards

Conflict of Interest

Barbara S. Wiggins has served as a consultant for Amgen Inc. Helina Kassahun, Armando Lira, and Ransi Somaratne are employees of Amgen Inc. and hold Amgen stock and/or stock options. Ransi Somaratne is an inventor on at least one pending patent application owned by Amgen Inc. relating to evolocumab. Jeffrey Senfield declares no conflict of interest.

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.

References

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

  1. 1.
    Centers for Disease Control and Prevention. Vital signs: prevalence, treatment, and control of high levels of low-density lipoprotein cholesterol—United States, 1999-2002 and 2005-2008. MMWR Morb Mortal Wkly Rep. 2011;60(4):109–14.Google Scholar
  2. 2.
    Cholesterol Treatment Trialists Collaboration, Baigent C, Blackwell L, 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.CrossRefGoogle Scholar
  3. 3.
    Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–97.CrossRefPubMedGoogle Scholar
  4. 4.
    Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP). Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA. 2001;285(19):2486–97.CrossRefGoogle Scholar
  5. 5.
    Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the national cholesterol education program adult treatment panel III guidelines. Circulation. 2004;110(2):227–39.CrossRefPubMedGoogle Scholar
  6. 6.
    •• 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. J Am Coll Cardiol. 2014;63(25 Pt B):2889–934. Current guidelines for the management of patients with and at risk for atherosclerotic cardiovascular disease CrossRefPubMedGoogle Scholar
  7. 7.
    Baigent C, Keech A, Kearney PM, 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. 2005;366(9493):1267–78.CrossRefPubMedGoogle Scholar
  8. 8.
    Sirvent P, Mercier J, Lacampagne A. New insights into mechanisms of statin-associated myotoxicity. Curr Opin Pharmacol. 2008;8(3):333–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Hirsh BJ, Smilowitz NR, Rosenson RS, Fuster V, Sperling LS. Utilization of and adherence to guideline-recommended lipid-lowering therapy after acute coronary syndrome: opportunities for improvement. J Am Coll Cardiol. 2015;66(2):184–92.CrossRefPubMedGoogle Scholar
  10. 10.
    Stein E, Stender S, Mata P, et al. Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin. Am Heart J. 2004;148(3):447–55.CrossRefPubMedGoogle Scholar
  11. 11.
    Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29(4):431–8.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Steinberg D, Witztum JL. Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels. Proc Natl Acad Sci U S A. 2009;106(24):9546–7.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lagace TA, Curtis DE, Garuti R, et al. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest. 2006;116(11):2995–3005.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Zhang DW, Lagace TA, Garuti R, 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. 2007;282(25):18602–12.CrossRefPubMedGoogle Scholar
  15. 15.
    Lopez D. PCSK9: an enigmatic protease. Biochim Biophys Acta. 2008;1781(4):184–91.CrossRefPubMedGoogle Scholar
  16. 16.
    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(3):514–23.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    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(8):1454–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Chan JC, Piper DE, Cao Q, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Foltz IN, Karow M, Wasserman SM. Evolution and emergence of therapeutic monoclonal antibodies: what cardiologists need to know. Circulation. 2013;127(22):2222–30.CrossRefPubMedGoogle Scholar
  20. 20.
    Repatha® (evolocumab) prescribing information. Thousand Oaks, CA: Amgen, Inc.; 2017.Google Scholar
  21. 21.
    European Medicines Agency. Repatha® (evolocumab). Summary of product characteristics. Thousand Oaks, CA: Amgen, Inc.; 2015.Google Scholar
  22. 22.
    Stein E, Wasserman S, Dias C, Scott R, Raal F. AMG145. Drug Future. 2013;38:451–9.CrossRefGoogle Scholar
  23. 23.
    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(9858):1995–2006.CrossRefPubMedGoogle Scholar
  24. 24.
    Giugliano RP, Desai NR, Kohli 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. 2012;380(9858):2007–17.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    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(23):2497–506.CrossRefPubMedGoogle Scholar
  26. 26.
    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(20):2408–17.CrossRefPubMedGoogle Scholar
  27. 27.
    Hirayama A, Honarpour N, Yoshida M, et al. Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk—primary results from the phase 2 YUKAWA study. Circ J. 2014;78(5):1073–82.CrossRefPubMedGoogle Scholar
  28. 28.
    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.CrossRefPubMedGoogle Scholar
  29. 29.
    Koren MJ, Giugliano RP, Raal FJ, 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.CrossRefPubMedGoogle Scholar
  30. 30.
    Desai NR, Kohli P, Giugliano RP, 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. 2013;128(9):962–9.Google Scholar
  31. 31.
    Koren MJ, Lundqvist P, Bolognese M, 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.CrossRefPubMedGoogle Scholar
  32. 32.
    Robinson JG, Nedergaard BS, Rogers WJ, 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.CrossRefPubMedGoogle Scholar
  33. 33.
    Kiyosue A, Honarpour N, Kurtz C, Xue A, Wasserman SM, Hirayama A. A phase 3 study of evolocumab (AMG 145) in statin-treated Japanese patients at high cardiovascular risk. Am J Cardiol. 2016;117(1):40–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370(19):1809–19.CrossRefPubMedGoogle Scholar
  35. 35.
    Stroes E, Colquhoun D, Sullivan D, 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.CrossRefPubMedGoogle Scholar
  36. 36.
    Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA. 2016;315(15):1580–90.CrossRefPubMedGoogle Scholar
  37. 37.
    Raal FJ, Honarpour N, Blom DJ, 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.CrossRefPubMedGoogle Scholar
  38. 38.
    • Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–22. First study to demonstrate a reduction in cardiovascular outcomes with the PCSK9 inhibitors. CrossRefPubMedGoogle Scholar
  39. 39.
    •• Nicholls SJ, Puri R, Anderson T, 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. First study to demonstrate plaque regression in patients treated with PCSK9 inhibitors already on chronic statin therapy. CrossRefPubMedGoogle Scholar
  40. 40.
    Raal FJ, Stein EA, Dufour R, 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.CrossRefPubMedGoogle Scholar
  41. 41.
    Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Sabatine MS, Giugliano RP, Keech A, et al. Rationale and design of the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk trial. Am Heart J. 2016;173:94–101.CrossRefPubMedGoogle Scholar
  43. 43.
    Bonaca MP, Nault P, Giugliano RP, et al Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk). Circulation; 2018;137(4):338–50.Google Scholar
  44. 44.
    Marcus FI, Baumgarten AJ, Fritz WL, Nolan PE Jr. Alternate-day dosing with statins. Am J Med. 2013;126(2):99–104.CrossRefPubMedGoogle Scholar
  45. 45.
    Rojas-Fernandez CH, Goldstein LB, Levey AI, Taylor BA, Bittner V, The National Lipid Association’s Safety Task Force. An assessment by the Statin Cognitive Safety Task Force: 2014 update. J Clin Lipidol. 2014;8(3 suppl):S5–16.Google Scholar
  46. 46.
    Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med. 2017;377(7):633–43.CrossRefPubMedGoogle Scholar
  47. 47.
    Blom DJ, Koren MJ, Roth E, et al. Evaluation of the efficacy, safety and glycaemic effects of evolocumab (AMG 145) in hypercholesterolaemic patients stratified by glycaemic status and metabolic syndrome. Diabetes Obes Metab. 2017;19(1):98–107.CrossRefPubMedGoogle Scholar
  48. 48.
    Sattar N, Preiss D, Robinson JG, et al. Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data. Lancet Diabetes Endocrinol. 2016;4(5):403–10.CrossRefPubMedGoogle Scholar
  49. 49.
    Sattar N, Toth PP, Blom DJ, et al. Effect of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on glycemia, body weight, and new-onset diabetes mellitus. Am J Cardiol. 2017;120(9):1521–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5(12):941–50.CrossRefPubMedGoogle Scholar
  51. 51.
    Koren MJ, Sabatine MS, Giugliano RP, et al. Long-term low-density lipoprotein cholesterol-lowering efficacy, persistence, and safety of evolocumab in treatment of hypercholesterolemia: results up to 4 years from the open-label OSLER-1 extension study. JAMA Cardiol. 2017;2(6):598–607.CrossRefPubMedGoogle Scholar
  52. 52.
    Hacquebard M, Carpentier YA. Vitamin E: absorption, plasma transport and cell uptake. Curr Opin Clin Nutr Metab Care. 2005;8(2):133–8.CrossRefPubMedGoogle Scholar
  53. 53.
    Qamar A, Bhatt DL. Effect of low cholesterol on steroid hormones and vitamin E levels: just a theory or real concern? Circ Res. 2015;117(8):662–4.CrossRefPubMedGoogle Scholar
  54. 54.
    Blom DJ, Djedjos CS, Monsalvo ML, 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.CrossRefPubMedGoogle Scholar
  55. 55.
    Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017;390(10106):1962–71.CrossRefPubMedGoogle Scholar
  56. 56.
    Lee E, Gibbs J, Wasserman SM, Block G, Emery MG, Abosaleem B, et al. Pharmacokinetics and pharmacodynamics of evolocumab in patients with renal impairment: P1710. European Heart J. 2016;37(suppl):343.Google Scholar
  57. 57.
    Bohula EA, Giugliano RP, Cannon CP, et al. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation. 2015;132(13):1224–33.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Barbara S. Wiggins
    • 1
  • Jeffrey Senfield
    • 2
  • Helina Kassahun
    • 3
  • Armando Lira
    • 3
  • Ransi Somaratne
    • 4
  1. 1.Department of Pharmaceutical Sciences, Pharmacy Clinical Specialist–CardiologyMedical University of South CarolinaCharlestonUSA
  2. 2.Clinical Cardiac ElectrophysiologistNovant Health Heart and Vascular InstituteCharlotteUS
  3. 3.Clinical Research Medical DirectorAmgen Inc.Thousand OaksUSA
  4. 4.Global Development Executive Medical DirectorAmgen Inc.Thousand OaksUSA

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