Targeting pro-protein convertase subtilisin kexin-9 as a novel therapy of hypercholesterolemia

  • Bambang Dwiputra Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Indonesia - National Cardiovascular Center Harapan Kita, Jakarta
  • Anwar Santoso Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Indonesia - National Cardiovascular Center Harapan Kita, Jakarta
  • Kian K. Poh Department of Cardiology, National University Heart Centre
Keywords: low density lipoprotein, PCSK-9 inhibitor, pro-protein convertase subtilisin kexin-9
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Abstract

Reducing low density lipoprotein (LDL) cholesterol level is an established primary and secondary prevention strategy for coronary heart disease. However, not all patients are able to achieve their LDL targets as recommended by the guidelines. Over the last 10 years, high plasma LDL level is known to be associated with a higher level of pro-protein convertase subtilisin kexin-9 (PCSK-9). Loss-of-function mutations in the PCSK-9 gene is associated with lower plasma LDL level and cardiovascular risk. Since its discovery in 2003, PCSK-9 has triggered many researchers to design a PCSK-9 inhibitor to reduce LDL cholesterol through competitive inhibition of this molecule. Some phase III clinical trials have showed promising results of PCSK-9 inhibitor efficacy in lowering LDL level and improving clinical outcome. This article aims to discuss the role of PCSK-9 in LDL metabolism and the efficacy of PCSK-9 inhibitor in reducing plasma LDL level.

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Author Biographies

Bambang Dwiputra, Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Indonesia - National Cardiovascular Center Harapan Kita, Jakarta
Department of Cardiology and Vascular Medicine, Faculty of Medicine Universitas Indonesia, National Cardiovascular center Harapan Kita Jakarta
Anwar Santoso, Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Indonesia - National Cardiovascular Center Harapan Kita, Jakarta
Department of Cardiology and Vascular Medicine, Faculty of Medicine Universitas Indonesia, National Cardiovascular center Harapan Kita Jakarta

References

  1. Kim HS, Wu Y, Lin SJ, Deerochanawong C, Zambahari R, Zhao L, et al. Current status of cholesterol goal attainment after statin therapy among patients with hypercholesterolemia in asian countries and region: The return on expenditure achieved for lipid therapy in asia (reality-asia) study. Curr Med Res Opin. 2008;24(7):1951-63. https://doi.org/10.1185/03007990802138731

  2. Cohen JC, Boerwinkle E, Mosley TH, Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-72. https://doi.org/10.1056/NEJMoa054013

  3. Gu HM, Zhang DW. Hypercholesterolemia, low density lipoprotein receptor and proprotein convertase subtilisin/kexin-type 9. J Biomed Res. 2015;29(5):356-61. DOI: 10.7555/JBR.29.20150067

  4. Schulz R, Schluter KD, Laufs U. Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9). Basic Res Cardiol. 2015;110(2):4. https://doi.org/10.1007/s00395-015-0463-z

  5. Urban D, Poss J, Bohm M, Laufs U. Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. J Am Coll Cardiol. 2013;62(16):1401-8. https://doi.org/10.1016/j.jacc.2013.07.056

  6. Lagace TA, Curtis DE, Garuti R, McNutt MC, Park SW, Prather HB, 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. https://doi.org/10.1172/JCI29383

  7. Moriarty PM, Jacobson TA, Bruckert E, Thompson PD, Guyton JR, Baccara-Dinet MT, 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(6):554-61. https://doi.org/10.1016/j.jacl.2014.09.007

  8. Roth EM, McKenney JM. Odyssey mono: Effect of alirocumab 75 mg subcutaneously every 2 weeks as monotherapy versus ezetimibe over 24 weeks. Future Cardiol. 2015;11(1):27-37. https://doi.org/10.2217/fca.14.82

  9. Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, 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. https://doi.org/10.1016/j.ahj.2015.03.004

  10. 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;36:1186-94. https://doi.org/10.1093/eurheartj/ehv028

  11. 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. https://doi.org/10.1016/j.jacc.2014.03.018

  12. 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;311:1870-82. https://doi.org/10.1001/jama.2014.4030

  13. 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;117:731-41. https://doi.org/10.1161/CIRCRESAHA.115.307071

  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. https://doi.org/10.1016/j.jacc.2014.03.019

  15. 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. https://doi.org/10.1016/S0140-6736(14)61399-4

Published
2017-08-18
How to Cite
1.
Dwiputra B, Santoso A, Poh KK. Targeting pro-protein convertase subtilisin kexin-9 as a novel therapy of hypercholesterolemia. Med J Indones [Internet]. 2017Aug.18 [cited 2024Oct.10];26(2):152-7. Available from: https://mji.ui.ac.id/journal/index.php/mji/article/view/1443
Section
Review Article