Hypolipidemic drugs inhibiting the proprotein convertase of subtilisin/kexin type 9 (PCSK9): monoclonal antibodies, antisense oligonucleotides, small interfering ribonucleic acids
- Authors: Chaulin A.M.1,2
-
Affiliations:
- Samara State Medical University
- Samara Regional Cardiology Dispensary
- Issue: Vol 19, No 1 (2021)
- Pages: 37-46
- Section: Original study articles
- Submitted: 14.05.2021
- Accepted: 14.05.2021
- Published: 21.05.2021
- URL: https://journals.eco-vector.com/RCF/article/view/70612
- DOI: https://doi.org/10.17816/RCF19137-46
- ID: 70612
Cite item
Abstract
Hypolipidemic therapy is one of the essential components for the management of patients with cardiovascular diseases (CVD). In this regard, the main task of modern research is to find new targets for creating additional effective groups of hypolipidemic drugs. In 2003, canadian and french research groups led by N. Seidah and M. Abifadel discovered a new enzyme – proprotein convertase subtilisin/kexin type 9 (PCSK9), which later turned out to play an important role in lipid metabolism. The main mechanism of action of PCSK9 is to regulate the density of low-density lipoprotein receptors (LDLR) in the cell membrane of hepatocytes. Increased activity of PCSK9 significantly accelerates the degradation of LDL and leads to an increase in the concentration of atherogenic classes of lipoproteins-low-density lipoproteins (LDL). In contrast, reduced PCSK9 activity is accompanied by a decrease in LDL concentrations and a reduced risk of developing atherosclerosis and CVD. The second of the recently discovered and less studied mechanism of PCSK9 protearogenic action is an increase in inflammatory processes in the atherosclerotic plaque. Given this adverse contribution of PCSK9 to the development and progression of atherosclerosis and CVD, the main task of the researchers was to develop drugs that inhibit THIS enzyme. To date, several new groups of drugs have been developed that target the stages of biosynthesis and the function of PCSK9. In this article, we will focus in detail on discussing the mechanisms of action and effectiveness of the following groups of hypolipidemic drugs: anti-PCSK9 monoclonal antibodies (alirocumab, evolocumab), small interfering ribonucleic acids (incliciran), and antisense nucleotides.
Full Text
About the authors
Aleksey M. Chaulin
Samara State Medical University; Samara Regional Cardiology Dispensary
Author for correspondence.
Email: alekseymichailovich22976@gmail.com
ORCID iD: 0000-0002-2712-0227
SPIN-code: 1107-0875
post-graduate student; MD, Doctor
Russian Federation, 89 Chapaevskaya str., Samara, 443099; SamaraReferences
- Chaulin AM, Grigorieva YV, Suvorova GN, Duplyakov DV. Methods of modeling of atherosclerosis in rabbits. Modern Problems of Science and Education. 2020;(5). (In Russ). Available from: http://www.science-education.ru/ru/article/view?id=30101. Cited: 2021 Feb 23.
- Chaulin AM, Karslyan LS, Grigoriyeva EV, et al. Clinical and Diagnostic Value of Cardiac Markers in Human Biological Fluids. Kardiologiia. 2019;59(11):66–75. (In Russ.) doi: 10.18087/cardio.2019.11.n414
- Chaulin AM, Duplyakov DV. Biomarkers of acute myocardial infarction: diagnostic and prognostic value. Part 1. Journal of Clinical Practice. 2020;11(3):75–84. (In Russ.) doi: 10.17816/clinpract34284
- Gasanov MZ, Batiushin MM, Terentev VP. Professor A.I. Ignatowski a founder of the theory of atherosclerosis. The Russian Archives of Internal Medicine. 2017;7(6):407–414. (In Russ.) doi: 10.20514/2226-6704-2017-7-6-407-414
- Kukharchuk VV. N.N. Anichkov (1885–1964). The Journal of Atherosclerosis and Dyslipidemias. 2010;1(1):58–60. (In Russ.)
- Susekov AV, Nikitin AE. The past and near future of statin therapy in Russia. Lechebnoye delo. 2018;(3):30–37. (In Russ.)
- Malay LN. Statins in the treatment and prevention of cardiovascular diseases: repetition of the past and optimism for the future. Rational Pharmacotherapy in Cardiology. 2014; 10(5):513–524. (In Russ). doi: 10.20996/1819-6446-2014-10-5-513-524
- Sergienko IV. The story of statins, The Journal of Atherosclerosis and Dyslipidemias. 2011;(1):57–66. (In Russ.)
- Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004;44(3): 720–732. doi: 10.1016/j.jacc.2004.07.001
- Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333(20):1301–1307. doi: 10.1056/NEJM199511163332001
- Haria M, McTavish D. Pravastatin. A reappraisal of its pharmacological properties and clinical effectiveness in the management of coronary heart disease. Drugs. 1997;53(2):299–336. doi: 10.2165/00003495-199753020-00008
- Ahsan F, Oliveri F, Goud HK, et al. Pleiotropic Effects of Statins in the Light of Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis. Cureus. 2020;12(9): e10446. doi: 10.7759/cureus.10446
- Turner RM, Pirmohamed M. Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components. J Clin Med. 2019;9(1):22. doi: 10.3390/jcm9010022
- Nguyen KA, Li L, Lu D, et al. A comprehensive review and meta-analysis of risk factors for statin-induced myopathy. Eur J Clin Pharmacol. 2018;74(9):1099–1109. doi: 10.1007/s00228-018-2482-9
- 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. USA. 2003;100(3):928–933. doi: 10.1073/pnas.0335507100
- Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 2003;34(2):154–156. doi: 10.1038/ng1161
- Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci USA. 2005;102(6): 2069–2074. doi: 10.1073/pnas.0409736102
- Tavori H, Fan D, Blakemore JL, et al. Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor: evidence for a reciprocal regulation. Circulation. 2013;127(24):2403–2413. doi: 10.1161/CIRCULATIONAHA.113.001592
- Abifadel M, Guerin M, Benjannet S, et al. Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia. Atherosclerosis. 2012;223(2):394–400. DOI: 10.1016/j. atherosclerosis.2012.04.006
- 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):1264–1272. doi: 10.1056/NEJMoa054013
- Scartezini M, Hubbart C, Whittall RA, et al. The PCSK9 gene R46L variant is associated with lower plasma lipid levels and cardiovascular risk in healthy U.K. men. Clin Sci (Lond). 2007;113(11):435–441. doi: 10.1042/CS20070150
- Chaulin AM, Duplyakov DV. PCSK-9: modern views about biological role and possibilities of use as a diagnostic marker for cardiovascular diseases. (Part 1). Cardiology: News, Opinions, Training. 2019;7(2):45–57. (In Russ.) doi: 10.24411/2309-1908-2019-12005
- Tóth Š, Fedačko J, Pekárová T, et al. Elevated Circulating PCSK9 Concentrations Predict Subclinical Atherosclerotic Changes in Low Risk Obese and Non-Obese Patients. Cardiol Ther. 2017;6(2): 281–289. doi: 10.1007/s40119-017-0092-8
- Chaulin AM, Duplyakov DV. PCSK-9: modern views about biological role and possibilities of use as a diagnostic marker for cardiovascular diseases. (Part 2). Cardiology: News, Opinions, Training. 2019;7(4):24–35. (In Russ.) doi: 10.24411/2309-1908-2019-14004
- Chaulin AM, Mazaev AYu, Aleksandrov AG. The role of proprotein convertase subtilisin/kexin of type 9 (PCSK-9) in cholesterol metabolism and new opportunities of lipid corrective therapy. International Research Journal. 2019. 4–1(82):124–126. (In Russ.) doi: 10.23670/IRJ.2019.82.4.025
- 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 USA. 2009;106(24):9820–9825. doi: 10.1073/pnas.0903849106
- Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489–1499. doi: 10.1056/NEJMoa1501031
- 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):1500–1509. doi: 10.1056/NEJMoa1500858
- Mayor S. PCSK9 inhibitors reduce cardiovascular events, preliminary data show. BMJ. 2015;350: h1508. DOI: 10.1136/ bmj.h1508
- Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults with Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med. 2015;163(1):40–51. doi: 10.7326/M14-2957
- Cainzos-Achirica M, Martin SS, Cornell JE, et al. PCSK9 Inhibitors: A New Era in Lipid-Lowering Treatment? Ann Intern Med. 2015;163(1):64–65. doi: 10.7326/M15-0920
- Schmidt AF, Pearce LS, Wilkins JT, et al. PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2017;4(4): CD011748. doi: 10.1002/14651858.CD011748.pub2
- Schmidt AF, Carter JL, Pearce LS, et al. PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2020;10: CD011748. doi: 10.1002/14651858.CD011748.pub3
- Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713–1722. doi: 10.1056/NEJMoa1615664
- Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097–2107. doi: 10.1056/NEJMoa1801174
- Farnier M, Colhoun HM, Sasiela WJ, et al. Long-term treatment adherence to the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in 6 ODYSSEY Phase III clinical studies with treatment duration of 1 to 2 years. J Clin Lipidol. 2017;11(4):986–997. doi: 10.1016/j.jacl.2017.05.016
- Arrieta A, Page TF, Veledar E, Nasir K. Economic Evaluation of PCSK9 Inhibitors in Reducing Cardiovascular Risk from Health System and Private Payer Perspectives. PLoS One. 2017;12(1): e0169761. doi: 10.1371/journal.pone.0169761
- Fire A, Xu S, Montgomery MK, Kostas SA, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391(6669):806–811. doi: 10.1038/35888
- webcitation.org [internet]. Fire AZ, Mello CC. The Nobel Prize in Physiology or Medicine 2006. URL: https://www.webcitation.org/61CfnnPLi?url=http://www.nobelprize.org/nobel_prizes/medicine/laureates/2006/adv.html Cited: 2021 Feb 21.
- Bernards R. Exploring the uses of RNAi – gene knockdown and the Nobel Prize. N Engl J Med. 2006;355(23):2391–2393. doi: 10.1056/NEJMp068242
- Carthew RW, Sontheimer EJ. Origins and Mechanisms of miRNAs and siRNAs. Cell. 2009;136(4):642–655. doi: 10.1016/j.cell.2009.01.035
- 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(9911): 60–68. doi: 10.1016/S0140-6736(13)61914-5
- Nair JK, Willoughby JL, Chan A, et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc. 2014;136(49):16958–16961. doi: 10.1021/ja505986a
- Khvorova A. Oligonucleotide Therapeutics – A New Class of Cholesterol-Lowering Drugs. N Engl J Med. 2017;376(1):4–7. doi: 10.1056/NEJMp1614154
- Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017;376(15):1430–1440. doi: 10.1056/NEJMoa1615758
- Ray KK, Stoekenbroek RM, Kallend D, et al. Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins: Prespecified Secondary End Points in ORION1. Circulation. 2018;138(13): 1304–1316. doi: 10.1161/CIRCULATIONAHA.118.034710
- Bennett CF, Swayze EE. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol. 2010;50:259–293. doi: 10.1146/annurev.pharmtox.010909.105654
- Graham MJ, Lemonidis KM, Whipple CP, et al. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J Lipid Res. 2007;48(4):763–767. doi: 10.1194/jlr.C600025-JLR200
- Gupta N, Fisker N, Asselin MC, et al. A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo. PLoS One. 2010;5(5): e10682. doi: 10.1371/journal.pone.0010682
- Lindholm MW, Elmén J, Fisker N, et al. PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates. Mol Ther. 2012;20(2):376–381. doi: 10.1038/mt.2011.260
- van Poelgeest EP, Hodges MR, Moerland M, et al. Antisense-mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9): a first-in-human randomized, placebo-controlled trial. Br J Clin Pharmacol. 2015;80(6):1350–1361. doi: 10.1111/bcp.12738
- van Poelgeest EP, Swart RM, Betjes MG, et al. Acute kidney injury during therapy with an antisense oligonucleotide directed against PCSK9. Am J Kidney Dis. 2013;62(4):796–800. doi: 10.1053/j.ajkd.2013.02.359