Lipid Lowering with PCSK9 Inhibitors

Overview

Journal Nat Rev Cardiol

Specialty Cardiology & Vascular Diseases

Date 2014 Jun 25

PMID 24958078

Citations 87

Authors

Razvan T Dadu

Christie M Ballantyne

Affiliations

Soon will be listed here.

Abstract

Statins are the most-effective therapy currently available for lowering the LDL-cholesterol (LDL-C) level and preventing cardiovascular events. Additional therapies are necessary for patients who cannot reach the target LDL-C level when taking the maximum-tolerated dose of a statin. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme with an important role in lipoprotein metabolism. Rare gain-of-function mutations in PCSK9 lead to a high LDL-C level and premature coronary heart disease, whereas loss-of-function variants lead to a low LDL-C level and a reduced incidence of coronary heart disease. Furthermore, the PCSK9 level is increased with statin therapy through negative feedback, which promotes LDL-receptor degradation and decreases the efficacy of LDL-C lowering with statins. PCSK9 inhibition is, therefore, a rational therapeutic target, and several approaches are being pursued. In phase I, II, and III trials, inhibition of PCSK9 with monoclonal antibodies has produced an additional 50-60% decrease in the LDL-C level when used in combination with statin therapy, compared with statin monotherapy. In short-term trials, PCSK9 inhibitors were well tolerated and had a low incidence of adverse effects. Ongoing phase III trials will provide information about the long-term safety of these drugs, and their efficacy in preventing cardiovascular events.

Citing Articles

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References

Agarwal S, Avery C, Ballantyne C, Catellier D, Nambi V, Saunders J . Sources of variability in measurements of cardiac troponin T in a community-based sample: the atherosclerosis risk in communities study. Clin Chem. 2011; 57(6):891-7. PMC: 4928588. DOI: 10.1373/clinchem.2010.159350. View

Cariou B, Ouguerram K, Zair Y, Guerois R, Langhi C, Kourimate S . PCSK9 dominant negative mutant results in increased LDL catabolic rate and familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol. 2009; 29(12):2191-7. DOI: 10.1161/ATVBAHA.109.194191. View

Humphries S, Whittall R, Hubbart C, Maplebeck S, Cooper J, Soutar A . 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(12):943-9. PMC: 2563208. DOI: 10.1136/jmg.2006.038356. View

Genser B, Marz W . Low density lipoprotein cholesterol, statins and cardiovascular events: a meta-analysis. Clin Res Cardiol. 2006; 95(8):393-404. DOI: 10.1007/s00392-006-0403-x. View

Frank-Kamenetsky M, Grefhorst A, Anderson N, Racie T, Bramlage B, Akinc A . Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci U S A. 2008; 105(33):11915-20. PMC: 2575310. DOI: 10.1073/pnas.0805434105. View

Poirier S, Mayer G, Benjannet S, Bergeron E, Marcinkiewicz J, Nassoury N . The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J Biol Chem. 2007; 283(4):2363-72. DOI: 10.1074/jbc.M708098200. View

Koren M, Lundqvist P, Bolognese M, Neutel J, Monsalvo M, Yang J . Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014; 63(23):2531-2540. DOI: 10.1016/j.jacc.2014.03.018. View

Zhang L, McCabe T, Condra J, Ni Y, Peterson L, Wang W . An anti-PCSK9 antibody reduces LDL-cholesterol on top of a statin and suppresses hepatocyte SREBP-regulated genes. Int J Biol Sci. 2012; 8(3):310-27. PMC: 3282994. DOI: 10.7150/ijbs.3524. View

Graham M, Lemonidis K, Whipple C, Subramaniam A, Monia B, Crooke S . Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J Lipid Res. 2007; 48(4):763-7. DOI: 10.1194/jlr.C600025-JLR200. View

10.

Labonte P, Begley S, Guevin C, Asselin M, Nassoury N, Mayer G . PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression. Hepatology. 2009; 50(1):17-24. DOI: 10.1002/hep.22911. View

11.

Zhao Z, Tuakli-Wosornu Y, Lagace T, Kinch L, Grishin N, Horton J . Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet. 2006; 79(3):514-23. PMC: 1559532. DOI: 10.1086/507488. View

12.

Rashid S, Curtis D, Garuti R, Anderson N, Bashmakov Y, Ho Y . Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci U S A. 2005; 102(15):5374-9. PMC: 556275. DOI: 10.1073/pnas.0501652102. View

13.

Scharnagl H, Nauck M, Wieland H, Marz W . The Friedewald formula underestimates LDL cholesterol at low concentrations. Clin Chem Lab Med. 2001; 39(5):426-31. DOI: 10.1515/CCLM.2001.068. View

14.

Sibal L, Neely R, Jones A, Home P . Friedewald equation underestimates low-density lipoprotein cholesterol at low concentrations in young people with and without Type 1 diabetes. Diabet Med. 2010; 27(1):37-45. DOI: 10.1111/j.1464-5491.2009.02888.x. View

15.

Martin S, Blaha M, Elshazly M, Brinton E, Toth P, McEvoy J . Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J Am Coll Cardiol. 2013; 62(8):732-9. DOI: 10.1016/j.jacc.2013.01.079. View

16.

Fasano T, Cefalu A, Di Leo E, Noto D, Pollaccia D, Bocchi L . A novel loss of function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol. Arterioscler Thromb Vasc Biol. 2006; 27(3):677-81. DOI: 10.1161/01.ATV.0000255311.26383.2f. View

17.

Pasternak R, Smith Jr S, Bairey-Merz C, Grundy S, Cleeman J, Lenfant C . ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002; 40(3):567-72. DOI: 10.1016/s0735-1097(02)02030-2. View

18.

Zaid A, Roubtsova A, Essalmani R, Marcinkiewicz J, Chamberland A, Hamelin J . Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. Hepatology. 2008; 48(2):646-54. DOI: 10.1002/hep.22354. View

19.

Preiss D, Seshasai S, Welsh P, Murphy S, Ho J, Waters D . Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011; 305(24):2556-64. DOI: 10.1001/jama.2011.860. View

20.

Brautbar A, Ballantyne C . Pharmacological strategies for lowering LDL cholesterol: statins and beyond. Nat Rev Cardiol. 2011; 8(5):253-65. DOI: 10.1038/nrcardio.2011.2. View