PCSK9 inhibition in patients with hypercholesterolemia

Trends in Cardiovascular Medicine
Nihar R Desai, Marc S Sabatine

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that plays an important role in modulating low-density lipoprotein cholesterol (LDL-C) levels by targeting LDL-C receptors for lysosomal degradation. Genetic association studies have demonstrated that loss-of-function mutations in PCSK9 are associated with low plasma LDL-C levels and a reduction in the incidence of adverse cardiovascular events. Monoclonal antibodies directed against PCSK9 have been developed and have been shown in phase 1, 2, and 3 trials to dramatically reduce LDL-C regardless of background lipid-lowering therapy, including in clinically challenging populations such as patients intolerant to statin therapy and those with familial hypercholesterolemia. To date, the clinical trials have not raised any significant safety concerns, with no appreciable excess of myalgias, elevation in aminotransferases, or other adverse events. Large, cardiovascular outcomes trials are underway to assess definitively the efficacy and safety of 3 monoclonal antibodies (evolocumab, alirocumab, and bococizumab), while additional non-monoclonal antibody approaches to inhibit PCSK9 continue in the early-phase development.

References

May 6, 2003·Nature Genetics·Marianne AbifadelCatherine Boileau
Jan 29, 2005·Proceedings of the National Academy of Sciences of the United States of America·Kara N MaxwellJan L Breslow
Mar 24, 2006·The New England Journal of Medicine·Jonathan C CohenHelen H Hobbs
Jan 12, 2007·Trends in Biochemical Sciences·Jay D HortonHelen H Hobbs
Apr 24, 2007·Biochemical and Biophysical Research Communications·L-M NilssonC Einarsson
Nov 24, 2007·Journal of Lipid Research·Holly E CareskeyRobert J Konrad
Jan 17, 2008·Biochemistry·Daping FanSergio Fazio
Aug 13, 2008·Proceedings of the National Academy of Sciences of the United States of America·Maria Frank-KamenetskyKevin Fitzgerald
Aug 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Da-Wei ZhangHelen H Hobbs
Apr 9, 2009·The Journal of Clinical Endocrinology and Metabolism·Susan G LakoskiHelen H Hobbs
Jul 7, 2009·Drug Discovery Today·Laird Bloom, Valerie Calabro
Dec 15, 2010·The Journal of Biological Chemistry·Taichi YamamotoRobert O Ryan
Dec 30, 2011·The New England Journal of Medicine·Andrew W Artenstein, Steven M Opal
Jan 4, 2012·Nature Reviews. Drug Discovery·Sarah Crunkhorn
Apr 24, 2012·Protein and Peptide Letters·Ajoy BasakPriyambada Mishra
Sep 1, 2012·Revista clínica española·R Bailén Almorox
Nov 2, 2012·The New England Journal of Medicine·Eli M RothEvan A Stein
Oct 29, 2013·Annual Review of Pharmacology and Toxicology·Giuseppe Danilo NorataAlberico Luigi Catapano
Apr 1, 2014·The New England Journal of Medicine·Dirk J BlomUNKNOWN DESCARTES Investigators
Apr 3, 2014·Journal of the American College of Cardiology·Michael J KorenUNKNOWN MENDEL-2 Investigators
Apr 16, 2014·The Lancet. Diabetes & Endocrinology·Robert A HegeleUNKNOWN European Atherosclerosis Society Consensus Panel

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Citations

Nov 13, 2015·Expert Opinion on Pharmacotherapy·Maria-Corina SerbanDimitri P Mikhailidis
Dec 17, 2015·Clinical Pharmacology and Therapeutics·D M Roden, J C Denny
Jun 5, 2015·Circulation Journal : Official Journal of the Japanese Circulation Society·Elizabeth M McNally, Megan J Puckelwartz
May 21, 2015·Trends in Cardiovascular Medicine·James P Walsh
Apr 16, 2016·Future Cardiology·Peter P TothAndrew M Tershakovec
Jul 20, 2016·Circulation Journal : Official Journal of the Japanese Circulation Society·Sasha A SinghMasanori Aikawa
Aug 31, 2016·Annual Review of Pharmacology and Toxicology·Amy C BurkeMurray W Huff
Feb 17, 2017·International Journal of Molecular Medicine·Bin DongJingwen Liu
Feb 14, 2020·Endocrine, Metabolic & Immune Disorders Drug Targets·Frederick J RaalDirk J Blom

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