title: PCSK9 (Proprotein convertase subtilisin/kexin type 9) inhibitors: past, present, and the future.
abstract: Reduction in low-density lipoprotein cholesterol (LDL-C), mainly with statins, has decreased the risk of cardiovascular events over the last few decades. However, there are several patient populations that warrant further decrease in LDL-C by additional cholesterol-lowering therapy other than statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a new class of drugs that have been shown to further decrease LDL-C by 50-70% when administered as a monotherapy or on a background therapy with statins. Proprotein convertase subtilisin/kexin type 9 inhibitors are also an excellent example of drug development in which discovery of gene mutations and its clinical effects have rapidly progressed into successful preclinical and clinical studies with multiple Phases 1-3 clinical trials completed or ongoing to date. This review summarizes the rapid evolution of the drug from genetic discovery to identification of targets for the drugs, to animal and human testing, and to large clinical outcomes trials, followed by discussion on foreseeable challenges of PCSK9 inhibitors.
authors.affiliation: Harvard Clinical Research Institute, Boston, MA, USA Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA yshimada@partners.org.
authors.forename: Yuichi J
authors.initials: YJ
authors.lastname: Shimada
authors.affiliation: Harvard Clinical Research Institute, Boston, MA, USA Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D008078:Cholesterol, LDL / Q000187:drug effects; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000188:drug therapy*; D009154:Mutation / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: Cardiovascular disease; Hypercholesterolaemia; Low-density lipoprotein cholesterol; Proprotein convertase subtilisin/kexin type 9 inhibitors