title: PCSK9 inhibition: current concepts and lessons from human genetics.
abstract: Low-density lipoprotein cholesterol (LDL-C) plays a central role in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Statins are the cornerstone of therapy for the treatment of elevated LDL-C and for the primary and secondary prevention of ASCVD. However, some patients are intolerant of statins or are unable to achieve acceptable lipid levels on statin-based regimens alone. Proprotein convertase subtilisin/kexin type 9 (PCSK9) serves as an important regulator of hepatocyte LDL receptor expression and degradation, and recent genetic studies have highlighted the critical role of PCSK9 in human disease. Gain-of-function mutations in PCSK9 are associated with familial hypercholesterolemia, whereas loss-of-function mutations are protective against ASCVD. Therefore, PCSK9 inhibition offers a promising supplement or alternative to statin therapy in the reduction of LDL-C. Numerous phase II and III randomized control trials have demonstrated the tolerability of monoclonal antibodies against PCSK9 and their efficacy in lowering LDL-C by an additional 40-70 %. In this article, we review the growing role of PSCK9 inhibition in LDL-C reduction for diverse patient populations.
authors: Division of Cardiovascular Medicine, Stanford University, 300 Pasteur Dr, Stanford, CA, 94305, USA.
authors: Fatima
authors: F
authors: Rodriguez
authors: Joshua W
authors: JW
authors: Knowles
mesh_terms: D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000235:genetics*; D005826:Genetics, Medical; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
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