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PCSK9 Inhibition: Current Concepts and Lessons from Human Genetics

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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.

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Conflict of Interest

Fatima Rodriguez and Joshua W. Knowles declare that they have no conflict of interest.

Dr. Knowles is the volunteer Chief Medical Officer for the FH Foundation a patient led, 501c-3 nonprofit organization founded and led by patients with familial hypercholesterolemia. The FH Foundation receives support from several of the companies making PCSK9 inhibitors.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Rodriguez, F., Knowles, J.W. PCSK9 Inhibition: Current Concepts and Lessons from Human Genetics. Curr Atheroscler Rep 17, 7 (2015). https://doi.org/10.1007/s11883-015-0487-8

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