Clinical trials have unequivocally shown that inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) efficaciously and safely prevents cardiovascular events by lowering levels of LDL cholesterol. PCSK9 in the circulation is derived mainly from the liver, but the protein is also expressed in the pancreas, the kidney, the intestine and the central nervous system. Although PCSK9 modulates cholesterol metabolism by regulating LDL receptor expression in the liver, in vitro and in vivo studies have suggested that PCSK9 is involved in various other physiological processes. Although therapeutic PCSK9 inhibition could theoretically have undesired effects by interfering with these non-cholesterol-related processes, studies of individuals with genetically determined reduced PCSK9 function and clinical trials of PCSK9 inhibitors have not revealed clinically meaningful adverse consequences of almost completely eradicating PCSK9 from the circulation. The clinical implications of PCSK9 functions beyond lipid metabolism in terms of wanted or unwanted effects of therapeutic PCSK9 inhibition therefore appear to be limited. The objective of this Review is to describe the physiological role of PCSK9 beyond the LDL receptor to provide a rational basis for monitoring the effects of PCSK9 inhibition as these drugs gain traction in the clinic.
PCSK9 is expressed in several tissues other than the liver, including the pancreas, the kidney, the intestine and the brain.
Although PCSK9 might be involved in various pathophysiological and physiological processes in different organ systems, the clinical implications for therapeutic PCSK9 inhibition seem to be limited.
Clinical trials of PCSK9 inhibitors and studies of individuals with genetically determined reduced PCSK9 activity have provided reassurance regarding the safety of therapeutic PCSK9 inhibition.
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The authors are supported by grants from the Fondation LEDUCQ (13CVD03) to B.C. and by the French national project CHOPIN (Cholesterol Personalized Innovation) to B.C. and G.L., which was granted by the Agence Nationale de la Recherche (ANR-16-RHUS-0007) and coordinated by the Centre hospitalier universitaire de Nantes. G.K.H. is holder of a Vidi grant (016.156.445) from the Netherlands Organisation for Scientific Research (NWO), and is supported by a grant from the European Union (TransCard: FP7-603091-2).
Nature Reviews Endocrinology thanks N. Seidah and other anonymous reviewers for their contribution to the peer review of this work.
G.L. has received research funding, honoraria and consulting fees from Affiris, Amgen, Pfizer, Regeneron and Sanofi. B.C. has received research funding from Pfizer, Regeneron and Sanofi and honoraria from Amgen, Merck Sharpe & Dohme (Merck & Co.), Regeneron and Sanofi. G.K.H.’s institution has received payment for conducting clinical trials from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Ionis Pharmaceuticals, Kowa, Pfizer, Regeneron, Roche, Sanofi and Synageva and for lectures and/or advisory panel participation from Amgen, Pfizer, Roche and Sanofi. R.M.S. declares no competing interests.
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