Inhibiting PCSK9 — biology beyond LDL control. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Stoekenbroek, Robert; Lambert, Gilles; Cariou, Bertrand; Hovingh, G.
• Is Part Of: Nature reviews. Volume 15:Issue 1(2019)
• Page Start: 52
• Page End: 62
• Publication Date: 2018-12
• Subjects: Endocrinology -- Periodicals; 616.4005
• DOI: 10.1038/s41574-018-0110-5
• Languages: English
• ISSNs: 1759-5029

Abstract

Abstract 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. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors prevent cardiovascular events by lowering levels of LDL cholesterol derived from the liver. However, PCSK9 is expressed in many other tissues, including the pancreas and central nervous system. This Review explores the functions of PCSK9 beyond the control of cholesterol levels. Key points 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.