Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and Its Inhibitors: a Review of Physiology, Biology, and Clinical Data

Abstract

Atherosclerotic cardiovascular disease (ASCVD) remains the number one killer in the western world. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and ezetimibe has been shown to reduce the risk of cardiovascular events. Now, proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mabs) are available for high-risk individuals with ASCVD or familial hypercholesterolemia on maximally tolerated statin therapy but requiring greater LDL-C reduction. PCSK9 mab outcome trial results from the Further Cardiovascular Outcomes Research with PCSK9 Inhibitions in Subjects with Elevated Risk (FOURIER) study, which was presented at the American College of Cardiology in March 2017, which demonstrated a decrease of 15% in primary and 20% secondary end points over a 2-year period [1••]. These results firmly demonstrated additional benefit beyond maximally tolerated statin therapy in high-risk individuals. Thus, management of LDL-C will soon become more complex, as a new class of medication is added to our standard armamentarium. This review explores the discovery of PCSK9, its biology and physiology, and the development of the PCSK9 mabs.

Effect of varying quantities of lean beef as part of a Mediterranean-style dietary pattern on lipids and lipoproteins: a randomized crossover controlled feeding trial

“…When compared with the AAD control diet only the MED0.5 and MED2.5 elicited greater reductions in total LDL particle number and large LDL particle number. With lower PCSK9 concentrations being associated with greater removal of LDL particles from circulation ( 20 ) it is possible that the reduction in PCSK9 could have contributed to the decrease in LDL particle number. Although it remains unclear why PCSK9 was reduced to a greater magnitude relative to baseline with the MED0.5, despite a similar reduction in LDL particle number by the MED2.5, a nonsignificant downward trend in PCSK9 in the MED2.5 was observed.…”

Sometimes they come back: endocytosis provides localization dynamics of a subtilase in cells committed to cell death

“…A related and instructive example is provided by the animal subtilisin-like protease PCSK9. Upon binding of PCSK9 to the complex formed by the low-density lipoprotein receptor and its low-density lipoprotein cholesterol ligand, the ternary complex is stabilized, internalized through a clathrin-mediated endocytic pathway, and transported for lysosomal degradation of all three constituents (Nassoury et al , 2007; Durairaj et al , 2017). However, for phytaspases this destructive scenario seems unlikely for (at least) two reasons.…”

What is new in lipid‐lowering therapies in diabetes?

“…PCSK9 binds to the LDL : LDL-receptor-complex, marking the LDL receptor for degradation and so preventing receptor re-cycling. 16 PCSK9 inhibition increases LDL-receptor number and clearance of LDL from the circulation. 16 Evolocumab and alirocumab are fully human monoclonal antibodies that inhibit PCSK9.…”

“…16 PCSK9 inhibition increases LDL-receptor number and clearance of LDL from the circulation. 16 Evolocumab and alirocumab are fully human monoclonal antibodies that inhibit PCSK9. Evolocumab is currently the only PCSK9 inhibitor available in Australia on the Pharmaceutical Benefits Scheme (PBS).…”

“…Normally, the LDL : LDL‐receptor‐complex is internalised, the LDL is degraded enzymatically, and the receptor is recycled to the cell surface. PCSK9 binds to the LDL : LDL‐receptor‐complex, marking the LDL receptor for degradation and so preventing receptor re‐cycling . PCSK9 inhibition increases LDL‐receptor number and clearance of LDL from the circulation …”