Unpacking and Understanding the Impact of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors on Apolipoprotein B Metabolism
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Articles, see p 338 and 352
In the relatively short time from first identification of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a potential therapeutic target to the imminent arrival of reports from large-scale outcome trials, there has been limited opportunity to explore the full impact of this regulatory protein on lipid and lipoprotein metabolism and to elucidate the detailed mechanism of action of PCSK9 inhibitors. On this occasion, genomics did deliver, with the characterization of gain-of-function and loss-of-function variants leading to clinically understandable phenotypes associated with altered risk of cardiovascular disease.1,2 When morbidity and mortality trials report in the next year or so, it will be important to understand which patients benefit most from this therapy and how PCSK9 inhibitors sit alongside other drugs such as statins and ezetimibe in their actions on the entire spectrum of atherogenic apolipoprotein B (apoB)–containing lipoproteins.
Animal- and cell-based investigations have given signposts as to how these antibody-based drugs work, but it is essential to consider the limitations of extrapolating from these to the clinical situation. With the production by the liver of particles across the entire very-low-density lipoprotein (VLDL)–intermediate-density lipoprotein (IDL)–low-density lipoprotein (LDL) spectrum and the generation of large quantities of circulating LDL via the action of intravascular lipases and transfer proteins, it is recognized that human lipoprotein metabolism is so distinctive that there is no good animal model that reliably reflects the intricacies of the metabolic pathways in humans. Hence, there is no substitute for time-consuming and technically demanding in vivo kinetic studies of the type reported in the current issue of Circulation by Watts et al3 and Reyes-Soffer et al.4 Model systems have revealed that PCSK9, in addition to its key role in regulating cell surface LDL receptor abundance,1,2 potentially influences the …