Targeting PCSK9 beyond the liver: evidence from experimental and clinical studies

Introduction: PCSK9 has been widely studied as a target for lipid-lowering as its inhibition increases
LDLR recycling on the surface of hepatocytes, which promotes the catabolism of LDL particles. PCSK9
can be synthesized in extra-hepatic tissues, including in the brain, the pancreas, and the heart, and in
immune cells. It is of interest to understand whether the extra-hepatic effects observed when PCSK9 is
genetically inhibited by naturally occurring mutations are also recapitulated by pharmacology.
Area covered: Genetics studies reported an increased risk of developing new-onset diabetes, ectopic
adiposity, and reduced immune-inflammatory responses with PCSK9 deficiency. However, these aspects
were not observed in clinical trials and data from real-world medicine with monoclonal antibodies
(mAbs) and gene silencing approaches targeting PCSK9.
Expert opinion: It is possible that the biological adaptations occurring when PCSK9 is inhibited
lifelong, as in the case of genetic studies, could explain the discrepancy with the data obtained by
clinical studies testing the pharmacological inhibition of PCSK9. Also, PCSK9 mAbs have been in use for
12 years; thus, probably, in this time window, a pharmacological reduction of circulating PCSK9 up to
80–90% does not lead to changes other than the impressive reduction in LDL-C and in CVD events.