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

Abstract

Introduction: PCSK9 has been widely studied as a target for lipid-lowering as its inhibition increases LDL-R 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, the heart, and in immune cells. This 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.