Update on PCSK9 therapies for the treatment of dyslipidemia

Abstract

The mechanistic role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in cholesterol metabolism has been well elucidated, and serves as an example of how genetics has informed modern drug development with the advent of PCSK9 inhibitors. PCSK9 is intimately involved in the hepatic regulation of the Low-density lipoprotein (LDL) receptor, which in turn plays a key role in the circulation of serum LDL. Monoclonal antibodies targeting PCSK9, which act by inhibiting PCSK9 thereby allowing for constitutively active LDL receptors, are now well established as an effective method for significant LDL lowering. Ongoing cardiovascular outcomes trials will hopefully highlight a concomitant and clinically meaningful reduction in adverse outcomes with their use. In the meantime, the PCSK9 journey, from initial discovery and description in 2003, to FDA approval in 2015, illustrates the interest and need for novel lipid therapies, as there are large populations for whom statin therapy alone is not adequate in optimizing their cardiovascular risk profile.

KEYWORDS:

• Proprotein convertase subtilisin/kexin type 9
• inhibitors
• LDL
• monoclonal antibodies
• cardiovascular

Financial & competing interests disclosure

M. Davidson is a consultant to Amgen, Regeneron and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• While it is unlikely that PCSK9 inhibitors will entirely supplant statin therapy, the large LDL-C reductions seen with their use (as much as 60–70%) are promising as adjunctive strategies to lowering CV risk.

• From a mechanistic standpoint, the rise of PCSK9 levels following treatment with current lipid lowering drugs (statins, fibrates, ezetimibe) allows for an additive, and synergistic, role seen with the use of PCSK9 inhibitors.

• Though it is early in use of these agents, preliminary prespecified analyses of outcomes data have suggested additional risk reduction with their use. However, outcomes-driven trials are still ongoing.

• Adverse events related with their use seem rare, but neurocognitive complaints are a concern that will have to be addressed with further study.

• The current cost structure and subcutaneous administration of these agents may be relevant barriers to their use.