A review of PCSK9 inhibition and its effects beyond LDL receptors

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an integral role in the degradation of low-density lipoprotein receptors (LDL-R), making it an intriguing target for emerging pharmacotherapy. Two PCSK9 inhibitors, alirocumab and evolocumab, have been approved and are available in the United States and European Union. However, much of the PCSK9 story remains to be told. The pipeline for additional pharmacotherapy options is rich with several compounds under development, using alternative strategies for inhibiting PCSK9. Perhaps, more intriguing is the interaction between PCSK9 and non-LDL-R targets, including mediators of inflammation and immunological processes, which remain under intense investigation. This review will discuss the currently available PCSK9 inhibitors, the development of novel approaches to PCSK9 modulation, and the potential non-LDL-R-mediated effects of PCSK9 inhibition.

Clinical utility of evolocumab in the management of hyperlipidemia: patient selection and follow-up

“…PCSK9 is a novel target for lowering LDL-C 4. Synthesized in the liver, PCSK9 binds to the LDL receptor (LDL-R) resulting in endocytosis and lysosomal degradation (Figure 1).…”

Association of a 3′ untranslated region polymorphism in proprotein convertase subtilisin/kexin type 9 with HIV viral load and CD4+ levels in HIV/hepatitis C virus coinfected women

“…CD81 and VLDLR are used by HCV to gain entry into cells [40] and PCSK9 levels modulate HCV infectivity in vitro [39] . The role of PCSK9 in inflammation, immunologic processes and infection is an area of active investigation [41, 42] .…”

Evolving Role of Non‐Statin Therapy for the Management of Dyslipidemia and Cardiovascular Risk Reduction: Past, Present, and Future

“…The PCSK9 inhibitors, alirocumab and evolocumab, were approved by the FDA in 2015 for individuals with FH or clinical ASCVD who are receiving maximally tolerated statin therapy and require additional LDL‐C level lowering . Both alirocumab and evolocumab lower LDL‐C level by up to 60% on top of what can be achieved with statin therapy alone.…”

“…Following publication of the ACC/AHA cholesterol guideline and NLA patient-centered recommendations, two novel proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab and evolocuamb, were approved by the FDA in 2015. 7 Additionally, the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial was the first to demonstrate a reduced risk of ASCVD by adding a nonstatin (ezetimibe) to background statin therapy in patients with recent acute coronary syndrome (ACS). 8 As a result, an Expert Consensus Decision Pathway (ECDP) on the role of non-statins was published in 2016 to guide clinical decision making on the use of non-satins in the four statin benefit groups of the 2013 ACC/AHA cholesterol guideline.…”

“…The PCSK9 inhibitors, alirocumab and evolocumab, were approved by the FDA in 2015 for individuals with FH or clinical ASCVD who are receiving maximally tolerated statin therapy and require additional LDL-C level lowering. 7 Both alirocumab and evolocumab lower LDL-C level by up to 60% on top of what can be achieved with statin therapy alone. The exact role of PCSK9 inhibitors was initially unclear because these therapies were not approved until after release of the 2013 ACC/AHA cholesterol guideline, and clinical outcomes data were unavailable on their market launch.…”