PCSK9 Inhibitors as Adjunctive Therapies in Hypercholesterolemia: Benefits, Limitations, and Possible Alternatives

Mawieh Hamad*, Jibran Sualeh Muhammad, Bilal Rah, Haydar Hasan, Jalal Taneera, Abdulsalam Soofi, Samir Awadallah

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

The clinical application of statins as anti-hypercholesterolemia medications, while very beneficial, remains limited by intolerance and side effects. Statins increase the production of proprotein convertase subtilisin/kexin type 9 (PCSK9), which degrades low-density lipoprotein (LDL) receptor and limits circulating LDL cholesterol (LDLC) uptake. PCSK9 also promotes cardiomyocyte and vascular smooth muscle cell apoptosis and vascular injury. Several PCSK9 inhibitors (evolocumab, alirocumab, and inclisiran) are highly effective at reducing plasma LDLC levels and moderately effective at protecting against cardiovascular disease. However, their long-term use needs to take the following issues into account: i) PCSK9 deficiency leads to various pathologies like heart failure and liver steatosis, ii) PCSK9 regulates lipid homeostasis, iii) depletion of circulating PCSK9 may itself upregulate PCSK9 expression, and iv) the cost of available inhibitors is beyond the reach of most people. Therefore, the long-term safety and affordability of PCSK9 inhibitors needs to be revisited and additional therapeutic options need to be explored.

Original languageEnglish
Article number2300107
Number of pages14
JournalAdvanced Therapeutics
Volume6
Issue number9
Early online date13 Jun 2023
DOIs
Publication statusPublished - Sept 2023

Bibliographical note

Publisher Copyright:
© 2023 Wiley-VCH GmbH.

Keywords

  • hypercholesterolemia
  • LDLR
  • metformin
  • PCSK9
  • PCSK9 inhibitors
  • statins

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology
  • Pharmaceutical Science
  • Genetics(clinical)
  • Biochemistry, medical
  • Pharmacology (medical)

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