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Changes in PCSK9 and LDL cholesterol concentrations by everolimus treatment and their effects on polymorphisms in

Shiori Sato1, Yumiko Akamine1, Hideaki Kagaya1

  • 1Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.

Pharmacological Reports : PR
|March 28, 2020
PubMed
Abstract

Insights

Everolimus treatment significantly increased proprotein convertase subtilisin/kexin type 9 (PCSK9) levels in renal transplant patients. This elevation, linked to mTORC1 gene variants, may contribute to hyperlipidemia.

Area of Science:

  • Pharmacology
  • Genetics
  • Nephrology

Background:

  • Renal transplant recipients often require immunosuppressants like everolimus.
  • Understanding drug effects on lipid metabolism and genetic factors is crucial for patient management.
  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in LDL cholesterol regulation.

Purpose of the Study:

  • To investigate the impact of everolimus on proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein (LDL) cholesterol levels.
  • To explore the influence of genetic polymorphisms in PCSK9 and mTORC1 genes on these effects.
  • To analyze these interactions in 53 renal transplant recipients.

Main Methods:

  • Blood and plasma samples were collected before and after 15 days of everolimus administration.
  • Concentrations of everolimus, PCSK9, and LDL cholesterol were measured.
  • Genetic polymorphisms in mTORC1 (rs2536T>C, rs2295080T>G) and PCSK9 (rs505151G>A, rs562556G>A, rs11593680C>T) were analyzed.

Main Results:

  • Everolimus treatment significantly increased mean PCSK9 plasma concentrations (295 vs. 214 ng/mL, p=0.004).
  • A significant correlation was found between everolimus exposure (AUC0-12) and the rate of PCSK9 concentration change (r=0.316, p=0.021).
  • Higher PCSK9 change rates were observed in patients with the mTORC1 rs2295080G allele, higher everolimus AUC0-12, and in females.

Conclusions:

  • Everolimus administration significantly elevates plasma PCSK9 concentrations.
  • This increase in PCSK9 may be a contributing factor to hyperlipidemia observed during everolimus therapy.
  • Genetic variations in mTORC1 influence the response of PCSK9 levels to everolimus.
Keywords:
EverolimusLow-density lipoprotein cholesterolMammalian target of rapamycin complex 1PolymorphismProprotein convertase subtilisin/kexin type 9

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