Received on October 30, 2007
Accepted on March 25, 2008

Lipids, Lipoproteins, and Cardiovascular Risk Factors

Plasma PCSK9 Concentrations Correlate with LDL and Total Cholesterol in Diabetic Patients and Are Decreased by Fenofibrate Treatment

¹ The Heart Research Institute, Sydney, Australia, and Université de Nantes, INSERM U539, Nantes, France
² GlaxoSmithkline, CVU CEDD, Les Ulis, France
³ The Heart Research Institute, Sydney, Australia
⁴ the Royal Prince Alfred Hospital, Sydney, Australia
⁵ The Heart Research Institute, Sydney, Australia, and The University of Sydney, Sydney, Australia

^* To whom correspondence should be addressed. E-mail: lambertg{at}hri.org.au.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the LDL receptor (LDLr) in hepatocytes, and its expression in mouse liver has been shown to decrease with fenofibrate treatment.

METHODS: We developed a sandwich ELISA using recombinant human PCSK9 protein and 2 affinity-purified polyclonal antibodies directed against human PCSK9. We measured circulating PCSK9 concentrations in 115 diabetic patients from the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study before and after fenofibrate treatment.

RESULTS: We found that plasma PCSK9 concentrations correlate with total (r = 0.45, P = 0.006) and LDL (r = 0.54, P = 0.001) cholesterol but not with triglycerides or HDL cholesterol concentrations in that cohort. After 6 weeks of treatment with comicronized fenofibrate (200 mg/day), plasma PCSK9 concentrations decreased by 8.5% (P = 0.041 vs pretreatment). This decrease correlated with the efficacy of fenofibrate, as judged by a parallel reduction in plasma triglycerides (r = 0.31, P = 0.015) and LDL cholesterol concentrations (r = 0.27, P = 0.048).

CONCLUSIONS: We conclude that this decrease in PCSK9 explains at least in part the LDL cholesterol–lowering effects of fenofibrate. Fenofibrate might be of interest to further reduce cardiovascular risk in patients already treated with a statin.