Abstract
BackgroundPCSK9 inhibition is a new powerful cholesterol-lowering strategy. Recently, it was reported that CETP inhibitors influence PCSK9 levels as an off-target effect. We explored the relationship between circulating PCSK9 levels and CETP activity in patients with metabolic disease who were not on lipid-lowering therapy.MethodsPlasma CETP activity and PCSK9 levels were measured in 450 participants (median age, 58 years; 49 % women) who attended the metabolism unit because of metabolic syndrome (MetS) (78 %), atherogenic dyslipidemia (32 %), obesity (50 %), type 2 diabetes mellitus (72 %), and other risk factors (13 %). A 6 week lipid-lowering drug wash-out period was established in treated patients.ResultsBoth PCSK9 levels and CETP activity were higher in patients with an increasing number of MetS components. PCSK9 levels were positively correlated with CETP activity in the entire cohort (r = 0.256, P < 0.0001) independent of age, gender, body mass index (BMI), systolic blood pressure (SBP), LDL cholesterol (LDL-C), triglycerides and glucose. Individuals with the loss-of-function PCSK9 genetic variant rs11591147 (R46L) had lower levels of PCSK9 (36.5 %, P < 0.0001) and LDL-C (17.8 %, P = 0.010) as well as lower CETP activity (10.31 %, P = 0.009). This association remained significant in the multiple regression analysis even after adjusting for gender, age, BMI, LDL-C, triglycerides, glucose, lecithin-cholesterol acyltransferase, SBP and MetS (P = 0.003).ConclusionsOur data suggest a metabolic association between PCSK9 and CETP independent of lipid-lowering treatment. The clinical implications of this metabolic relationship could be relevant for explaining the effect of PCSK9 and CETP inhibition on overall lipid profiles.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0428-z) contains supplementary material, which is available to authorized users.
Highlights
proprotein convertase subtilisin/kexin 9 (PCSK9) inhibition is a new powerful cholesterol-lowering strategy
The median age of the study participants was 60 years; 78 % had metabolic syndrome (MetS), 32 % had atherogenic dyslipidemia (AD), 50 % had obesity, 72 % had type 2 diabetes mellitus (T2DM), and 13 % had other risk factors. Both PCSK9 levels and cholesteryl ester transfer protein (CETP) activity were significantly elevated in patients with MetS [327.9 (261.9–417.9) vs 288.1 (233.7–360.9) ng/mL, P < 0.004, and 12.03 (10.3314.15) vs 10.90 (10.08–12.02) nmol/L per h, P < 0.0001, respectively]
After adjustment PCSK9 levels and CETP activity for age and gender, the association with the MetS components remained significant in both parameters (P < 0.0001)
Summary
PCSK9 inhibition is a new powerful cholesterol-lowering strategy. Recently, it was reported that CETP inhibitors influence PCSK9 levels as an off-target effect. We explored the relationship between circulating PCSK9 levels and CETP activity in patients with metabolic disease who were not on lipid-lowering therapy. Over the past few decades, mortality related to cardiovascular disease has steadily decreased in western countries; in recent years, the decline has been offset by the increase in obesity. PCSK9 inhibitors increase cell surface LDLR expression and reduce LDL-C levels by more than 60 % [7]. Gain-of-function mutations in PCSK9 decrease the number of LDLRs on the cell surface and represent a rare cause of familial hypercholesterolemia [8], while loss-of-function (LOF) mutations in PCSK9 result in an increased number of LDLRs on the cell surface, leading to a lifelong low levels of LDL-C and a markedly reduced cardiovascular risk [9, 10]
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