Circulating PCSK9 levels and CETP plasma activity are independently associated in patients with metabolic diseases.

Background: 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. Methods: Plasma 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. Results: Both 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). Conclusions: Our 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. [ABSTRACT FROM AUTHOR]