['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.', 'Plasma CETP activity and PCSK9 levels were measured in 450 participants (median age, 58\xa0years; 49\xa0% women) who attended the metabolism unit because of metabolic syndrome (MetS) (78\xa0%), atherogenic dyslipidemia (32\xa0%), obesity (50\xa0%), type 2 diabetes mellitus (72\xa0%), and other risk factors (13\xa0%). A 6\xa0week lipid-lowering drug wash-out period was established in treated patients.', '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\xa0=\xa00.256, P\xa0<\xa00.0001) 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\xa0%, P\xa0<\xa00.0001) and LDL-C (17.8\xa0%, P\xa0=\xa00.010) as well as lower CETP activity (10.31\xa0%, P\xa0=\xa00.009). 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\xa0=\xa00.003).'] Are circulating PCSK9 levels and CETP plasma activity independently associated in patients with metabolic diseases?