title: Circulating PCSK9 levels and CETP plasma activity are independently associated in patients with metabolic diseases.
abstract: 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 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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira i Virgili, IISPV, C Sant Llorenç, 21, 43201, Reus, Spain.|Spanish Biomedical Research Centre in Diabetes and AssociatedMetabolic Disorders (CIBERDEM), Madrid, Spain.
authors.forename: Josefa
authors.initials: J
authors.lastname: Girona
authors.affiliation: Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira i Virgili, IISPV, C Sant Llorenç, 21, 43201, Reus, Spain.|Spanish Biomedical Research Centre in Diabetes and AssociatedMetabolic Disorders (CIBERDEM), Madrid, Spain.
authors.forename: Daiana
authors.initials: D
authors.lastname: Ibarretxe
authors.affiliation: Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira i Virgili, IISPV, C Sant Llorenç, 21, 43201, Reus, Spain.|Spanish Biomedical Research Centre in Diabetes and AssociatedMetabolic Disorders (CIBERDEM), Madrid, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Plana
authors.affiliation: Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira i Virgili, IISPV, C Sant Llorenç, 21, 43201, Reus, Spain.|Spanish Biomedical Research Centre in Diabetes and AssociatedMetabolic Disorders (CIBERDEM), Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Guaita-Esteruelas
authors.affiliation: Biosfer Teslab, Reus and Department of Electronic Engineering, Universitat Rovira i Virgili, IISPV, Tarragona, Spain.|Spanish Biomedical Research Centre in Diabetes and AssociatedMetabolic Disorders (CIBERDEM), Madrid, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Amigo
authors.affiliation: Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira i Virgili, IISPV, C Sant Llorenç, 21, 43201, Reus, Spain.|Spanish Biomedical Research Centre in Diabetes and AssociatedMetabolic Disorders (CIBERDEM), Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Heras
authors.affiliation: Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira i Virgili, IISPV, C Sant Llorenç, 21, 43201, Reus, Spain. luis.masana@urv.cat.|Spanish Biomedical Research Centre in Diabetes and AssociatedMetabolic Disorders (CIBERDEM), Madrid, Spain. luis.masana@urv.cat.
authors.forename: Luis
authors.initials: L
authors.lastname: Masana
mesh_terms: D001794:Blood Pressure / Q000502:physiology; D053480:Cholesterol Ester Transfer Proteins / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology; D008055:Lipids / Q000097:blood*; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism*; D008875:Middle Aged; D000071449:Proprotein Convertase 9 / Q000235:genetics / Q000378:metabolism*
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL; D008055:Lipids; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: CETP; Lipids; Metabolic syndrome; PCSK9; rs11591147