title: Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus: results from a crossover study.
abstract: BACKGROUND
  Bezafibrate and fenofibrate show different binding properties against peroxisome proliferator-activated receptor subtypes, which could cause different clinical effects on circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and on various metabolic markers.
  
  
  METHODS
  An open, randomized, four-phased crossover study using 400 mg of bezafibrate or 200mg of fenofibrate was performed. Study subjects were 14 dyslipidemia with impaired glucose tolerance or type 2 diabetes mellitus (61 ± 16 years, body mass index (BMI) 26 ± 3 kg/m², total cholesterol (TC) 219 ± 53 mg/dL, triglyceride (TG) 183 ± 83 mg/dL, high-density lipoprotein-cholesterol (HDL-C) 46 ± 8 mg/dL, fasting plasma glucose 133 ± 31 mg/dL and HbA1c 6.2 ± 0.8%). Subjects were given either bezafibrate or fenofibrate for 8 weeks, discontinued for 4 weeks and then switched to the other fibrate for 8 weeks. Circulating PCSK9 levels and other metabolic parameters, including adiponectin, leptin and urine 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured at 0, 8, 12 and 20 weeks.
  
  
  RESULTS
  Plasma PCSK9 concentrations were significantly increased (+39.7% for bezafibrate and +66.8% for fenofibrate, p<0.001) in all patients except for one subject when treated with bezafibrate. Both bezafibrate and fenofibrate caused reductions in TG (-38.3%, p<0.001 vs. -32.9%, p<0.01) and increases in HDL-C (+18.0%, p<0.001 vs. +11.7%, p<0.001). Fenofibrate significantly reduced serum cholesterol levels (TC, -11.2%, p<0.01; non-HDL-C, -17.3%, p<0.01; apolipoprotein B, -15.1%, p<0.01), whereas bezafibrate significantly improved glucose tolerance (insulin, -17.0%, p<0.05) and metabolic markers (γ-GTP, -38.9%, p<0.01; adiponectin, +15.4%, p<0.05; urine 8-OHdG/Cre, -9.5%, p<0.05).
  
  
  CONCLUSIONS
  Both bezafibrate and fenofibrate increased plasma PCSK9 concentrations. The addition of a PCSK9 inhibitor to each fibrate therapy may achieve beneficial cholesterol lowering along with desirable effects of respective fibrates.
authors.affiliation: Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Noguchi
authors.forename: Junji
authors.initials: J
authors.lastname: Kobayashi
authors.forename: Kunimasa
authors.initials: K
authors.lastname: Yagi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nohara
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaaki
authors.forename: Masako
authors.initials: M
authors.lastname: Sugihara
authors.forename: Naoko
authors.initials: N
authors.lastname: Ito
authors.forename: Rie
authors.initials: R
authors.lastname: Oka
authors.forename: Masa-Aki
authors.initials: MA
authors.lastname: Kawashiri
authors.forename: Hayato
authors.initials: H
authors.lastname: Tada
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Takata
authors.forename: Akihiro
authors.initials: A
authors.lastname: Inazu
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamagishi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D054392:Adipokines / Q000378:metabolism*; D052242:Adiponectin / Q000097:blood; D000328:Adult; D000368:Aged; D001629:Bezafibrate / Q000008:administration & dosage*; D015992:Body Mass Index; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D018592:Cross-Over Studies; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage*; D005951:Glucose Tolerance Test; D006801:Humans; D020738:Leptin / Q000097:blood; D008297:Male; D008875:Middle Aged; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
chemical_list: D054392:Adipokines; D052242:Adiponectin; D008076:Cholesterol, HDL; D020738:Leptin; D047492:Peroxisome Proliferator-Activated Receptors; D014280:Triglycerides; D000080242:8-Hydroxy-2'-Deoxyguanosine; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D003849:Deoxyguanosine; D011345:Fenofibrate; D001629:Bezafibrate