title: Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome.
abstract: The metabolic syndrome is characterized by insulin resistance and abnormal apolipoprotein AI (apoAI) and apolipoprotein B-100 (apoB) metabolism that may collectively accelerate atherosclerosis. The effects of atorvastatin (40 mg/day) and micronised fenofibrate (200 mg/day) on the kinetics of apoAI and apoB were investigated in a controlled cross-over trial of 11 dyslipidemic men with the metabolic syndrome. ApoAI and apoB kinetics were studied following intravenous d(3)-leucine administration using gas-chromatography mass spectrometry with data analyzed by compartmental modeling. Compared with placebo, atorvastatin significantly decreased (P < 0.001) plasma concentrations of cholesterol, triglyceride, LDL cholesterol, VLDL apoB, intermediate-density lipoprotein (IDL) apoB, and LDL apoB. Fenofibrate significantly decreased (P < 0.001) plasma triglyceride and VLDL apoB and elevated HDL(2) cholesterol (P < 0.001), HDL(3) cholesterol (P < 0.01), apoAI (P = 0.01), and apoAII (P < 0.001) concentrations, but it did not significantly alter LDL cholesterol. Atorvastatin significantly increased (P < 0.002) the fractional catabolic rate (FCR) of VLDL apoB, IDL apoB, and LDL apoB but did not affect the production of apoB in any lipoprotein fraction or in the turnover of apoAI. Fenofibrate significantly increased (P < 0.01) the FCR of VLDL, IDL, and LDL apoB but did not affect the production of VLDL apoB. Relative to placebo and atorvastatin, fenofibrate significantly increased the production (P < 0.001) and FCR (P = 0.016) of apoAI. Both agents significantly lowered plasma triglycerides and apoCIII concentrations, but only atorvastatin significantly lowered (P < 0.001) plasma cholesteryl ester transfer protein activity. Neither treatment altered insulin resistance. In conclusion, these differential effects of atorvastatin and fenofibrate on apoAI and apoB kinetics support the use of combination therapy for optimally regulating dyslipoproteinemia in the metabolic syndrome.
authors.affiliation: Lipoprotein Research Unit, Department of Medicine, University of Western Australia, Royal Perth Hospital, Box X2213 GPO, Perth, WA 6847, Australia. gfwatts@cyllene.uwa.edu.au
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Watts
authors.forename: P Hugh R
authors.initials: PH
authors.lastname: Barrett
authors.forename: Juying
authors.initials: J
authors.lastname: Ji
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Serone
authors.forename: Dick C
authors.initials: DC
authors.lastname: Chan
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Croft
authors.forename: Franziska
authors.initials: F
authors.lastname: Loehrer
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Johnson
mesh_terms: D000328:Adult; D016632:Apolipoprotein A-I / Q000097:blood; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000097:blood; D000069059:Atorvastatin; D001786:Blood Glucose / Q000032:analysis; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D018592:Cross-Over Studies; D004032:Diet; D004311:Double-Blind Method; D011345:Fenofibrate / Q000627:therapeutic use*; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007700:Kinetics; D008074:Lipoproteins / Q000097:blood*; D008075:Lipoproteins, HDL / Q000097:blood; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000188:drug therapy*; D008875:Middle Aged; D009765:Obesity / Q000097:blood; D010919:Placebos; D011758:Pyrroles / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood
chemical_list: D016632:Apolipoprotein A-I; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D000960:Hypolipidemic Agents; D007328:Insulin; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D010919:Placebos; D011758:Pyrroles; D014280:Triglycerides; C001521:lathosterol; D002784:Cholesterol; D000069059:Atorvastatin; D011345:Fenofibrate