Differential Regulation of Lipoprotein Kinetics by Atorvastatin and Fenofibrate in Subjects With the Metabolic Syndrome

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 3; pp. 803 - 811
• Main Authors: Watts, Gerald F., Barrett, P. Hugh R., Ji, Juying, Serone, Adrian P., Chan, Dick C., Croft, Kevin D., Loehrer, Franziska, Johnson, Anthony G.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.03.2003
• Subjects: Adult; Apolipoprotein A-I - blood; Apolipoprotein B-100; Apolipoproteins B - blood; Atorvastatin; Biological and medical sciences; Blood Glucose - analysis; Cholesterol - blood; Cholesterol, HDL - blood; Cholesterol, LDL - blood; Cross-Over Studies; Diet; Double-Blind Method; Fenofibrate - therapeutic use; Fundamental and applied biological sciences. Psychology; Heptanoic Acids - therapeutic use; Humans; Hypolipidemic Agents - therapeutic use; Insulin - blood; Insulin resistance; Kinetics; Lipoproteins - blood; Lipoproteins, HDL - blood; Lipoproteins, IDL; Lipoproteins, LDL - blood; Lipoproteins, VLDL - blood; Male; Metabolic Syndrome - blood; Metabolic Syndrome - drug therapy; Metabolic syndrome X; Middle Aged; Obesity - blood; Physiological aspects; Placebos; Pyrroles - therapeutic use; Triglycerides - blood; Australia
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.52.3.803

Differential Regulation of Lipoprotein Kinetics by Atorvastatin and Fenofibrate in Subjects With the Metabolic Syndrome Gerald F. Watts 1 , P. Hugh R. Barrett 1 , Juying Ji 1 , Adrian P. Serone 2 , Dick C. Chan 1 , Kevin D. Croft 1 , Franziska Loehrer 2 and Anthony G. Johnson 2 1 Lipoprotein Research Unit, Department of Medicine, University of Western Australia, the West Australian Institute for Medical Research, Perth, Western Australia 2 James Lance GlaxoSmithKline Medicines Research Unit, Prince of Wales Hospital, Sydney, Australia 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. Footnotes Address correspondence and reprint requests to Associate Professor G.F. Watts, University Department of Medicine, Royal Perth Hospital, Box X2213 GPO, Perth, WA 6847, Australia. E-mail: gfwatts{at}cyllene.uwa.edu.au Received for publication 28 August 2002 and accepted in revised form 2 December 2002. P.H.R.B. is a Career Development Fellow of the National Heart Foundation, and A.P.S., F.L., and A.G.J. are employees of GlaxoSmithKline. apoAI, apolipoprotein AI; apoB, apolipoprotein B-100; CETP, cholesteryl ester transfer protein; FCR, fractional catabolic rate; GCMS, gas chromatography; HOMA, homeostasis model assessment; HMG, hydroxymethylglutaryl; IDL, intermediate-density lipoprotein; LCAT, lecithin cholesterol acyltransferase; PPAR, peroxisome proliferator–activated receptor; PR, production rate. DIABETES