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Dose-Dependent Regulation of High-Density Lipoprotein Metabolism with Rosuvastatin in the Metabolic Syndrome

Metabolic Research Centre (E.M.M.O., G.F.W., P.H.R.B.), School of Medicine and Pharmacology, Royal Perth Hospital, University of Western Australia, Perth, Western Australia 6847, Australia; and Baker Heart Research Institute (P.J.N., D.S., A.H.), Melbourne, Victoria 8008, Australia

Address all correspondence and requests for reprints to: Professor P. Hugh R. Barrett, School of Medicine and Pharmacology, University of Western Australia, GPO Box X2213 Perth, Western Australia 6847, Australia. E-mail: Hugh.Barrett{at}uwa.edu.au.

Background: Low plasma concentration of high-density lipoprotein (HDL) cholesterol is a risk factor for cardiovascular disease and a feature of the metabolic syndrome. Rosuvastatin has been shown to increase HDL cholesterol concentration, but the mechanisms remain unclear.

Methods and Results: Twelve men with the metabolic syndrome were studied in a randomized, double-blind, crossover trial of 5-wk therapeutic periods with placebo, 10 mg/d rosuvastatin, or 40 mg/d rosuvastatin, with 2-wk placebo washout between each period. Compared with placebo, there was a significant dose-dependent increase in HDL cholesterol, HDL particle size, and concentration of HDL particles that contain apolipoprotein A-I (LpA-I). The increase in LpA-I concentration was associated with significant dose-dependent reductions in triglyceride concentration and LpA-I fractional catabolic rate, with no changes in LpA-I production rate. There was a significant dose-dependent reduction in the fractional catabolic rate of HDL particles containing both apolipoprotein A-I and A-II (LpA-I:A-II), with concomitant reduction in LpA-I:A-II production rate, and hence no change in LpA-I:A-II concentration.

Conclusions: Rosuvastatin dose-dependently increased plasma HDL cholesterol and LpA-I concentrations in the metabolic syndrome. This could relate to reduction in plasma triglycerides with remodeling of HDL particles and reduction in LpA-I fractional catabolism. The findings contribute to understanding mechanisms for the HDL-raising effect of rosuvastatin in the metabolic syndrome with implications for reduction in cardiovascular disease.

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