The dyslipidemia of Type II diabetes is characterized by anomalies of the metabolism and biological activities of both atherogenic lipoproteins containing apoB100 (VLDL, IDL and LDL) and of antiatherogenic HDL containing apoAI and/or apoAII. Such metabolic and functional anomalies are closely associated with elevated oxidative stress, endothelial dysfunction and premature macrovascular atherosclerotic disease. The ratio of atherogenic cholesterol (VLDL, IDL, LDL cholesterol) relative to HDL cholesterol (HDL-C) in normolipidemic subjects is typically less than 3; by contrast, ratios of 4 or more are typical of the dyslipidemia of Type II diabetes and are indicative of disequilibrium in proatherogenic versus antiatherogenic plasma lipoprotein levels, frequently due to low HDL-C concentration (<40 mg/dl). Such conditions favor enhanced deposition of cholesterol in the arterial wall and progression of atherosclerotic disease.
Atorvastatin is a potent synthetic HMG-CoA reductase inhibitor which markedly lowers plasma levels of LDL cholesterol (LDL-C); in addition, atorvastatin lowers plasma levels of triglycerides (TG) and TG-rich lipoproteins but equally raises levels of HDL-C and apoAI, the major HDL apolipoprotein. Atorvastatin-induced decrease in plasma TG is intimately related to decreased VLDL levels, accelerated VLDL turnover and normalized intravascular remodeling of apoB-containing lipoproteins. Importantly, atorvastatin reduces activities of plasma cholesteryl ester transfer protein (CETP) and hepatic lipase (HL), thereby leading to the normalized remodeling of both LDL and HDL particle populations. Furthermore, recent studies have revealed that in atherogenic Type IIB hyperlipidemia, atorvastatin induces a dose-dependent and progressive increase in the capacity of both plasma and HDL to mediate cellular cholesterol efflux via the SRB1 receptor pathway.
Plasma HDL is highly heterogeneous. When isolated on the basis of density by ultracentrifugation, human HDL is separated into two major subfractions, large, light HDL2 and small, dense HDL3. HDL remodeling by CETP, HL and LCAT can alter absolute and relative concentrations of HDL2 and HDL3 in plasma. It remains contradictory however as to whether plasma levels of HDL2 or HDL3 are predictors of cardiovascular risk. HDL exerts a spectrum of antiatherosclerotic actions; central among them are reverse cholesterol transport, the capacity of HDL to protect LDL against oxidative stress, the anti-inflammatory actions of HDL on arterial wall cells as well as antithrombotic activities. We have recently found that small, dense HDL3 particles exert potent protection of atherogenic LDL subspecies against oxidative stress in normolipidemic subjects and that HDL-associated paraoxonase (PON) 1, platelet-activating factor acetylhydrolase (PAF-AH) and lecithin:cholesterol acyltransferase (LCAT) activities can contribute to such antioxidative properties. HDL particles are however dysfunctional in diabetic dyslipidemias; for example, diabetic HDL are deficient in antioxidant activity, and in addition, their cholesterol-efflux capacity is impaired. Such dysfunction may lead to impairment of the antiatherogenic actions of HDL in diabetic dyslipidemia.
The investigators hypothesize that atorvastatin can increase plasma levels of HDL subfractions with potent antioxidant activity as a result of enhanced surface and core remodeling of TG-rich lipoproteins, (such as VLDL-1 and VLDL-2), reduced CETP activity, and stimulation of apoAI production. Indeed, Asztalos et al. showed that atorvastatin induced significant increase in the ?1, ?2, pre- ?1 and pre-?1 HDL subfractions in dyslipidemic subjects with mean LDL-C, 198 mg/dl; mean TG, 167 mg/dl.