Dyslipidemia in Patients With Diabetes Mellitus Clinical Trial
Official title:
Atorvastatin Action on Oxidative Stress and Inflammation in Type II Diabetes: The HDL Particle Protection Study
Atorvastatin is a statin that significantly decreases LDL level. At 10 mg/day, atorvastatin increases HDL level by 4-5%. At 80 mg/day, atorvastatin does not increase HDL level. However, atorvastatin is more protective at 80 mg/day than at 10 mg/day. This is due to a better reduction in LDL level at 80 mg, but we also think that 80 mg/day of atorvastatin is superior to 10 mg/day in improving the QUALITY of HDL, such as improving HDL particle number and function (better anti-oxydant activity)
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.
Working hypothesis:
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 α1, α2, pre- α1 and pre-β1 HDL subfractions in dyslipidemic
subjects with mean LDL-C, 198 mg/dl; mean TG, 167 mg/dl.
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