The HDL Particle Protection Study
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.
Inclusion Criteria: patient should have all of the 3 criteria:

 1. Patient with diabetes mellitus, defined by at least 1 of the following:

 Fasting glucose > 125 mg/dL confirmed on 2 occasions HbA1C > 6.5% Patients receiving
 any glucose lowering agent (oral or subcutaneous)

 2. Lipid profile should have ALL of the following characteristics:

 Triglycerides >150 mg/dL HDL <45 mg/dL LDL < 190 mg/dL

 3. Lp(a) level < 30 mg/dL

 Exclusion Criteria:

 1. Patients with known coronary artery disease defined by at least one of the following:

 -  Prior myocardial infarction

 -  Prior PCI

 -  Prior CABG

 -  Known coronary stenosis > 50% on coronary angiography

 -  A non invasive study revealing myocardial ischemia (such as a stress test, a
 nuclear perfusion study or a stress echo)

 2. Poor diabetic control defined by an HbA1c > 8.5% in the preceding 3 months

 3. Patients with known diabetic retinopathy, nephropathy or neuropathy

 4. Patients with a creatinin clearance < 75 ml/min as calculated by the Cockcroft-Gault
 equation

 5. Patients who have received any lipid lowering therapy within 6 weeks prior to
 inclusion (statin, fibrates, ezetimibe, niacin, resin binding agent)

 6. Patients with underlying malignancy or infection or inflammatory disease

 7. Patients with SGPT or SGOT or CK > 2.5 times upper reference value

 8. Patients allergic to statins or who experienced prior significant side effects with
 statins such as elevation of liver enzymes or CK > 2.5 upper reference value

 9. Patients older than 80

 10. Females who are premenopausal

 11. Patients unable to give informed consent