Background: HMG-CoA reductase inhibitors (statins) are effective lipid-lowering agents and are known to reduce cardiovascular events. Beneficial effects of statins seem to occur very early in the course of their therapy and subgroup analysis of large trials indicates that subjects in statin-treated arms have less cardiovascular events than subjects in placebo-controlled arm with comparable serum cholesterol levels. Therefore, it has been suggested that statins may have antiatherogenic effects beyond their cholesterol lowering effect. Many studies have demonstrated a rapid improvement in vascular function with atorvastatine which cannot solely be accounted for by achieved lipid reduction. A rapid oxidative stress lowering effect of atorvastatin has been proposed as the probable mechanism of this action. Whether atorvastatine has stronger antioxidant effect and whether atorvastatin lowers oxidative stress earlier in the course of therapy than other statins has not been studied yet.

Objective: To compare the rapidity of onset and the extent of oxidative stress lowering of atorvastatin with that of an (in terms of LDL lowering) equipotent dosage of simvastatin.

Methods: We plan to recruit sixty statin naive patients, with diabetes mellitus type 2 and/or obesity (BMI > 25) and/or hypertension (RR>140/90 mmHg). Patients with K/DOQI stage 5 chronic kidney disease (Cockcroft-Gault clearance of less than 15 ml/min/1.73m2), patients who use any vitamin preparation, or statins in the last three months and patients with LDL cholestrerol < 2.5 mmol/l will be excluded from the study. Because of the influence of angiotensin-converting enzyme inhibitors (ACE-inhibitors) on oxidative stress, patients will be stratified for prior ACE-inhibitor use during randomization. All included patients are randomized to treatment with simvastatin 40 mg daily or atorvastatin 10 mg daily to achieve a comparable lipid reduction. Established parameters of oxidative stress such as oxidized LDL, malondealdehyde and isoprostane will be measured in plasma on inclusion, one week, six weeks and three months after inclusion. We also plan to measure endothelial function parameters such as soluble Vascular Adhesion Molecule (sVCAM) and von Willebrand factor. In addition, parameters of inflammation such as high sensitive C - reactive protein, TNF-alfa, interleukin-6 and myeloperoxidase will be measured to investigate whether there is any correlation between oxidative stress lowering and endothelial function and inflammation. The inhibitory effect of HDL to prevent oxidation of LDL will be determined by measurement of lipid peroxides formed during in vitro oxidation of LDL co-incubated with HDL. The inflammatory / anti-inflammatory properties of HDL will be tested by measurement of the HDL capacity to inactivate oxidized palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (ox-PAPC). Collections of 24 hours of urine at the beginning and after one week, six weeks and three months will be used to measure urine F2-isoprostane levels.

Analyses: All parameters of oxidative stress before and during treatment with both statins will be compared to determine whether atorvastatin causes a stronger and quicker reduction of oxidative stress than simvastatin. Generalized estimating equations (GEE) will be used to compare these effects. We plan to include a minimum of 30 patients in each treatment-group from the outpatient clinic of the department of internal medicine of the VU University Medical Center in Amsterdam.

Expected results: Atorvastatin will reduce oxidative parameters stronger and earlier than simvastatin.