Published Online
on October 21, 2002

A more recent version of this article appeared on November 12, 2002

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Submitted on July 23, 2002
Revised on September 3, 2002
Accepted on September 3, 2002

Low-Density Lipoprotein Level Reduction by the 3-Hydroxy-3-Methylglutaryl Coenzyme-A Inhibitor Simvastatin Is Accompanied by a Related Reduction of F₂-Isoprostane Formation in Hypercholesterolemic Subjects. No Further Effect of Vitamin E

Raffaele De Caterina MD, PhD^*, Francesco Cipollone MD, Francesca Paola Filardo MD, Marco Zimarino MD, Walter Bernini , Guido Lazzerini , Tonino Bucciarelli MD, Angela Falco MD, Paola Marchesani MD, Raffaella Muraro MD, Andrea Mezzetti MD, and Giovanni Ciabattoni MD

From the Chair of Cardiology (R.D.C., M.Z.), the Departments of Medicine and Aging (F.C., A.F., P.M., A.M.), Biomedical Sciences (T.B.), Oncology and Neurosciences (R.M.), and Drug Sciences (G.C.), "G. d'Annunzio" University, Chieti, Italy, and the Laboratory for Thrombosis and Vascular Research (R.D.C., F.P.F., W.B., G.L.), C.N.R. Institute of Clinical Physiology, Pisa, Italy.

^* To whom correspondence should be addressed. E-mail: rdecater{at}unich.it.

Background—Both statins and vitamin E, by reducing the rate of lipid peroxidation, may interfere with oxidative stress, but the impact of their combination is unknown.

Methods and Results—We randomized 43 hypercholesterolemic patients (21 men, 22 women, age 63±11 years) to either simvastatin, to achieve >20% reduction of total cholesterol, or simvastatin plus 600 mg/d vitamin E for 2 months. Patients were then crossed over to the alternative treatment. Lipid parameters documented patients' compliance to simvastatin, whereas plasma levels of vitamin E documented compliance and absorption of vitamin E. We assessed urinary excretion of the isoprostane 8-iso-prostaglandin F₂ (8-iso-PGF₂) as an in vivo index of oxidative stress at baseline and after each month of therapy. 8-Iso-PGF₂ was significantly reduced by simvastatin, from 361±148 pg/mg creatinine (mean±SD) at baseline to 239±124 pg/mg creatinine after 1 month. The addition of vitamin E did not reduce such levels any further (256±125 after 1 month). Linear regression analysis showed a weak inverse relationship of 8-iso-PGF₂ with vitamin E levels but a much stronger relationship with LDL cholesterol (R²=0.162; P<0.001).

Conclusions—In hypercholesterolemic patients, LDL cholesterol is a major correlate of oxidative stress. Concomitant with LDL cholesterol reduction, simvastatin causes a drastic reduction of oxidative stress to a level that is not further reduced by the addition of vitamin E. Results of clinical trials with vitamin E may have been hampered by inadequate knowledge of the background level of lipid peroxidation, which is a major determinant of vitamin E bioactivity.

Key words: atherosclerosis • lipids • pharmacology • peroxidation • stress

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