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.
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.


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 F(2alpha) (8-iso-PGF(2alpha)) as an in vivo index of oxidative stress at baseline and after each month of therapy. 8-Iso-PGF(2alpha) 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-PGF(2alpha) with vitamin E levels but a much stronger relationship with LDL cholesterol (R(2)=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.
De Caterina
Raffaele
R
Chair of Cardiology, G. d'Annunzio University, Chieti, Italy. rdecater@unich.it
Cipollone
Francesco
F
Filardo
Francesca Paola
FP
Zimarino
Marco
M
Bernini
Walter
W
Lazzerini
Guido
G
Bucciarelli
Tonino
T
Falco
Angela
A
Marchesani
Paola
P
Muraro
Raffaella
R
Mezzetti
Andrea
A
Ciabattoni
Giovanni
G
D000975:Antioxidants / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood*; D018592:Cross-Over Studies; D015237:Dinoprost / Q000031:analogs & derivatives*; D004359:Drug Therapy, Combination; D028441:F2-Isoprostanes / Q000652:urine*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D010349:Patient Compliance; D019821:Simvastatin / Q000627:therapeutic use*; D014810:Vitamin E / Q000097:blood / Q000627:therapeutic use*
D000975:Antioxidants; D008078:Cholesterol, LDL; D028441:F2-Isoprostanes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D014810:Vitamin E; C075750:8-epi-prostaglandin F2alpha; D002784:Cholesterol; D019821:Simvastatin; D015237:Dinoprost