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

Circulation. 2002 Nov 12;106(20):2543-9. doi: 10.1161/01.cir.0000038500.43292.d7.

Abstract

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 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.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / therapeutic use
  • Cholesterol / blood
  • Cholesterol, LDL / blood*
  • Cross-Over Studies
  • Dinoprost* / analogs & derivatives*
  • Drug Therapy, Combination
  • F2-Isoprostanes / urine*
  • Female
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Hypercholesterolemia / blood
  • Hypercholesterolemia / drug therapy*
  • Hypercholesterolemia / urine
  • Lipid Peroxidation / drug effects
  • Lipoproteins, LDL / blood
  • Male
  • Middle Aged
  • Oxidative Stress
  • Patient Compliance
  • Simvastatin / therapeutic use*
  • Vitamin E / blood
  • Vitamin E / therapeutic use*

Substances

  • Antioxidants
  • Cholesterol, LDL
  • F2-Isoprostanes
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Lipoproteins, LDL
  • oxidized low density lipoprotein
  • Vitamin E
  • 8-epi-prostaglandin F2alpha
  • Cholesterol
  • Simvastatin
  • Dinoprost