Simvastatin and oxidative stress in humans: A randomized, double-blinded, placebo-controlled clinical trial.
Simvastatin reduces the blood concentration of cholesterol by inhibiting hydroxymethylglutaryl-coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis, and thereby reduces the risk of cardiovascular disease. In addition, simvastatin treatment leads to a reduction in fluxes in mitochondrial respiratory complexes I and II and might thereby reduce the formation of reactive oxygen species, which have been implicated in the pathogenesis of arteriosclerosis. Therefore, we hypothesized that simvastatin may reduce oxidative stress in humans in vivo. We conducted a randomized, double-blinded, placebo-controlled study in which subjects were treated with either 40mg of simvastatin or placebo for 14 days. The endpoints were six biomarkers for oxidative stress, which represent intracellular oxidative stress to nucleic acids, lipid peroxidation and plasma antioxidants, that were measured in urine and plasma samples. A total of 40 participants were included, of which 39 completed the trial. The observed differences between simvastatin and placebo groups in the primary outcomes, DNA and RNA oxidation, were small and nonsignificant (p=0.68), specifically, 3% in the simvastatin group compared to 7.1% in the placebo group for DNA oxidation and 7.3% in the simvastatin group compared to 3.4% in the placebo group. The differences in biomarkers related to plasma were not statistically significant between the treatments groups, with the exception of total vitamin E levels, which, as expected, were reduced in parallel with the reduction in plasma cholesterol. In healthy young male volunteers, short-term simvastatin treatment, which considerably reduces cholesterol, does not lead to a clinically relevant reduction in a panel of measures of oxidative stress. Whether simvastatin has effects on oxidative stress in diseased populations, such as diabetes or hemochromatosis, where oxidative stress is prominent, is unknown but seems unlikely.
Laboratory of Clinical Pharmacology, Rigshospitalet, Ole Maaløes Vej 26, Entrance 76, Section Q7642, DK-2200 Copenhagen N, Denmark.
Sanne Tofte
ST
Rasmussen
Department of Clinical Pharmacology, Bispebjerg Frederiksberg Hospitals, Bispebjerg Bakke 23, 2400 Copenhagen NW, Denmark.
Jon Trærup
JT
Andersen
Laboratory of Clinical Pharmacology, Rigshospitalet, Ole Maaløes Vej 26, Entrance 76, Section Q7642, DK-2200 Copenhagen N, Denmark.
Torben Kjær
TK
Nielsen
Laboratory of Clinical Pharmacology, Rigshospitalet, Ole Maaløes Vej 26, Entrance 76, Section Q7642, DK-2200 Copenhagen N, Denmark.
Vanja
V
Cejvanovic
Laboratory of Clinical Pharmacology, Rigshospitalet, Ole Maaløes Vej 26, Entrance 76, Section Q7642, DK-2200 Copenhagen N, Denmark; Department of Clinical Pharmacology, Bispebjerg Frederiksberg Hospitals, Bispebjerg Bakke 23, 2400 Copenhagen NW, Denmark.
Kasper Meidahl
KM
Petersen
Laboratory of Clinical Pharmacology, Rigshospitalet, Ole Maaløes Vej 26, Entrance 76, Section Q7642, DK-2200 Copenhagen N, Denmark.
Trine
T
Henriksen
Laboratory of Clinical Pharmacology, Rigshospitalet, Ole Maaløes Vej 26, Entrance 76, Section Q7642, DK-2200 Copenhagen N, Denmark.
Allan
A
Weimann
Section of Experimental Animal Models, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, DK-1870, Frederiksberg C, Denmark.
Jens
J
Lykkesfeldt
Laboratory of Clinical Pharmacology, Rigshospitalet, Ole Maaløes Vej 26, Entrance 76, Section Q7642, DK-2200 Copenhagen N, Denmark; Department of Clinical Pharmacology, Bispebjerg Frederiksberg Hospitals, Bispebjerg Bakke 23, 2400 Copenhagen NW, Denmark; Institute of Clinical Medicine, University Hospital Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: hepo@rh.dk.
Henrik Enghusen
HE
Poulsen
D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D064368:Healthy Volunteers; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D055815:Young Adult
D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017382:Reactive Oxygen Species; D019821:Simvastatin
8-oxodg; 8-oxoguo; DNA oxidation; Oxidative stress; RNA oxidation; Randomized clinical trial; Reactive oxygen species; Simvastatin