Simvastatin and oxidative stress in humans: A randomized, double-blinded, placebo-controlled clinical trial

Abstract

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 40 mg 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.

Diabetic Polyneuropathy in Type 2 Diabetes Mellitus: Inflammation, Oxidative Stress, and Mitochondrial Function

“…However, a study performed in coronary artery disease patients where Ezetimibe/Simvastatin 10/20 mg was compared to Simvastatin 80 mg as monotherapy demonstrated that inflammation biomarkers (CRP, IL-6, monocyte chemoattractant protein-1, and soluble CD40) were unaltered after 6 weeks of treatment, probably explained by the theory that the target of statins resides on oxidative stress rather than inflammatory response [136]. A study performed in healthy male subjects treated with Simvastatin monotherapy showed no changes in oxidative stress to nucleic acids, LPO, and plasma antioxidants [137], probably due to the lack of free radicals increase, since Ezetimibe alone has been shown to reduce 8-isoprostanes and reactive oxygen metabolites levels only in hypercholesterolemic patients with high oxidative stress at baseline, but not in those with near-normal oxidative status [138]. Rosuvastatin 20 mg was assessed in 17 patients with type 2 DM and DPN, and a reduction of Neuropathic Symptoms Score (NSS) and NCS were observed after 12 weeks of treatment, along with a significant reduction in LPO but no changes in nerve growth factor beta [139].…”

Cardiovascular and All-Cause Mortality Risk Associated With Urinary Excretion of 8-oxoGuo, a Biomarker for RNA Oxidation, in Patients With Type 2 Diabetes: A Prospective Cohort Study

“…We used validated and highly specific ultraperformance liquid chromatography tandem mass spectrometry to detect 8-oxoGuo levels, which were then compared with the levels of 8-oxodG (the biomarker for DNA modification by oxidation) in spot urine samples corrected for urinary creatinine (21). The validation procedures were in accordance with the U.S. Food and Drug Administration guidelines, and the lower limit of quantification was 1.0 nmol/L for both 8-oxoGuo and 8-oxodG (21). According to recently published data, the accuracy of this method was 98.7% for 8-oxoGuo and 95.7% for 8-oxodG (21).…”

“…The validation procedures were in accordance with the U.S. Food and Drug Administration guidelines, and the lower limit of quantification was 1.0 nmol/L for both 8-oxoGuo and 8-oxodG (21). According to recently published data, the accuracy of this method was 98.7% for 8-oxoGuo and 95.7% for 8-oxodG (21). The average within-day precision was 2.9% for 8-oxoGuo and 3.7% for 8-oxodG; average between-day precision was 1.5% for 8-oxoGuo and 3.4% for 8-oxodG (21).…”

“…The average within-day precision was 2.9% for 8-oxoGuo and 3.7% for 8-oxodG; average between-day precision was 1.5% for 8-oxoGuo and 3.4% for 8-oxodG (21). Specificity was achieved by measuring two characteristic fragmentation ions (quantifier and qualifier ions) and applying the relevant acceptance criteria for the response ratio between the two ions (21).…”

Clarithromycin, trimethoprim, and penicillin and oxidative nucleic acid modifications in humans: randomised, controlled trials

“…Even though statins lower calcium-induced oxidative modifications [43], simvastatin did not reduce oxidative modifications in healthy humans [44]. The limited and inconsistent literature exploring a possible antioxidant effect of statins are not sufficient to rule out whether the reversed effect of statins in the CLARICOR results could be explained by an antioxidant effect by the statins.…”