Oxidative stress is thought to underlie cardiovascular and many other diseases. Oxidative stress reflects an imbalance between the byproducts of humans being on fire (oxidizing), and human’s ability to readily repair that damage with our antioxidant systems. Malondialdehyde (MDA) is a complex molecule that serves as a marker for oxidative stress, the higher the MDA, the worse the oxidative stress.
Inflammation (Latin root “to set alight or burn”) is a complex biological response to harmful stimuli, such as pathogens, damaged cells, toxins, or antigens. Inflammation is an attempt by the organism to remove the injurious stimuli and begin the healing process. C-reactive protein (CRP) is a protein found in the blood, the levels of which rise in response to inflammation: the higher the CRP, the worse the inflammation.
Both statins and vitamin D have pleiotropic effects, meaning they have many different effects on the body and appear to work in different ways. Pleiotropic comes from the Greek, meaning “more,” and “convert.” While the mechanism of action of vitamin D’s pleiotropy is easy to explain (vitamin D has as many mechanisms of action as genes it regulates), the same cannot be said of statins. How do they work other than reducing cholesterol?
Dr Thozhukat Sathyapalan and colleagues of the Hull York Medical School in England recently conducted a remarkable study of two statins.
Sathyapalan T, Shepherd J, Atkin SL, Kilpatrick ES. The effect of atorvastatin and simvastatin on vitamin D, oxidative stress and inflammatory marker concentrations in patients with type 2 diabetes: a crossover study. Diabetes Obes Metab. 2013 Jan 28.
The two statin drugs studied were atorvastatin (Lipitor) and simvastatin (Zocor). Both lower cholesterol equally well and both are used to prevent cardiovascular disease. However, at least one study shows that cardiovascular events are lower with atorvastatin than simvastatin.
Jacobson TA, Wertz DA, Hoy T, Kuznik A, Grochulski D, Cziraky M. Comparison of cardiovascular event rates in patients without cardiovascular disease in whom atorvastatin or simvastatin was newly initiated. Mayo Clin Proc. 2008 Dec;83(12):1316-25.
That is, Lipitor may work better than Zocor in preventing cardiovascular disease. Is that because Lipitor reduces oxidative stress and inflammation better than Zocor? Remember, both drugs lower cholesterol equally well. If Lipitor works better at lowering inflammation and oxidative stress than Zocor does, what is Lipitor’s mechanism of action? We know that statins as a group elevate vitamin D levels.
However, Dr Sathyapalan wanted to find out if Lipitor increased vitamin D levels more than Zocor, and if so, was that elevation associated with better CRP and MDA levels. So he studied lipid levels, 25(OH)D levels, markers of inflammation (CRP) and a marker of oxidative stress (MDA) in 26 patients taking one or the other drug. He then did a cross-over study.
After 3 months on one statin, lipids, CRP, 25OHD and MDA were measured repeatedly. The patient’s statin was then switched and the same procedure was then followed after taking the other statin. LDL cholesterol concentrations were similar whether the same patients took Zocor or Lipitor. However, the mean 25OHD was higher and both the CRP and MDA concentrations lower while on Lipitor compared to Zocor.
Furthermore, the average 25OHD was higher after Lipitor than Zocor. What’s more, the changes in 25OHD predicted the changes in CRP (p=0.002) and MDA (p=0.001) levels. Thus, compared to Zocor, Lipitor demonstrates more beneficial effects in raising 25OHD levels, and Lipitor lowers markers of oxidative stress and inflammation better than Zocor.
Is that why Lipitor works better than Zocor, because it raises vitamin D levels higher?
The authors wrote,
“In conclusion, 25OHD concentrations are higher in patients when taking atorvastatin rather than simvastatin at doses that lead to equivalent reductions in LDL. The vitamin D rise is associated with significant improvements in markers of oxidative stress and inflammation suggesting this may be a mechanism by which atorvastatin, in particular, exerts its pleiotropic effects.”