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Department of Experimental Medicine and Pathology, University of Rome, La Sapienza, Rome 00161, Italy
* To whom correspondence should be addressed. E-mail: francesco.violi{at}uniroma1.it.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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Among the several issues that have been raised for explaining such divergent results, we have previously pointed out that the prerequisite to test the clinical efficacy of vitamin E in atherosclerotic patients should be that they have to had low plasma vitamin E concentrations as a result of oxidative stress-mediated vitamin E consumption (6). This suggestion is based on several considerations. Thus, observational studies have shown an enhanced rate of cardiovascular events in populations with low circulating concentrations of plasma vitamin E:cholesterol ratio (<5 µmol/mmol) (7). Also, a recent large observational study showed that high baseline levels of vitamin E were associated with lower risk of mortality for coronary heart disease and stroke (8), reinforcing the results of previous observational trials and suggesting an important role for vitamin E dietary intake in modulating atherosclerotic progression (9,10). Moreover, in humans, vitamin E plasma concentrations seem to be regulated by oxidative stress; e.g. they have been shown to be lowered by cigarette smoking, a phenomenon that was inhibited by the assumption of an antioxidant (11–13). The interventional trials with vitamin E did not take this issue into account, because the baseline levels of vitamin E have never been considered as an inclusion criteria. Also, very few trials measured vitamin E circulating levels to assess compliance (14–16); this is another crucial issue of interventional trials, because vitamin E is scarcely absorbed unless it is consumed after meals (17).
We argued, on the contrary, that baseline values of the vitamin should represent a crucial inclusion criteria to identify patients as candidates for vitamin E supplementation (18). This suggestion is based on the assumption that vitamin E supplementation would hardly reduce oxidative stress in subjects with normal vitamin E plasma concentrations. This point, which is of crucial relevance for interpreting the trials with vitamin E, has been carefully investigated by Meagher et al. (19), who supplemented healthy subjects with up to 1342 mg/d vitamin E (d-
-tocopherol) and found no changes in the urinary excretion of isoprostanes, a marker of oxidative stress. As these subjects likely had normal plasma concentrations of vitamin E, this study supports the concept that vitamin E supplementation is likely useless in subjects with vitamin E plasma concentrations within the normal range.
Based on these considerations, we have already noticed that in the very few studies reporting baseline vitamin E values, the data clearly indicated that a large part of the population screened could have normal values of vitamin E (20). Even if a large variability of vitamin E plasma concentrations can be found in the populations at risk of cardiovascular disease (21), we speculated that in such trials, concomitant treatment could have influenced oxidative stress and the circulating levels of vitamin E. In particular, we focused our attention on the possibility that, in vitamin E-allocated patients, concomitant use of statins reduced oxidative stress and spared vitamin E consumption, thus increasing its circulating values. This hypothesis is based on the results of a recent interventional trial with atorvastatin in patients with hypercholesterolemia. Here, we demonstrated that as early as after 1 mo of statin treatment, vitamin E plasma concentrations increased as a consequence of reduced excretion of isoprostanes, reaching values comparable to those of healthy subjects (22). This effect was concomitant with reduced urinary isoprostanes, suggesting that inhibition of oxidative stress could spare vitamin E consumption and eventually increase its plasma concentrations. In vitro study reinforced this suggestion by demonstrating that atorvastatin inhibited the formation of isoprostanes and spared vitamin E consumption elicited by LDL-treated platelets (22). Our hypothesis that statin enhances circulating vitamin E plasma concentrations may be at variance with previous studies showing that statins reduce both serum cholesterol and vitamin E (23). It is of note, however, that in statin studies, the decrease of serum cholesterol is more marked; therefore, the vitamin E:cholesterol ratio is actually increased (23).
To analyze the potential interplay between vitamin E and statins, we took into account only the interventional trials with more than 1000 patients. Of the 9 trials (Table 1), the use of concomitant lipid-lowering agents was not reported in 4 (14,24–26), which, however, included patients who had clear indications for statins treatment. Thus, a relatively large population had hypercholesterolemia or had experienced previous cardiovascular events and, hence, it was not possible to exclude a concomitant use of statins before and during the follow-up.
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5% of vitamin E-allocated patients concomitantly used statins, a value that rose to >45% during the follow-up. In the HOPE studies (15,28), approximately one-third of the patients allocated to vitamin E concomitantly used statins at the entry in the study; it was not reported, however, if this figure changed during the follow-up. In the HPS study (16), 20% of vitamin E-allocated patients concomitantly used statins at the entry of the study; this figure reached values >50% during the follow-up (29). In the PPP study (30), which examined the clinical effect of vitamin E in primary prevention, >15% of vitamin E-allocated patients concomitantly used statins at the entry of the study, but it was not reported if this figure changed during the follow-up. Together, the analysis of these trials clearly shows that in the interventional trials with vitamin E, a large number of patients allocated to vitamin E were also taking statins. It is of note that in 1 of these trials, the HPS study, the participants and their general practitioners were encouraged to use nonstudy statins during the follow-up as the emergent results from other studies indicated the clinical usefulness of statin treatment (29).
Based on this analysis of interventional trials with vitamin E, we think that these trials have been biased by the concomitant use of statins that precluded the assessment of the potential usefulness of vitamin E. In fact, assuming that patients included in these studies really needed vitamin E supplementation because of enhanced oxidative stress, the concomitant use of a statin rendered useless the vitamin E supplementation in a large number of patients, because it normalized vitamin E plasma concentrations. The consequence of this argument is that meta-analyses of trials with vitamin E have intrinsic drawbacks that preclude definite conclusion. A novel meta-analysis, which excludes patients who took both vitamin E and statins, could provide more useful information on the effects of vitamin E in patients at risk or with cardiovascular events.
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FOOTNOTES |
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2 Author disclosures: F. Violi and R. Cangemi, no conflicts of interest.
Manuscript received 14 February 2008. Initial review completed 7 March 2008. Revision accepted 2 April 2008.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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