We investigated the relations between supplemental vitamin E intake and risk of cardiovascular disease and all-cause mortality in the Framingham Heart Study, a large community-based observational study. Observational studies on vitamin E have generally investigated primary prevention, whereas intervention trials mainly focused on secondary prevention. The purpose of our study was to investigate both, primary and secondary prevention within an observational study, a novel systematic approach that has not been reported in the literature before. We conducted the analyses separately in participants who were free of overt CVD and in participants who had CVD at baseline.
Whether vitamin E supplement intake is beneficial or without any effect in the prevention of CVD has been vividly discussed in the scientific literature over the past decades. The discussion around vitamin E has gained special momentum over the course of the last three years when several studies were published reporting adverse effects of vitamin E supplementation, an effect that has not been reported before. These reports came from two meta-analyses of vitamin E intervention trials which reported increased risk of all-cause mortality7, 8
and from two individual studies, the HOPE and GISSI studies9, 10
, which reported increased risk of heart failure. Bjelakovic et al. conducted a meta-analysis on randomized trials of antioxidant supplement intake and reported significantly increased mortality with vitamin E supplement intake. Miller et al. conducted a meta-analysis of the dose-response relationship between vitamin E supplementation and total mortality and reported a statistically significant relationship between vitamin E dosage and all-cause mortality with increased risk of high dose intake. The report by Miller et al., however, has been repeatedly questioned due to several limitations it had. The majority of trials included were secondary prevention trials, thus participants already had chronic diseases and therefore may have had a higher risk of mortality. It therefore is not applicable to a population free of chronic disease. Further, it combined trials that used synthetic and natural vitamin E which have different bioavailability18
. The report also did not assess the adherence of study participants to vitamin E supplement intake18
and the reported effect size of vitamin E treatment was quite small.
The two individual studies which reported adverse effect of vitamin E, were conducted in patients with pre-existing cardiovascular disease or diabetes, and the majority of intervention trials included in both meta-analyses were also conducted in patients with various pre-existing chronic diseases or risk factors thereof. Observational studies conducted in the 1990ies, on the other hand, have never reported adverse effects with supplemental vitamin E intake and the majority has observed beneficial effects. Observational studies are generally conducted in participants without overt chronic diseases.
Based on this background, we hypothesized that a possible reason for the discordance between observational studies (no effect or protective effect) and the recently published studies reporting adverse effects is the underlying health status of their study participants. However, there are other differences in design between intervention studies and observational studies of vitamin E supplements and CVD. A major difference is the greater susceptibility of observational studies to bias. Other differences include the usual duration of exposure of vitamin E supplements, which tends to be longer in observational studies.
The underlying rationale for our hypothesis was based on recent data, albeit limited, suggesting that high vitamin E intake may affect drug metabolism19–21
. It has been reported that high alpha-tocopherol (the most biologically active form of vitamin E and almost exclusively used in vitamin E intervention trials) intake may adversely affect drug metabolism by up-regulating CYP3A, the major enzyme involved in the metabolism of a majority of therapeutic agents. This up-regulation could therefore lead to a faster metabolizing of therapeutic agents and thus decrease their efficacies19–21
. Given that individuals with pre-existing chronic diseases are more likely to be on medications for their conditions, vitamin E supplement use could therefore potentially diminish the effect of these medications, leading to a higher incidence of CVD or all-cause mortality in these individuals compared to individuals not taking medications.
Our analyses did not support this hypothesis. We did not observe any evidence of increased risk of CVD or all-cause mortality with supplemental vitamin E intake in individuals with pre-existing CVD, nor did we see any evidence of decreased risk in individuals without chronic disease in the Framingham Heart Study. However, given the width of the confidence intervals for all-cause mortality in participants without pre-existing disease, we cannot rule out an elevated risk among supplement users. Likewise, for we cannot rule out a possible protective association with all-cause mortality among those with pre-existing CVD. These relatively wide confidence intervals are a consequence of the relatively small number of participants taking vitamin E supplements.
Other potential limitations of our study was its observational design, limiting causal inference and increasing the likelihood of confounding relative to intervention trials, and the possible lack of generalizability of our findings from this cohort that is predominantly Caucasian. The strength of the present study includes the large community-based cohort of men and women, and the well-characterized CVD endpoints.
Although our results are inconsistent with our hypothesis of a differential effect of vitamin E supplementation among those with and without pre-existing disease, the above mentioned limitations prevent us from drawing any definitive conclusions about the benefit or harm of supplemental vitamin E intake from this study. Therefore, discrepancy between the results from observational studies and from the recent clinical and meta-analyses studies reporting adverse effects has not been resolved and the basis of this difference is not clear yet. Further systematic exploration of this intriguing hypothesis in other populations is warranted in order to find out if study participants’ underlying health statuses may be the reason for the discrepancy.