Recently, there has been considerable media attention as to whether or not vitamin E supplementation is safe or helpful. The attention has been largely driven by publication of two papers in medical science journals over the past year which reported potential adverse health effects of vitamin E supplementation10,11. As a result, physicians and other health professionals have been deluged with questions from their patients about vitamin E and sales of vitamin E supplements have plummeted.

What is the scientific basis of the claims of benefits and harms conveyed by vitamin E supplements?

Why Vitamin E Supplements are Popular
Over the past two decades, some scientists have proposed a so-called 'oxidant theory of disease. This hypothesis contends that oxidative metabolism, and the free radicals that arise from it, is the core pathophysiologic mechanism underlying a number of chronic degenerative diseases including cancer and cardiovascular disease (CVD). This theory, furthermore, postulates that adequate, or even large doses of anti-oxidant nutrients such as vitamins C, E, the carotenoids and selenium can protect against such damage. Amongst all of these possible benefits, the potential protective effects against CVD and cancer have been the two most extensively submitted to the test of randomized clinical trials.

How Widespread is the Use of Vitamin E Supplements?
The daily use of dietary supplements, and in particular vitamin E, has grown to be a widespread habit. Most surveys performed in the past five years have observed regular intake (more than 5 times/week) among 25-50% of the adult population and, in almost all cases, the prevalence incrementally increases by age and with the presence of chronic degenerative diseases. Commonly, these adults take daily doses of 400 mg or more. Even among doctors, vitamin E supplementation for their personal consumption is a growing practice.

A Perspective on the Doses Contained in Vitamin E Supplements
The growing acceptance of vitamin E as a useful nutritional supplement has been greatly enhanced by the apparent safety of the vitamin, with upper limits of safe intake set by the National Academy of Sciences at 1000 mg/day, or approximately seventy times the recommended daily allowance (RDA) for the vitamin. So, although the most commonly used dosage for single-nutrient vitamin E supplements is 400 mg or roughly 30-fold greater than the RDA, that level of supplementation is still less than half the purported upper limit of safe intake.

With such a wide array of benefits and with an apparent solid margin of safety, it is not surprising that large segments of the public, as well as health professionals, have adopted the same philosophy uttered recently by a prominent heart researcher, who said about high dose vitamin E: 'It can't hurt and might help, so why not take it?'

So, just what do the studies with respect to presumed risk benefit for coronary heart disease and cancer show? And do they confirm the perspective expressed by this researcher?

Vitamin E Supplements and Cardiovascular Disease
Large, observational studies published in the latter part of the 1980s and early 1990s consistently observed a strong association between habitual vitamin E consumption and the risk of coronary heart disease, with risk reductions of 30-60%. These studies demonstrated a remarkably strong decrease in risk associated primarily with the use of high doses of vitamin E but considerably weak effects of low doses of the vitamin.

However, when scientists tried to duplicate these findings in controlled studies of volunteers divided into two groups — one given vitamin E, one given a placebo — where the individuals were followed going forward in time, the results were considerably different. Three large trials observed a neutral effect of vitamin E: neither benefits nor harm were seen. In addition, two other studies — named HATS and HOPE-TOO — also provided no compelling evidence for a consistent benefit of vitamin E in the secondary prevention of cardiovascular disease but nevertheless raised concerns about potential negative side effects. In the HATS trial, the use of vitamin E supplements diminished the angiographic benefits obtained from the use of niacin and a cholesterol-lowering statin drug. In the HOPE-TOO trial, the use of vitamin E supplements slightly, but significantly, increased the risk of congestive heart failure.

However, because one large study, the CHAOS trial, did demonstrate substantial and significant benefits, the case for or against vitamin E is still confused. To resolve this uncertainty, medical statisticians tried to solve the dilemma with a technique called meta-analysis, which we shall come to shortly.

Vitamin E Supplements in Cancer Prevention
A parallel evolution in thought occurred regarding vitamin E's supposed benefits in cancer prevention. Large, observational studies in the 1990s, such as one that was conducted as a cross sectional analysis of 10,000 women and men participating in the NHANES survey (National Health and Nutrition Examination Survey: a representative sampling of the U.S. population), observed what appeared to be a remarkably strong protective effect of vitamin E against lung cancers among those at risk-smokers, but only those who were mild-to-moderate smokers.

Further weight of evidence to the theory of antioxidant protection was attributed to the fact that high intakes of multiple antioxidant nutrients appeared to be synergistic, that is, the total effect was greater than each individual effect added together. In contrast to the epidemiologic literature on cardiovascular disease, this study found no evidence of increasing protection against cancer with high intakes from supplemental E compared to vitamin E coming solely from the diet.

However, as was the case with cardiovascular disease, when this concept of antioxidant protection against cancer was rigorously tested, the results were not compelling. In the largest trial by far, the ATBC trial, ~29,000 male, Finnish smokers were prospectively administered vitamin E, beta-carotene, both or a placebo and followed for nearly a decade. There was no protection against lung cancer, the primary endpoint, and neither was protection conveyed against colorectal or urinary tract cancers. A follow-up study did, however, observe some promising protection against prostate cancer, which is now being followed up with the SELECT trial (see below).

The Linxian trial in rural China also observed some benefit with a 'cocktail' of antioxidant supplements. However, this trial is perceived by most as questionably applicable to Western medicine since this trial was conducted in a population where deficiencies of several of the administered supplements are widespread. Thus, vitamin E supplements have not yet been proven to be efficacious in cancer prevention.

Vitamin E Supplementation for Infection Control in the Elderly
I'll briefly touch on just one other issue pertinent to potential benefits of vitamin — strengthening the immune system of the elderly. There is some evidence that the well-documented decline in immunoresponsiveness of the elderly is related to the activity of oxygen free radicals and that free radical scavengers such as vitamin E can be helpful.One recent study of institutionalized (hospital or nursing home) elderly patients showed a modest, but significant, 15% decline in the risk of upper respiratory infections, primarily the common cold.

Recent Meta-analyses
Two recent meta-analyses in which researchers look at data from several selected trials have reawakened concern over the use of high-dose vitamin E supplementation. The first analysis tested if antioxidant supplements prevented gastrointestinal cancers and showed a beneficial effect overall. However, no benefit was observed in cancer prevention, with the exception that selenium may have shown some modest benefit.10 When only the studies of the highest methodologic quality were examined, there was an increase in all-cause mortality of 6%.

Another meta-analysis encompassing 136,000 subjects published in 2005 examined the issue of the dose of vitamin E. The 2005 study found a slow rise in all-cause mortality associated with vitamin E supplementation with increasing dose such that only daily doses exceeding 150 mg presented some risk. At doses greater than 400 mg/d, the increased risk of death was 39 per 10,000 individuals.

What Conclusions Are to Be Drawn?
A physician is forever confronted with the dilemma of treating patients with imperfect and incomplete information and this is certainly the case here. A reasonable conclusion, based on the information available to date, is that high doses of vitamin E (greater than 100 mg/day) have not conclusively been shown to provide any benefit and might increase the risk of harm, though to a very small degree. Until further insights are acquired in this field, your doctors need to critically challenge themselves as to why vitamin E supplementation may be useful to you. If your doctor, nevertheless, chooses to suggest supplementation, it is best if they recommend dosages less than 100 mg/day.

The multi-center SELECT trial is presently underway in North America and will examine, over a 7-year period, whether 400 mg of vitamin E per day, with or without selenium, is effective in preventing prostate cancer among 32,000 men. This trial will hopefully answer many of the concerns raised in this article.