Vitamin E: Current Controversies
Chester J. Zelasko, Ph.D. | November 16, 2004

In the latest episode of science by press conference, researchers reported at the recent meeting of the American Heart Association that high doses of vitamin E contribute to an increase in all-cause mortality (death for any reason). This elicited an immediate response from the Council for Responsible Nutrition criticizing the study. When reading these arguments in the lay press, it’s a cause for concern for anyone taking vitamin E as a dietary supplement. What you want to know is simple: should I continue to take vitamin E or not--and if so, how much? This Newsletter will attempt to answer that question by reviewing the study (1).

The study was a meta-analysis of the efficacy of vitamin E as a treatment for disease. The purpose of using meta-analysis is to increase the pool of subjects by combining the data from several studies. In that way, subtle differences that were not statistically significant in the individual studies might be significant when the data are pooled.

The primary concern with this study is that the studies included in the analysis were not chosen at random.
Typically, the subjects in most research studies are randomly chosen from an available pool of subjects or if that’s not possible, subjects at least are randomly assigned to treatment groups in order to eliminate confounding variables that could bias results. In that way, any characteristic of the subjects that could affect the results would be randomly distributed. That was specifically not done in the meta-analysis in order to meet the criteria for mortality and duration of study. Out of 2,170 potential studies the researchers identified as possible for inclusion 2,134 were rejected. In other words, 98% of the studies that could have been included were omitted. In effect, this is not a study of over 135,000 subjects randomly selected or randomly assigned to placebo or treatment groups as the paper claims; rather, this is an analysis of the subjects who were participants in 19 studies selected according to very specific criteria that used vitamin E as a treatment for disease--not to prevent disease, or any of the other reasons people use vitamin E. There is no real way of knowing what bias that introduced into the analysis.

Other issues in the study:

Subjects in 13 out of 19 of the studies had a mean age over 60 years.
Aging is related to an increase in mortality and may have biased the results. Including studies with younger subjects who used vitamin E, either healthy or with the same conditions and diseases, might have changed the results--positive or negative.

Two studies were included that had over 20,000 subjects each; one study used 50 IU vitamin E while the other used 660 IU vitamin E, yet both resulted in a very slight increase in all-cause mortality.
If the response to vitamin E were dose-dependent as the researchers claimed, there should have been a much higher death rate with the higher dose.

In the graphic used in the study to depict the dose-dependent nature of all-cause mortality with vitamin E, there are obvious outliers included in the analysis.
Outliers are subjects with extreme responses to the experimental intervention, either much higher or much lower than the majority of subjects. In typical studies, outliers either are excluded from the analysis or the statistics are re-analyzed excluding those data points to see if they affect the results. Neither was done in this analysis.

In the Age-Related Eye Diseases Study (AREDS) used in the meta-analysis (2), a follow-up study published earlier this year found that there was a higher mortality rate in subjects who had age-related macular degeneration (AMD) (3); they also reported a decrease in all-cause mortality in subjects who used antioxidants, including vitamin E and zinc.
This raises two points: first, the original group of subjects did not experience an increased risk of all-cause mortality if they used antioxidants, and that contradicts the findings of the meta-analysis. Second, subjects who had AMD, nuclear opacity, and cataract surgery had an increased mortality. That may mean that there are other factors that should have been considered in the analysis, not just the amount of vitamin E used by the subjects; pre-existing disease may have impacted the outcome.

If all of this research stuff is mumbo jumbo to you, here’s the simplest explanation that I can come up with. There were 135,967 subjects from studies that were included in the analysis. Of those, 12,504 mostly elderly subjects died over a period of time from one year to more than six years. That’s 9.2% of the subject group. The risk-ratio for 500 IU of vitamin E supplementation was estimated to be 1.04 in the study. Translated to actual numbers, that means:
  • 96 out of 1,000 subjects died over the time frame when taking 500 IU vitamin E
  • 92 out of 1,000 subjects died when taking 100 IU vitamin E
It might be statistically significant, but it’s not meaningful in the real world.

This study is a scientific curiosity--nothing more, nothing less. It raises questions about the direction of future research on vitamin E, but it’s certainly not enough on which to base public health policy as the researchers suggest.

So what does this mean to you: should you take vitamin E or not?
The most conservative approach would be to follow the recommendations of the researchers and not exceed 150 IU vitamin E per day--knowing that this is based on questionable research. The most liberal approach would be to not exceed the Upper Limits of 1,000 IU vitamin E established by the Institutes of Medicine (4). A reasonable middle ground is to take 200-400 IU vitamin E per day if you feel you want additional antioxidant protection.

What we at Better Life say is that eating a good diet, exercising regularly, managing stress, and taking supplements are all part of a healthy lifestyle. But know this: you can’t possibly take enough dietary supplements to make up for a bad lifestyle. You have to earn your better life through a better lifestyle every day.

References:
  1. Miller, ER, et al. Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality. Ann Intern Med. 2004;142. (Electronic version--page numbers unassigned).

  2. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS Report No. 9. Arch Ophthalmol. 2001 Oct;119(10):1439-52.

  3. Clemons TE, Kurinij N, Sperduto RD; AREDS Research Group. Associations of mortality with ocular disorders and an intervention of high-dose antioxidants and zinc in the Age-Related Eye Disease Study: AREDS Report No. 13. Arch Ophthalmol. 2004 May;122(5):716-26.

  4. Institute of Medicine. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Food Nutrition Board. Washington, DC: National Academies Press. 2000.
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