Study Flaws Cast Doubt on Claims of Vitamin E Danger
By Alan R. Gaby, MD
Healthnotes Newswire (November 18, 2004)—Although a large body of evidence suggests that vitamin E may help or prevent many health conditions, a study to be published in the Annals of Internal Medicine (January 2005) has concluded that supplementing with large doses of vitamin E (400 IU per day or more) may increase death rates. However, the claim that vitamin E may be harmful is far from proven, as significant flaws in the study call this conclusion into question. In addition to the researchers’ acknowledgement that their findings may apply only to people with chronic illnesses (as opposed to healthy people), the millions of people who take this antioxidant vitamin to preserve health and prevent heart disease should also consider the limitations outlined below.
In the study, researchers combined the results of 19 previously published vitamin E supplementation trials that included a total of 135,967 participants. The patients in the various studies were randomly assigned to take vitamin E (in amounts ranging from 16.5 to 2,000 IU per day) or a placebo for at least one year. Most of the patients had one or more chronic diseases (such as heart disease, diabetes, Parkinson’s disease, Alzheimer’s disease, or kidney failure) or were at high risk of developing heart disease. In the 19 studies combined, the risk of death due to any cause did not differ significantly between people assigned to vitamin E and those assigned to placebo. However, the effect of vitamin E supplementation on mortality differed according to how much vitamin E was used. In the low-dose studies (less than 400 IU per day), vitamin E supplementation was associated with a small and not statistically significant reduction in the death rate. In the 11 high-dose studies (400 IU per day or more), those who took vitamin E had a 4% increase in risk of death, an increase which, though small, was statistically significant. Based on these findings, the authors of the new study recommend that people limit their vitamin E intake to less than 400 IU per day.
For a number of reasons, that recommendation may be unwarranted. In some of the high-dose studies, certain aspects of the study design preclude any meaningful conclusion about vitamin E. For example, in the Age-Related Eye Disease Study (AREDS), participants received not only vitamin E, but also 80 mg of zinc and 2 mg of copper per day, as well as other nutrients. Supplementing with large doses of zinc (80 mg per day is a fairly large dose) for long periods of time can lead to copper deficiency, which can increase the risk of heart disease and other chronic illnesses. Although copper was also supplemented, it was given in the form of cupric oxide, an insoluble compound that cannot be absorbed by humans. The increase in mortality found in this study could have been due to zinc-induced copper deficiency, and may have had nothing to do with vitamin E supplementation.
In another high-dose vitamin E study (Cambridge Heart Antioxidant Study), the results were complicated by the fact that the vitamin E and placebo groups were not comparable. Even though assignment to the two groups was done randomly, the vitamin E group had significantly higher serum cholesterol levels and significantly greater percentages of participants with high blood pressure, diabetes, cigarette smoking, and severe coronary artery disease, compared with the placebo group. Thus, the people taking vitamin E were sicker than those taking the placebo, a fact that could account for the slight increase in mortality seen in the vitamin E group.
In a third high-dose study (the MRC/BHF Heart Protection Study), participants received synthetic beta-carotene in addition to vitamin E. Researchers have questioned the safety of synthetic beta-carotene (which is chemically different than food-derived beta-carotene), particularly for people who smoke cigarettes or drink alcohol. Previous studies have shown that supplementing with synthetic beta-carotene increases the risk of lung cancer among smokers and increases alcohol-induced liver damage in laboratory animals. It is possible that the increase in mortality found in the MRC/BHF Heart Protection Study was due to the use of synthetic beta-carotene, and may have had nothing to do with vitamin E.
The three studies mentioned in the previous paragraphs included a total of more than 27,000 participants, fully two-thirds of all of the patients in the 11 high-dose vitamin E studies. Consequently, the conclusion that high-dose vitamin E is dangerous is based primarily on the results of these three apparently flawed studies.
Furthermore, if any adverse effect of high-dose vitamin E does exist, the findings might be explained by the type of vitamin E used in the research studies. Vitamin E (also called tocopherol) occurs naturally in food in four different forms, known as alpha-, beta-, gamma-, and delta-tocopherol. Although approximately 70% of the vitamin E in food is in the form of gamma-tocopherol, most of the nutritional supplements on the market contain only alpha-tocopherol, and all 19 studies included in the new report used alpha-tocopherol by itself.
While alpha-tocopherol has a number of biochemical actions (such as preventing the oxidation of LDL (“bad”) cholesterol and inhibiting platelet aggregation) that would be expected to prevent heart disease, certain functions are performed better by gamma-tocopherol. For example, the formation of nitric-oxide-derived free radicals, which appears to be a factor in heart disease development, is inhibited to a greater extent by gamma-tocopherol than by alpha-tocopherol. In addition, gamma-tocopherol possesses certain anticancer effects that are not shared by alpha-tocopherol. Supplementing with large amounts of alpha-tocopherol alone has been found to deplete gamma-tocopherol. Consequently, whatever positive effects are produced by alpha-tocopherol supplementation might be counterbalanced by a reduction of gamma-tocopherol levels in the body, a reduction that would presumably be more pronounced when using higher doses of pure alpha-tocopherol.
If high-dose alpha-tocopherol does adversely affect some people, one might reasonably expect that “mixed tocopherols,” which contain all four naturally occurring forms of vitamin E, would not have the same negative effects. Although mixed tocopherols are more expensive than alpha-tocopherol, the available evidence suggests that mixed tocopherols are the preferable form of vitamin E, both in terms of safety and effectiveness.
Although all of the 19 studies reviewed in the new report used alpha-tocopherol, not all of them used the same type. Alpha-tocopherol is commercially available in two forms: D-alpha-tocopherol (the form that occurs in food and in the body) and D,L-alpha-tocopherol (an equal mixture of D-alpha-tocopherol and its mirror image, L-alpha-tocopherol). The D,L- mixture is less expensive to manufacture than the D- form, and is frequently used in research studies. L-alpha-tocopherol does not occur naturally in food or in the body and has little or no vitamin E activity; preliminary evidence suggests that it may even interfere with some of the effects of D-alpha-tocopherol. Moreover, not much is known about the long-term safety of L-alpha-tocopherol. Of note, in the only large study that used the naturally occurring D-alpha-tocopherol (the Heart Outcomes Prevention Evaluation), the mortality rates in the vitamin E and placebo groups were identical. Thus, if there is a small negative effect of high-dose vitamin E, it might be attributable in part to the use of the unnatural D,L- mixture.
The issues raised in this commentary cast doubt on the reliability of the new study’s conclusions. Of course, if the only good thing one could say about high-dose vitamin E is that it probably does not kill people, there would be no point to this discussion. Years of research, however, suggests that vitamin E may help prevent heart attacks, slow the progression of Alzheimer’s disease, reduce the deleterious effects of air pollution, and aid in the treatment of intermittent claudication, fibrocystic breast disease, premenstrual syndrome, childhood epilepsy, certain forms of chronic hepatitis, osteoarthritis, and infertility. Nearly all of these studies used 400 IU or more of vitamin E per day. Whether lower doses of mixed tocopherols would be as effective as higher doses of alpha-tocopherol should be a topic of future research.
Alan R. Gaby, MD, an expert in nutritional therapies, testified to the White House Commission on CAM upon request in December 2001. Dr. Gaby served as a member of the Ad-Hoc Advisory Panel of the National Institutes of Health Office of Alternative Medicine. He is the author of Preventing and Reversing Osteoporosis (Prima, 1994), and co-author of The Natural Pharmacy, 2nd Edition (Healthnotes, Three Rivers Press, 1999), the A–Z Guide to Drug-Herb-Vitamin Interactions (Healthnotes, Three Rivers Press, 1999), Clinical Essentials Volume 1 and 2 (Healthnotes, 2000), and The Patient’s Book of Natural Healing (Prima, 1999). A former professor at Bastyr University of Natural Health Sciences, in Kenmore, WA, where he served as the Endowed Professor of Nutrition, Dr. Gaby is the Chief Medical Editor for Healthnotes, Inc.
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