Council for Responsible Nutrition - November 2004
Like many people, you may have questions about some of the recent stories that have been in the news about vitamin E. Here is some useful advice to help you better understand the safety and benefits of vitamin E.
"I recommend vitamin E to my patients, and I will continue to do so."
Mary Hardy, MD, Associate Director, Botanical Research Center, Center for Human Nutrition, UCLA
Vitamin E meta-analysis in Annals of Internal Medicine:
What's wrong with this picture?
What is a meta-analysis?
A meta-analysis is not a clinical trial. It is a statistical technique for combining the results of many existing studies in order to clarify possible effects. When studies are done with a few hundred or even a few thousand people, it is often difficult to determine whether differences between the treatment group and the placebo group are "real" or just accidents due to chance. Combining studies provides more people for analysis and thus increases statistical power. While a meta-analysis is an important scientific tool, it also has limitations.
What is all-cause mortality?
Studies are generally designed to look at some particular outcome, like whether vitamin E reduced the risk of having a heart attack. However, in studies involving sick people and lasting for several years, there will be other outcomes, such as death. A certain number of people in longterm studies are going to die, and all-cause mortality is the number of people who died from any cause—whether or not the cause has anything to do with the purpose of the study. All-cause mortality includes people who died of heart disease or infectious disease or cancer or getting hit by a bus. The number of people who die in the treatment group and in the control group will rarely be exactly equal. Statistical analysis tells us whether differences in total mortality between the treatment group and the control group are significant or just the result of chance.
What did this study find, overall?
This study analyzed 19 clinical trials in which vitamin E was given, involving a total of almost 140,000 people. Eighteen of the 19 trials individually found no statistically significant increase in total mortality in the vitamin E group. Even when all of the 19 trials were combined, there was no significant increase in total mortality. The study authors say, "The average death risk across trials in the control groups was 1022 per 10,000 persons. Overall, vitamin E supplementation did not affect all-cause mortality."
What did the study find, relating to high and low doses of vitamin E?
When the trials were divided according to the dose of vitamin E, the researchers found that low doses of vitamin E slightly decreased total mortality while high doses of vitamin E (400 mg or more) slightly increased total mortality. The researchers said this was a statistically significant effect, but others have criticized whether it has practical meaning. Most of the high-dose studies were done in people who already had various diseases and the authors say that these findings may not be generalizable to healthy adults. However, they go on to generalize, saying that people should avoid high-dose vitamin E and indeed high doses of any vitamin—a conclusion much more sweeping than is justified by their analysis.
Were there other findings?
The researchers also did a dose-response analysis of the clinical trials, which found a statistically significant (but very small) increase in mortality only when the vitamin E dose was greater than 900 mg. This is contrary to the finding in their main meta-analysis that doses over 400 mg might confer increased risk.
What were the 19 studies used in this meta-analysis?
The studies chosen for the meta-analysis all lasted more than one year and reported at least 10 deaths from all causes. Studies in which no deaths occurred were not included in the analysis. The studies were originally published in the decade from 1993 to 2004. Some of the studies involved over 20,000 people, and some involved only a few hundred people. Doses used in the studies ranged from 16.5 mg to 2000 mg and were given for periods from one to 8 years. In some studies the vitamin E was given as part of a multivitamin or some other mixture of nutrients, and in some studies vitamin E was given as a single nutrient. The studies were conducted in various parts of the world—Europe, Asia, the Middle East, Australia, Canada, and the U.S. Vitamin E was given in these studies for many different purposes, including reducing the risk of heart disease, cancer, and macular degeneration and delaying the progression of cataracts, kidney disease, Alzheimer's disease and Parkinson's disease. Some of the studies found a benefit of vitamin E for these purposes.
Do any of the studies show a benefit from vitamin E?
Yes. Many of the 19 clinical studies used in this meta-analysis actually showed a health benefit from vitamin E. For example, one study in England showed that vitamin E at levels of 400 and 800 mg reduced the risk of heart attack by 75% in men who already had symptoms of heart disease. A study in patients with kidney failure found a reduced risk of heart attacks and of death from heart disease in people who were given 800 mg of vitamin E. Another of the studies found that vitamin E (400 mg) in combination with some other nutrients reduced the risk of age-related macular degeneration, the leading cause of blindness in elderly people. And one study showed that a very high dose of vitamin E (2000 mg) delayed the progression of Alzheimer's disease.
Do epidemiologic studies show a benefit from vitamin E?
Yes. Numerous epidemiologic studies have shown a benefit from vitamin E. In an epidemiologic study, researchers simply observe whether people who use certain products or adopt certain habits on their own have more or less disease than people who do not. A Harvard study of more than 80,000 nurses found a 41% reduction in the risk of heart disease in nurses who had used vitamin E supplements for at least 2 years. A Harvard study of almost 40,000 male health professionals (mostly dentists) found that men who took vitamin E supplements for more than 2 years had a 37% reduced risk of heart disease. A study conducted by the National Institute of Aging in 11,000 elderly people found that those who used supplements of vitamins C and E had a 53 percent reduction in mortality from heart disease and a 42 percent reduction in all-cause mortality, compared to non-users.
Are more studies being done using high-dose vitamin E?
Yes. A number of new clinical trials are now under way, and researchers are attempting to reassure the people enrolled in these trials that vitamin E is safe and that the research should continue. They include the Women's Health Study involving over 40,000 female health professionals, the Physicians' Health Study involving thousands of U.S. doctors, and the Women's Antioxidant Cardiovascular Disease Study. Also, the National Cancer Institute is sponsoring the Selenium and Vitamin E Chemoprevention Trial (SELECT) to evaluate the effects of these two nutrients in protecting against prostate cancer in more than 30,000 men.
Was it reasonable to select 400 mg as the cutoff between low-dose and high-dose vitamin E?
No. Four hundred mg was an arbitrary number. It is not evident how the researchers chose to define 400 mg and not some other value as the "high-dose" mark, except that it is the most commonly marketed dose in the U.S. Two important studies including the GISSI trial in Italy used 330 mg of vitamin E—not much lower than 400 mg. Including those in the high-dose group would have been reasonable, and the positive effects of the GISSI trial would have offset some of the studies showing a trend toward increased mortality. Below that dose, there is only one study at 200 mg, also showing a slightly beneficial effect on total mortality. The truly "low-dose" studies are the five that used only 60 mg or less of vitamin E. In short, it appears that 400 mg rather than 200 or 300 mg may have been arbitrarily selected as the high-dose cutoff in order to bolster a finding of risk.
How much vitamin E is safe?
The Institute of Medicine, a scientific advisory body, has concluded that vitamin E is safe for chronic use in the general population at levels up to 1000 mg. The Recommended Dietary Allowance for vitamin E is 15 mg, and only a small fraction of the population gets this much from diet alone. Most multivitamins contain 15 to 30 mg of vitamin E.
What should people think about this meta-analysis?
This meta-analysis does not change what is known about vitamin E safety. It used no new research but instead combined 19 studies in order to create statistical significance for a finding of a slight increase in all-cause mortality in studies that used 400 mg or more of vitamin E, but overall the studies showed no such increase and a dose-response analysis showed a significant increase only at levels above 900 mg. The authors have exaggerated the practical significance of their findings to attract attention and scare the public. As a result, numerous participants in ongoing clinical trials on high-dose vitamin E sponsored by the National Cancer Institute have been needlessly frightened, and the future of the studies may be endangered. Consumers who are already using vitamin E should continue to use it with confidence, and people who are not currently using at least a multivitamin containing vitamin E should consider doing so, since the overwhelming majority of the population fails to get the recommended amount of vitamin E from diet alone.
General Questions and Answers about Vitamin E
Q. I've seen some confusing news in the paper about vitamin E. Although I've taken vitamin E daily for almost 10 years, I now wonder about its safety. Is this vitamin safe?
A. Yes. Vitamin E is very safe. Like all vitamins, it is by definition essential for life. Your body needs it to protect against damage caused by free radicals, oxidized substances that can be associated with heart disease and cancer. In addition, many studies have shown that vitamin E boosts the immune system, reduces the risk of developing various vision disorders including cataracts or macular degeneration, and improves brain function –enhancing short term memory while reducing the risk of developing Alzheimer's disease.
Q. An article I read suggested that vitamin E may be harmful. What is that all about?
A. Some researchers from Johns Hopkins University conducted a meta-analysis (see related fact sheet) of 19 studies conducted with patient groups, many of whom were elderly, and taking multiple prescription medications because they already had chronic diseases including Alzheimer's disease, Parkinson's disease, kidney failure or heart disease. The researchers interpreted their data to suggest that high doses of vitamin E may be associated with a slight increased risk of death. Many of the nation's leading antioxidant experts reviewed the study and said they were not convinced of an increased risk and in fact noted that vitamin E is safe within a wide range of intakes.
Q. Can I get all the needed vitamin E through diet?
A. Most people do not get the Recommended Dietary Allowance of vitamin E (15 mg) from their diet alone. That's why so many of us need to take a supplement to ensure adequate intake. You can get more vitamin E into your diet by consuming such foods as nuts, green leafy vegetables and fortified cereals. You can also get vitamin E from a multivitamin or a single vitamin E supplement.
Q. Is it safe to take more vitamin E than what I can get in a multivitamin?
A. Yes, and for many people high doses of vitamin E is beneficial. The Institute of Medicine, a scientific advisory board, has set an Upper Level (a dose at which there is no known harm) for vitamin E at 1600 IU or 1000 mg.
Q. What is the common dose of vitamin E?
A. The most commonly marketed dose in the U.S. is 400 mg.
Q. What is the link between vitamin E and the protection of my eyesight?
A. A number of studies spotlight the association between vitamin E and reduced risk of cataracts (a major cause of blindness throughout the world) and macular degeneration (the number one cause of vision impairment in the United States). In one study of people taking a multivitamin or a supplement of C or E for a decade, results showed a 60% lower incidence of cataracts among the group taking a supplement. Other studies of people taking vitamins E, C and zinc demonstrated they were better protected from advanced macular degeneration than those individuals who didn't take them.
Q. Does vitamin E offer protection against developing Alzheimer's disease?
A. There is evidence to suggest that medications or vitamins (such as vitamin E) that increase the levels of catecholamines, certain chemicals in the brain, can protect the neurons from damage that could otherwise lead to Alzheimer's disease. In addition, according to a wide range of other studies, antioxidants like vitamin E can improve brain function, short-term memory, problem-solving and general reasoning skills.
Q. Does vitamin E help protect against cancer?
A. Studies have linked reduced rates of cancers of the prostate, breast, and bladder with higher intakes of vitamin E. It is believed that antioxidants such as vitamin E reduce the risk because they help protect cell membranes from free radicals—a byproduct of cellular metabolism. They bind free radicals before they can do damage to the cell.
Q. Does vitamin E help protect against heart disease?
A. A large body of experimental study and some clinical research studies have indicated a link between intake of the antioxidant vitamin E and a reduced risk of heart disease. In addition, several ongoing trials are being conducted between vitamin E and the risk of heart disease.
Q. Is it important to continue studying the effects of vitamin E?
A. Absolutely. Many studies underway around the world will add to our knowledge over the coming years, so that we can optimize the level and formulation of vitamin E for various age groups and for people with inherited risk factors for a wide range of diseases.
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