Vit E isn't a big one debated in the weight training circles - but if you are taking a multivitamin and it has lots and lots of vitamin E - might be worthwhile to read this article:

Meta-analysis Results Suggest High-Dose Vitamin E Increases All-Cause Mortality CME
News Author: Peggy Peck
CME Author: Charles Vega, MD, FAAFP



Nov. 12, 2004 — Results of a meta-analysis of 19 randomized, placebo-controlled trials suggest that high dosages of vitamin E increase risk of all-cause mortality, and this dose-dependent increase begins at doses of 150 IU/day, said lead author Edgar R. Miller, III, MD, PhD, an associate professor at Johns Hopkins University in Baltimore, Maryland.

The study was presented at the American Heart Association 2004 Scientific Sessions, New Orleans, Louisiana, and simultaneously published in the Nov. 10, 2004, Early Release Article issue of the Annals of Internal Medicine.

Miller said that when he pooled data from almost 136,000 patients who participated in 19 clinical trials of vitamin E, "it was clear that as the vitamin E dose increased, so does all cause mortality. At 400 IUs, which is the most common marketed dose, the risk of dying is about 10% higher than risk among people not taking the vitamin."

At mega-doses, such as the 2,000 IU/day used in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial and in the Alzheimer's Disease Cooperative Study (ADCS) — the increased risk was more than 20%, Dr. Miller said.

"Based on our findings, high dose vitamin E supplementation is unjustified," Dr. Miller said. Although vitamins and other supplements are not regulated by the Food and Drug Administration, an Institute of Medicine report issued in 2000 recommended 1,000 IU/day as the "upper tolerable limit" for vitamin E. "We recommend that the upper tolerable limit be lowered to 400 IUs/day," Dr. Miller said. Dr. Miller noted that adults receive about 10 IU of vitamin E from diet.

"This is the most important story from this meeting," Raymond Gibbons, MD, a professor of medicine at the Mayo Clinic in Rochester, Minnesota, told Medscape. Dr.Gibbons, who served as chair of the scientific program committee at the meeting, said he has been urging his patients to stop taking vitamin E for years. Dr. Gibbons said that cardiovascular disease prevention guidelines from "vitamin E is ‘not recommended'. It doesn't get clearer than that — don't take it."

Gibbons said he hopes this latest report will finally debunk the vitamin E myth.

That is unlikely judging from the lightening fast response from the Council for Responsible Nutrition (CRN), the trade group that lobbies for the supplement industry. Annette Dickinson, PhD, president of CRN told Medscape, "18 of the 19 studies in the analysis showed no statistically significant increase in total mortality. I believe he [Dr. Miller] pooled the data to arrive at a conclusion that is based on a statistical artifact."

Asked to comment on that criticism, Dr. Gibbons said, "that is just flat out wrong. In the British Heart Protection Study, the patients taking vitamin E ended up on the wrong side of the survival line. It was not a statistical glitch; it was a clear indication of increased mortality." The Medical Research Council/British Heart Foundation Heart Protection Study, which is the study cited by Dr. Gibbons, randomized 10,269 patients to 660 IU/day of vitamin E and 10,267 to placebo control. The vitamin E group was associated with about a 10% increase in mortality. The study also evaluated the effect of statin therapy.

Moreover, Dickinson said that all the people in the 19 studies were "already sick. They had heart disease or cancer or Alzheimer's disease. The definitive study to test vitamin E in a healthy population has not been done."

Again, Dr. Gibbons took exception with this statement. "There's no question that the British Heart Protection study was done in patients with known or presumed heart disease. However, the potential benefit [of a drug] is usually greater in those with the greatest risk. Aspirin is the prime example. Daily aspirin in people with heart disease reduces the risk of heart attack. No ifs, ands or buts — risk is reduced. But if you look at primary prevention with aspirin — giving aspirin to people with no heart disease — the results are mixed and low risk individuals shouldn't be taking daily aspirin."

In a prepared statement sent out to health care reporters nationwide, CRN quotes Dr. Miller's study this way: "The researchers themselves noted limitations in their meta-analysis, stating ‘the generalizability of the findings to healthy adults is uncertain. Precise estimation of the threshold at which risk increases is difficult.'"

However, a review of the published article finds that CRN has done some creative editing. Miller and his coauthors actually write: "In addition, high-dosage vitamin E trials were often performed in patients with various chronic diseases, and we could not evaluate the generalizability of our findings to healthy adults." Later in the same paragraph, the authors write, "Hence, although identifying precisely the threshold at which risk increases is difficult, our meta-analysis probably provides the best estimate of the dose-response effect of vitamin E supplementation on mortality."

The news about vitamin E will be surprising to many people because the vitamin was so widely touted for its ability to reduce the risk of heart disease, said Miller. In fact, at one point physicians — many of whom were taking the vitamin themselves — used to recommend that patients take vitamin E.

The driving force behind rise in popularity of vitamin E was reports from observational studies that people who took vitamin E had fewer heart attacks and strokes. The evidence for vitamin E benefit, said Dr.Miller, was very much like the "evidence" that postmenopausal women taking hormone replacement therapy had less heart disease — and just like estrogen, when put to rigorous scientific testing the benefit disappeared.

"But there was a general sense that while vitamin E didn't prevent heart disease, it didn't do any harm either," said Miller. In fact, three earlier meta-analyses reported that "vitamin E had no effect — good or bad — on survival," Dr. Miller said. Yet, a handful of studies of high-dose vitamin E reported increases in mortality, although the increases were not statistically significant.

"Individual studies usually test only one or two doses and we suspected that there might be a dose response between mortality risk and vitamin E, which is why we did this meta-analysis that includes doses as low at 16.5 IU all the way up to 2000 IU a day," Miller said.

Dr. Miller said there are several theories about why vitamin E increases risk. One theory is that it increases bleeding risk, which would increase the risk of hemorrhagic stroke, while another theory suggests that at high doses vitamin E stops working like an antioxidant that mops up free radicals that attack cells that line blood vessels and instead becomes a prooxidant and actually promotes the production of free radicals.

Still another scenario suggests that high-doses of vitamin E tend to destroy other fat-soluble antioxidants, which disrupts the body's natural antioxidant protection system.

Yet, even without a clear explanation of how vitamin E could increase mortality, Miller and colleagues conclude that vitamin E supplements should be avoided.

Ann Intern Med. Posted online Nov. 10, 2004.

... and here is a follow-up with a different point of view:

HIGH-DOSE VITAMIN E MAY INCREASE ALL-CAUSE MORTALITY?

Recent news stories have reported on a vitamin E study presented at the American Heart Association meeting in New Orleans by Edgar Miller and coworkers. The study warns that high-dose vitamin E supplementation may increase mortality in adults. After reviewing a draft of the full paper, which will be published in January 2005, we believe the research is flawed, and we see little or no evidence to support the authors' conclusions.

The current study is not a new clinical trial, but a statistical analysis (meta-analysis) of many diverse and dissimilar studies.

Many studies that could have been included in the analysis were eliminated because total mortality rates were low.

Many of the studies included in the analysis were conducted with older adults who had an advanced chronic degenerative disease. In other words, most studies were not conducted on normal, healthy adults.
Many of the studies were small, involving fewer than 1000 people. More importantly, only the smaller studies showed significant effects. None of the larger (and therefore more powerful) studies, involving several thousand subjects each, showed a statistically significant impact on mortality of vitamin E supplementation.

One study in particular (The Heart Protection Study) skewed the results of the meta-analysis toward a conclusion of increased mortality, even though the original research paper for the Heart Protection Study concluded that vitamin E supplementation did not have a significant effect on mortality.

Miller and coworkers state that high dosages of vitamin E are dangerous and that death rates increased with dose. However, their own secondary analysis showed that differences in death rates were statistically insignificant, and that at the highest dose, risk of death was actually lower.

In short, we find no strong and compelling evidence in the paper to support the authors' conclusions that high-dose vitamin E supplementation may increase mortality in adults.

That said, we want to make several related points. First, in most of the studies included in the meta-analysis, vitamin E was given as a stand-alone nutrient. USANA has never advocated taking high doses of any single nutrient. Rather, we promote a complete and balanced approach to supplementation, as evidenced by our Essentials, which contain over 40 active ingredients provided in a balanced formula.

Second, it is important to note that there is a wealth of clinical and epidemiological research supporting the health benefits of vitamin E supplementation. This research has linked elevated intakes of vitamin E with improved cardiovascular health and reduced incidence of multiple chronic diseases. These results, from dozens of studies, are at complete odds with the conclusions drawn by Miller and coworkers.

Finally, we believe that the press response to the Miller study is overblown... one that is largely designed to sell newspapers rather than to inform the public in an objective way. Our experience with these sorts of situations leads us to believe that if the Miller study had reported a 5% decrease in mortality (a health benefit) due to high-dose vitamin E supplementation, the authors would have concluded that the result was clinically insignificant and that much more research was necessary before any conclusions could be drawn. And the findings never would have ended up in the newspaper.

We firmly believe that optimal nutrition is a key to reducing the risk of chronic degenerative disease. High-quality, comprehensive and balanced supplementation, including vitamin E, is an important element of any program promoting true health.

John Cuomo, Ph.D.
Tim Wood, Ph.D.
Russ Barton, M.S., C.N.S.

For additional comments on this study, go to the following links:

http://www.crnusa.org/PR04_1110CRNAIM.html

http://www.lef.org/news/LefDailyNews.htm?NewsID=1297&Section=VITAMINS

http://www.lef.org/news/LefDailyNews.htm?NewsID=1296&Section=VITAMINS

-- Jeremy

Vit E isn't a big one debated in the weight training circles - but if you are taking a multivitamin and it has lots and lots of vitamin E - might be worthwhile to read this article:

I had read of some of the critiques of the study but not as full and detailed analysis as you provided here. It is amazing to me how much fuzzy data studies are produced in medical related areas leading to conclusions that are usually disproved a few years later.

Why take high dosages in the first place?

regards
Ludvig.

Well, the article defines a "high dose" as the typical amount contained in an average vitamin E supplement (400 IU) -- So people aren't deliberately trying to take high doses when they supplement.

Also, it would be interesting to see if studies using mixed tocopherols would yield different outcomes. Some suggest that vitamin E supplements may inhibit the action of the gamma form by oversaturation with the alpha form, which may be the cause of some problems and limited efficacy. Mixed tocopherol supplements might produce some benefits not seen with traditional vitamin E supplements.

In fact, I am thinking of taking the mixed variety myself....

Why take high dosages in the first place?

regards
Ludvig.

Well, the article defines a "high dose" as the typical amount contained in an average vitamin E supplement (400 IU) -- So people aren't deliberately trying to take high doses when they supplement.

Also, it would be interesting to see if studies using mixed tocopherols would yield different outcomes. Some suggest that vitamin E supplements may inhibit the action of the gamma form by oversaturation with the alpha form, which may be the cause of some problems and limited efficacy. Mixed tocopherol supplements might produce some benefits not seen with traditional vitamin E supplements.

In fact, I am thinking of taking the mixed variety myself....


Please explain mixed tocopherol and how to take them :drool:

Here's the information the scientists behind the product I use have to share. They support a single tocopherol, not mixed, but that is, of course, opinion and subject to debate. Personally, I chose this company because they are always on the cutting edge and willing to reformulate their products when evidence suggests it would benefit, so I'll stay with a single form for now ...

Vitamin E unlike other vitamins, is not a cofactor in the function of specific enzyme systems. Rather, it is a potent antioxidant that protects cells and tissues from oxidative damage induced by a wide variety of free radical species. D-alpha tocopherol is one of eight natural forms of Vitamin E, and is the form shown to have the greatest nutritional and biological value, in part because the body preferentially retains it.

Gamma tocopherol, the principal form of Vitamin E in the U.S. diet is also an effective antioxidant that compliments the activity of alpha tocopherol. The gamma form however, is removed from circulation and excreted by the body relatively quickly.

The antioxidant activity of Vitamin E is wide ranging. Because it is a fat-soluble vitamin, its protective effects involve the inhibition of lipid (fat) oxidation in the gut, blood stream, tissues, and cells. Specific activities include suppression of free radical formation, suppression of oxidative chain reactions, and repair of damaged cell constituents, particularly cell membranes.

These actions result in protection against several important degenerative disorders, including Alzheimer's disease, certain cancers, and most notably heart disease. An important study involving 2,000 patients with heart disease found that Vitamin E supplements reduced heart attacks by 75%. Two Harvard studies involving a total of about 135,000 health professionals, found that those who took daily supplements of Vitamin E had one-fourth to one-third less coronary risk than those who did not take the supplements. In a recent study, Vitamin E supplementation was further shown to boost immune function, particularly in the elderly. In conclusion, sound clinical evidence supports the value of Vitamin E supplementation.

Food sources of vitamin E include vegetable oils and products made from these oils, wheat germ, nuts and other grains. The RDA for vitamin E in adults ranges from 15-19 mg/day, however the average dietary intake of vitamin E among adults is less than 10 mg per day. Reported therapeutic benefits of vitamin E intake generally require supplementation of 200-800 mg per day. Vitamin E is relatively non-toxic when taken orally. However, in people deficient in vitamin K or participating in coumadin therapy, levels higher than 1,000 mg per day may potentially increase bleeding time.

References:

Niki E. Alpha-tocopherol. In Cadenas E, Packer L, editors. Handbook of Antioxidants. New York:Marcel Dekker Inc; 1996. p 3-25.
Traber MG. Biokinetics of vitamin E. In Cadenas E, Packer L, editors. Handbook of Antioxidants. New York:Marcel Dekker Inc; 1996. p 43-61.
Christen S et al. Gamma-tocopherol traps mutagenic electrophiles such as NOx and complements alpha-tocopherol: physiological implications. Proc Natl Acad Sci USA 4997; 94:3217-22.
Traber MG. Biokinetics of vitamin E. In Cadenas E, Packer L, editors. Handbook of Antioxidants. New York:Marcel Dekker Inc; 1996. p 43-61.
Sano M et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. New Eng J Med 1997;336:1216-22.
Machlin LJ. Critical assessment of the epidemiological data concerning the impact of antioxidant nutrients on cancer and cardiovascular disease. Critical Rev Food Sci and Nutr 1995; 35:41-50.
Stephens NG et al. Randomized controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781-6.
Stampfer MJ et al. A prospective study of vitamin E consumption and risk of coronary disease in women. N Engl J Med 1993;328:1444-9.
Rimm EB et al. Vitamin E consumption and risk of coronary heart disease among men. N Engl J Med 1993;328:1450-6.
Meydani SN et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects. J Am Med Assoc 1997; 277:1380-6.
Burton, G.W., et al. Comparison of free alpha-tocopherol and alpha-tocopherol acetate as sources of vitamin E in rats and humans. Lipids 1988; 23: 834-40.

Please explain mixed tocopherol and how to take them :drool:

I posted the original article because I felt it addressed both sides of the issue, and explained the limitations of a meta-analysis.

However, the whole point of a meta-analysis is to give added statistical power to the sample to get trends that are not found in smaller studies - so the criticism that the smaller studies did not find statistically significant findings so the meta-analysis shows statistical artifact is a bit sideways - as I said, it misses the whole point of a meta-analysis.

However, you have to trust the author of the study (Dr. Miller) to be exceedingly careful not to introduce statistical artifact in combining the samples - making sure that when he combines different studies, he doesn't compare apples to oranges.

I don't know anything about Dr. Miller - but I certainly don't trust the reports of CRN, who is, after all, a firm paid for by the supplement industry, which has an obvious monetary interest in having people think supplements are safe, and the more the better.

The criticism that the studies were done in sick people and the findings should not be generalized to the public at large is a valid one.

Vitamin E is a fat soluble vitamin and excess amounts can be stored in your fat. Vitamins D, A, and K are also fat soluble. Megadoses of any fat soluble vitamin seem like a bad idea, to me. The fact that vitamin E at 660 IU significantly increased risk of all cause mortality in a rather large British study - even though it was done in sick patients - still gives me pause about letting large doses build up in my body.

All best,

Bisous

"I don't know anything about Dr. Miller - but I certainly don't trust the reports of CRN, who is, after all, a firm paid for by the supplement industry, which has an obvious monetary interest in having people think supplements are safe, and the more the better."

Okay, that is ironic. CRN works with the World Health Organization and is actually an active proponent of health and wellness. Sure, the supplement industry has a monetary interest in promoting supplements. That is a billion dollar industry.

Let's talk about hte trillion dollar pharmaceutical industry, which has an obvious monetary interest in having people think supplements AREN'T safe so instead of naturally addressing their health problems, they can jump on prescription drugs. The CRN, at worst, is a healthy second opinion because many clinical trials and studies are conducted to reinforce prescription drugs. How about lowering the level at which doctors should prescribe cholesterol-lowering medications and effectively doubling the number of people who will be investing in the #1 internationally selling prescription medication?

Invalidating the CRN just because of their connection to the supplement industry means this entire thread is moot - are we discussing Vitamin E or opinions about the pharmaceutical industry, the supplement industry, etc?

Jeremy

I don't know anything about Dr. Miller -

Hi Guys,

Don't post often enough, and will be posting more in the near future, but I have to say- your debate came up pretty high on the Google returns which means the Fitness Forum is certainly on the map.

As it happens, I actually know Dr. Miller, and work at the same multi-disciplinary research center he does, although I am just a lowly graduate student. I have requested that he give his talk on Vitamin E this Friday to my department, and I'm going to read his paper before then, because I have to introduce him on Friday.

The previous description of what a meta-analysis is was pretty good. It's a study (really a data analysis method) that pools data from multiple previous studies in order to determine if associations exist where individual studies may lack the statistical power (which is to say the sample size) in order to make a reasonable statistical inference. All epidemiology studies try to take a sample or subset of a population and make inferences about the population from the estimates that we get in these analyses. Sometimes, our samples differ so much that the inferences differ, but as long as the individuals come from the same population, the data can be pooled as long as sampling criteria and certain sample characteristics are taken into account when you pool the datasets. These analytic designs are especially useful when there is a small increase in risk from some risk factor, but most studies have too few people to be able to determine if this small increase in risk is real or not. If you look in a large enough group of people, you can then make an inference, but it's not always financially possible to go out and recruit more people, and it will always require several more years of tracking on individuals to determine whether or not the amount of new disease in comparison groups differs. So meta-analysis allows us to better use the data we already have, with little additional cost. It's very rigorously done, and requires a very strict application of technique so that you don't make erroneous inferences, which is a huge danger if you don't meticulously apply your biostatistics.

Anyway, I'll keep you guys abreast of any interesting issues, and if you questions for Dr. Miller, send them along, and I'll see if I can get them answered.

AdamGrad

Cool! Ask him if he gets money from whoever makes Lipitor...

(no, kidding, though the article itself in the journal should list if he has any pharm ties...)

What I really want to know is why his interest in Vitamin E?

Thanks!

Bisous

Why don't we just eat healthy and get all our necessary vitamins and minerals from our food like we're supposed to?

I am not worried

Vitamin E Scare


Vitamin E users were recently frightened by news was that high doses of the nutrient may be dangerous — “High dose of vitamin E may increase death risk” was how USA Today put it.


Researchers from Johns Hopkins University reported that people who took more than 400 International Units (IUs)of vitamin E per day had about a 5 percent greater risk of premature death than subjects who took lower daily doses of vitamin E.


The researchers concluded that “High dosage vitamin E supplements may increase mortality and should be avoided.”


While I can’t assure you that “high dose” vitamin E supplementation will definitely improve your health, I’m pretty confident that the Hopkins study shouldn’t scare you about the nutrient.


The researchers didn’t study any vitamin E-users first-hand; instead they simply reviewed data from 19 earlier vitamin E clinical trials, including 11 "high dose" trials. But 10 of the 11 “high-dose” trials didn’t make any statistically significant correlations between vitamin E use and premature death.


Apparently this glaring fact didn’t fit with the researchers’ seemingly pre-determined conclusion, so they “cooked the books,” statistically speaking. They combined the 11 high-dose studies into one larger, supposedly more statistically robust study.


But while this “study stew” produced the appearance of a slightly elevated risk of premature death among high-dose vitamin E users, the reported “increase” was exceedingly small — too small to be considered reliable, particularly given the crudeness of the statistical method used to obtain it.


In a sense, it’s like the researchers tried to count atoms with the naked eye — it simply can’t be done.
The most prudent interpretation of the Hopkins’ results is that there is no persuasive evidence that “high dose” vitamin E users have a higher risk of premature death. But that wouldn’t be news, now would it?


Steven Milloy is the publisher of JunkScience.com, an adjunct scholar at the Cato Institute and the author of "Junk Science Judo: Self-Defense Against Health Scares and Scams" (Cato Institute, 2001).