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Editorials

The Antioxidant Sky Is Not Falling

6 March 2007
by Peter C. Everett, M.D.

Between February 28 and March 1, 2007, nearly every major news outlet in the English-speaking world presented an alarmist headline on the safety of antioxidant vitamins. "Antioxidants Don't Help You Live Longer" was the FOX News headline for an AP story that began, "Antioxidant vitamins taken by tens of millions of people around the world won't lead to a longer life...."

Even more arresting, "Vitamins 'could shorten lifespan'," wrote the BBC. The source was the March 1 issue of JAMA which presented a combined analysis of a large number of clinical trials of antioxidant vitamins that calls into question the safety and benefit of supplements broadly categorized as antioxidants.[1]

The meta-analysis behind the headlines, authored by Bjelakovic et al. raises some important issues about the safety and efficacy of vitamins. But it is vitally important to understand what the study does and does not say, and more generally to recognize how the impulse by the news media to sensationalize a story resulted in delivering the wrong message to millions of people.

The review of the literature asked the simple question, "Does antioxidant supplementation impact mortality, and if so, how?"

"Antioxidant supplementation" was broadly defined and included vitamins A, C, E, beta-carotene and the mineral selenium alone or in any of many combinations. The analysis identified 815 trials involving antioxidant supplementation, but included only 68 of them.

Most of the excluded trials were eliminated from analysis because nobody died in either the treatment or control groups, and thus could not contribute to the specific question of mortality. Most of the rest were excluded for methodological reasons. Therefore, the analysis represented only a tiny subset of the overall clinical trial experience with antioxidant supplementation.

Aggregate analysis of the 68 included trials showed no significant harm or benefit, but when analyzed for protection from bias, the 47 trials identified as having a low risk of bias showed a small but statistically significant increase (about 5 percent) in mortality among groups treated with antioxidants.

The study did not attempt to investigate the causes of death. When subgroups were analyzed, it appeared that the risk of death was mostly associated with high doses of vitamins A, E, or beta-carotene, while vitamin C had no effect and selenium appeared to be beneficial.

These arcane methodological details are crucial for understanding how very narrow these results are, and how non-representative they are of the way supplements are typically used.

The first thing to realize about the limitations of this analysis, is that it does not address the long-term use of balanced multivitamin combinations by essentially healthy, young or middle-aged people who are hoping to avoid age-related diseases. Of the 47 "low bias risk" trials from which the study's main conclusions were drawn, 70% of them were "secondary prevention" trials.

That means that they involved mostly elderly people in whom a lifetime of oxidative and other degenerative processes had already resulted in disease, and the trial investigated whether a short course of antioxidants, averaging less than three years, could slow, stop, or prevent recurrence of their disease.

While it would be nice if a short course of vitamins for less than 3 years could stop or reverse a lifetime of degeneration, this in no way resembles the rationale for taking vitamins by the vast majority of people. Most people die from heart disease or cancer [8], whose latency periods are a decade or more.

The second limitation has to do with the study's overly broad definition of what constitutes an "antioxidant" regimen, and the inclusion of combinations that are likely to be pro-oxidant. Different antioxidants work in different parts of the body, and work with each other to remove radicals from where they can cause harm.

In general terms, the fat-soluble antioxidants (A & E), gather free radicals from the cellular membranes. In doing so, they become potentially harmful radical molecules themselves.

The water-soluble antioxidants, like vitamin C, gather free radicals in the watery environment within and between cells. They also regenerate oxidized vitamins A and E in the membranes so that they can go back and continue to protect the cellular membrane and its protein machinery.[7]

It has been known for years now that high doses of vitamin E and beta-carotene when taken alone can be harmful [2, 3, 5], and it is easy to see how by imagining a bucket brigade. Imagine a flood in your bathroom. You set up a bucket brigade, with someone in the bathroom handing buckets to someone in the living room, who then throws the water safely out the front door.

Similarly, the fat-soluble antioxidants can hand radicals to the water-soluble antioxidants. If you add workers to the bathroom, incoming buckets will overwhelm the person in the living room, and the living room, where the furnishings are far less water-resistant, will flood.

Since it is the protein machinery of the cellular membrane that is most in need of protection, a relative excess of fat-soluble antioxidants can accumulate radicals in the membrane if they are unable to pass their radicals to the water-soluble antioxidants.

Bjelakovic et al. acknowledge this type of potential problem with their study noting, "We have compared antioxidants with different properties, given at different doses and duration, singly or combined. We are aware of the potential risks in assessing the effects of different types of antioxidants... It has been suggested that antioxidant supplements may show interdependency and may have effects only if given in combination."

The third limitation is that this study says nothing about food sources of antioxidant vitamins, and does nothing to refute the abundant epidemiologic evidence that consumption of antioxidant rich foods are associated with improved health, including a lower incidence of cardiovascular disease, neurodegenerative disease, and several major cancers.

The reasons why the data for individual supplements do not appear to agree with the data for foods are not known, but one suspected reason is that foods naturally contain balanced combinations of antioxidants that work together, avoiding the problems of relative excess.

Indeed, even in the Finnish trial, which showed more lung cancer in asbestos-exposed heavy smokers who took vitamin E and beta-carotene, the participants in the placebo group with the highest blood levels of these vitamins from their diets had the lowest incidence of lung cancer.[5]

Despite these limitations, there is useful information to be gained from this study. We now have more evidence that high dose supplementation of vitamins A, E and beta-carotene from non-food sources should probably be avoided in the absence of a condition-specific indication for them, where high-dose is approximately 400IU of vitamin E, 20mg of beta-carotene, or 15,000IU of vitamin A.

Those who wish to supplement with antioxidants because they are either not able or not inclined to consume enough antioxidant-rich foods would be wise to purchase combinations that do a reasonable job of approximating the mixture found in an antioxidant-rich diet, for which there is a wealth of evidence of benefit, and avoid single-substance formulations, with the possible exceptions of vitamin C and selenium.

About the author: Peter C. Everett, M.D. is a resident in internal medicine with a longstanding interest in dietary supplements and health optimization. Prior to his medical training, he participated in the successful effort to pass the Dietary Supplement Health and Education Act of 1994. Subsequently he assisted in the founding of the Dietary Supplement Quality Initiative. His research interests include the anti-cancer potential of curcumin.

References

1. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis. JAMA. 2007 Feb 28;297(8):842-57.

2. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005 Jan 4; 142(1): 37-46.

3. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, Barnhart S, Hammar S. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996 May 2;334(18):1150-5.

4. Goodman GE, Thornquist MD, Balmes J, Cullen MR, Meyskens FL Jr, Omenn GS, Valanis B, Williams JH Jr. The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. J Natl Cancer Inst. 2004 Dec 1;96(23):1743-50.

5. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. (1994) N. Engl. J. Med. 330, 1029–1035.

6. Virtamo J, Pietinen P, Huttunen JK, Korhonen P, Malila N, Virtanen MJ, Albanes D, Taylor PR, Albert P; ATBC Study Group. Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA. 2003 Jul 23;290(4):476-85.

7. Sies H, Stahl W, Sundquist AR. Antioxidant functions of vitamins. Vitamins E and C, beta-carotene, and other carotenoids. Ann N Y Acad Sci. 1992 Sep 30;669:7-2.

8. Center for Disease Control, National Center for Health Statistics, NCHC - FASTSTATS - Leading Causes of Death. Referenced on March 2, 2007.end-of-story

 

 

   
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