Copenhagen, Denmark - The largest analysis of data on antioxidant vitamins ever conducted has shown that beta-carotene, vitamin A, and vitamin E probably increase mortality [1]. Two other antioxidant substances—vitamin C and selenium—had no effect on mortality.

The meta-analysis of 68 randomized trials with a total of 232 606 participants, published in the February 28, 2007 issue of the Journal of the American Medical Association, was conducted by a group led by Dr Goran Bjelakovic (Copenhagen University Hospital, Denmark).

Coauthor Dr Christian Gluud (Copenhagen University Hospital) commented to heartwire: "This is the most comprehensive collection of data on antioxidant vitamins ever conducted, and we have shown that on the whole these agents have no benefit. Indeed, vitamin A, vitamin E, and beta-carotene are associated with an increase in mortality at the doses studied. Vitamin A and beta-carotene seem to have a dose-related effect, with mortality increasing as doses increase, whereas vitamin E does not appear to have a dose-related effect, with all doses associated with increased mortality."

Gluud added that the jury is still out on vitamin C and selenium. "Vitamin C does not appear to be detrimental, but it is not beneficial either, and all the trials of selenium together suggest a small benefit, but when only the well-conducted trials are included, there appears to be neither benefit nor harm.

"Our data show that antioxidant vitamins should not be taken in an effort to prevent illness. People should instead eat a balanced diet and take regular exercise," he said.

In the paper, the authors note that many people are taking antioxidant supplements in the belief that they improve health and prevent diseases. Many primary- or secondary-prevention trials of antioxidant supplements have been conducted to investigate the prevention of several diseases—mainly cardiovascular disease and cancer—but results have generally not been positive, with some trials showing increases in mortality.

To find out more, they conducted the current systematic review to analyze the effects of antioxidant supplements on all-cause mortality of adults included in primary- and secondary-prevention trials. They included all primary- and secondary-prevention published trials in adults randomized to receive beta-carotene, vitamin A, vitamin C, vitamin E, or selenium vs placebo or no intervention.

Results showed that when all trials of antioxidant supplements were pooled together, there was no significant effect on mortality, but when the 47 trials said to have a low risk of bias (in a total of 180 938 participants) were analyzed alone, the antioxidant supplements as a whole significantly increased mortality, and beta-carotene, vitamin A, and vitamin E were all associated with increased mortality when given alone or in combination. Vitamin C and selenium had no significant effect on mortality.

The researchers note that more than two thirds of the included trials fell into the category of those with a low risk of bias, which they say highlights the validity of their results. "Antioxidant supplements not only seem to be one of the most researched topics in the world, they also seem to be one of the most adequately researched clinical questions," they say.

They point out that a large number of unpublished trials on supplements may exist, but as unpublished trials are more likely to have been either neutral or negative than to have shown beneficial effects, this suggests their estimate of a 5% increase in mortality is likely to be conservative.

Noting that 10% to 20% of the adult population (80 million-160 million people) in North America and Europe may consume these supplements, Bjelakovic et al say the public-health consequences may be substantial.

Speculating on possible mechanisms, they point out that although oxidative stress has a hypothesized role in the pathogenesis of many chronic diseases, it may be the consequence of pathological conditions, and that eliminating free radicals may interfere with some essential defensive mechanisms.

In an interview with heartwire, Gluud also suggested that the antioxidant vitamins could actually also have pro-oxidant effects. "We don't know exactly how they are doing harm, but rather than preventing cardiovascular disease and cancer, they actually seem to be accelerating these conditions."

He said these observations were "a huge disappointment" but added that at least it has been discovered. "We must see the positives in this. The question has been thoroughly addressed and we now know the answer—these agents are harmful. The companies selling these antioxidant vitamins have been able to dodge the issue for a long time, saying that any negative data have not been comprehensive. They cannot do this any longer. There are lessons to be learned here— for example, the importance of conducting trials with these agents and publishing the results."

Gluud added that food supplements should be regulated in the same way as medical products. "The governments of the world now have the responsibility to inform people of these results. They have been too slow in the past in requesting that health supplements be properly evaluated before allowing these products to be added to foods. People have been buying these supplements and foods advertised as having these supplements added under the impression that they are good for them, when in actual fact they are harmful. Any potential health supplements should not be allowed to be added to foods unless they have been shown to be beneficial or at least proven not to be harmful."