Mortality in Randomized Trials of Antioxidant Supplements for
Primary and Secondary Prevention: Systematic Review and
Goran Bjelakovic; JAMA. 2007;297:842-857.
All randomized trials involving adults comparing beta carotene, vitamin A, vitamin C (ascorbic acid), vitamin E, and selenium either singly or combined vs placebo or vs no intervention were included in our analysis. We included 68 randomized trials with 232 606 participants (385 publications).
the antioxidant supplements significantly increased mortality beta carotene, vitamin A, and vitamin E. singly or combined, significantly increased mortality. Vitamin C and selenium had no significant effect on mortality.
Conclusions Treatment with beta carotene, vitamin A, and vitamin E may increase mortality. The potential roles of vitamin C and selenium on mortality need further study.
|Oxidative stress is implicated in
most human diseases. Antioxidants may decrease the
oxidative damage and its alleged harmful effects.
Many people are taking antioxidant supplements, believing
to improve their health and prevent diseases.
Whether antioxidant supplements are
beneficial or harmful is uncertain.
Many primary or secondary prevention trials of
antioxidant supplements have been conducted to prevent
We found that antioxidant supplements, with the potential exception of selenium, were without significant effects on gastrointestinal cancers and increased all-cause mortality. We did not examine the effect of antioxidant supplements on all-cause mortality in all randomized prevention trials. Our aim with the present systematic review was to analyze the effects of antioxidant supplements (beta carotene, vitamins A and E, vitamin C [ascorbic acid], and selenium) on all-cause mortality of adults included in primary and secondary prevention trials.
Our systematic review contains a number of findings. Beta carotene, vitamin A, and vitamin E given singly or combined with other antioxidant supplements significantly increase mortality. There is no evidence that vitamin C may increase longevity. We lack evidence to refute a potential negative effect of vitamin C on survival. Selenium tended to reduce mortality, but we need more research on this question. We confirm that trials with inadequate bias control overestimate intervention effects. Our findings support and extend our previous findings regarding antioxidant supplements and increased mortality.
A large number of unpublished trials on supplements may exist. Their results are more likely to have been either neutral or negative than to have shown beneficial effects. Accordingly, our estimates of increased mortality of about 5% is likely to be conservative.
We only assessed all-cause mortality. We are not able to determine the cause of the increased mortality. It is likely that increased cancer and cardiovascular mortality are the main reasons for the increased all-cause mortality. Further study of causes of mortality is needed. We fear that its assessment may be difficult due to varying definitions in the included trials. Our results extend previous reviews and guidelines, suggesting that antioxidant supplements may not be beneficial.
Beta carotene, administered singly or in combination with other antioxidants, significantly increased all-cause mortality. Recent studies have suggested that beta carotene may act as a cocarcinogen. Vitamin A combined with other antioxidants significantly increased mortality. We found that vitamin E given singly or combined with 4 other antioxidants did not significantly influence mortality. After exclusion of high-bias risk trials, however, vitamin E given singly or combined significantly increased mortality. This is in agreement with a recent meta-analysis. Dose of vitamin E was without significant effect on mortality in our analysis. The chance that vitamin E may benefit seems low.
The trials in which vitamin C was applied singly or in different combinations with beta carotene, vitamin A, vitamin E, and selenium found no significant effect on mortality. According to the CIs, small beneficial or large harmful effects cannot be excluded. We calculated the proportion of participants who died in the trials in which participants took vitamin C alone. In the control group it was 0.019 and in the vitamin C group it was 0.017. With set to .05 and power to .90, the required sample size would be 186 000 participants. We are still far from having examined a sufficient sample. Studies have demonstrated that vitamin C may act as both a pro-oxidant and as an antioxidant in vivo, and trials should be monitored closely for harm.
Selenium given singly or in combination with other supplements seemed to significantly decrease mortality, but after exclusion of high-bias risk trials, the effect disappeared. Results of ongoing randomized trials with selenium will likely increase our understanding of the effects of selenium.
Our findings contradict the findings of observational studies, claiming that antioxidants improve health. Considering that 10% to 20% of the adult population (80-160 million people) in North America and Europe may consume the assessed supplements, the public health consequences may be substantial. We are exposed to intense marketing with a contrary statement, which is also reflected by the high number of publications per included randomized trial found in the present review.
There are several possible explanations for the negative effect of antioxidant supplements on mortality. Although oxidative stress has a hypothesized role in the pathogenesis of many chronic diseases, it may be the consequence of pathological conditions. By eliminating free radicals from our organism, we interfere with some essential defensive mechanisms like apoptosis, phagocytosis, and detoxification. Antioxidant supplements are synthetic and not subjected to the same rigorous toxicity studies as other pharmaceutical agents. Better understanding of mechanisms and actions of antioxidants in relation to a potential disease is needed.
Because we examined only the influence of synthetic antioxidants, our findings should not be translated to potential effects of fruits and vegetables.