Some Antioxidant Supplements Linked to Lethality

COPENHAGEN, Feb. 27 -- The antioxidant supplements beta carotene and vitamins A and E have a dark side, carrying an increased risk of all-cause mortality, according to a meta-analysis of 68 randomized trials.

In high-quality trials, singly or combined, after exclusion of selenium trials, beta carotene was associated with a 7% increased risk of mortality (RR, 1.07; CI, 1.02-1.11), Goran Bjelakovic, M.D., of the Copenhagen University Hospital here, and colleagues, reported in the Feb. 28 issue of the Journal of the American Medical Association.

Recent studies, the researchers added, have suggested that beta carotene may act as a cocarcinogen.

Meanwhile, vitamin A had a 16% increased mortality risk (RR, 1.16, CI, 1.10-1.24), while for vitamin E, the mortality risk was 4% (RR, 1.04; 95% CI, 1.01-1.07), a finding in agreement with another recent meta-analysis. The dose of vitamin E had no effect on mortality in this analysis, the investigators said.

These data emerged from a meta-analysis of the effect of antioxidant supplements in randomized primary and secondary prevention trials published by October 2005, that included 232,606 participants, mean age 62.

In the analysis, vitamin C and selenium came through with no excess mortality risk, although their potential role, either harmful or beneficial, requires further study, according to the Danish group.

Many people taking antioxidant supplement have come to believe the pills make them healthier and prevent disease, although whether these supplements are harmful or beneficial has been uncertain, said Dr. Bjelakovic.

These findings contradict those of observational studies, claiming that antioxidants improve health. Considering that 10% to 20% of the adult population (80 to 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," the investigators cautioned.

The trials were classified as high-quality or low-quality, according to the methods (randomization, blinding, and follow-up) used in the studies. The trials were conducted in Europe, North and South America, Asia, and Australia. Mean duration of follow-up was 3.3 years.

The researchers noted that they were able to assess only all-cause mortality, although it was likely that increased cancer and cardiovascular disease mortality were the main components of the increase.

When supplement risks from all low- and high-quality trials were pooled, there was no significant effect on mortality (RR, 1.02; 95% CI, 0.98-1.06), the researchers reported.

However, in 47 high-quality trials with 180,938 participants, the antioxidant supplements overall were associated with a 5% increased risk of mortality (RR, 1.05; 95% CI, 1.02- 1.08).

There was no evidence that vitamin C increased longevity, and there was also no evidence to refute a potential negative effect of vitamin C on survival. According to the CIs, small beneficial or large harmful effects cannot be excluded, the researchers wrote.

Selenium given singly or in combination with other supplements tended to decrease mortality when analyzed separately. However, after low-quality trials were removed from the analysis, the effect disappeared. Results of ongoing randomized trials with selenium will likely increase our understanding of the effects of selenium, the researchers said.

There are several possible explanations for the negative effect of antioxidant supplements on mortality, Dr. Bjelakovic and colleagues wrote. 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," the investigators wrote.

"Antioxidant supplements are synthetic and not subjected to the same rigorous toxicity studies as other pharmaceutical agents," they added. What is needed, they said, is a better understanding of mechanisms and actions of antioxidants in relation to a potential disease.

Because this study examined only the influence of synthetic antioxidants, these findings should not be translated to potential effects of fruits and vegetables, they cautioned.

The researchers noted many study limitations. As in all systematic reviews, the findings and interpretations are limited by the quality of available evidence, they said. These populations came mostly from countries without overt deficiencies of specific supplements, and so it was not possible to assess the effects of supplementation in groups with specific needs.

Other limitations included comparison of different antioxidants with different properties, given at different doses and duration, singly or combined. Also, there is debate about whether vitamin A is an antioxidant, they said.

Most trials assessed combinations of different supplements, which reflects the way supplements are marketed and taken by people. In addition, the researchers were not able to point to the specific biochemical mechanisms behind the detrimental effects.

Trials examining the individual supplements singly were rare. Finally, most trials investigated the effects of supplements administered at higher doses than those commonly found in a balanced diet, and some of the trials used doses well above the recommended daily allowances.

Summing up, Dr. Bjelakovic's team wrote, "We did not find convincing evidence that antioxidant supplements have beneficial effects on mortality. Even more, beta carotene, vitamin A, and vitamin E seem to increase the risk of death. Further randomized trials are needed to establish the effects of vitamin C and selenium."