A meta-analysis of 67 randomised trials with antioxidant supplements has reported that vitamins A and E, and beta-carotene may increase mortality risk by up to 16 per cent.
On the other hand, vitamin C did not have an effect on mortality and the antioxidant mineral selenium was associated with a nine per cent decrease in all-cause mortality.
"We could find no evidence to support taking antioxidant supplements to reduce the risk of dying earlier in healthy people or patients with various diseases," said Goran Bjelakovic from the Copenhagen Trial Unit at the Copenhagen University Hospital in Denmark.
A republishing of last year's antioxidant meta-analysis in the prestigious Cochrane Systematic Review today looks set to refocus attention on the efficacy of antioxidant supplements, and raise questions over their safety.
The meta-analysis was originally published in the Journal of the American Medical Association (2007, Vol. 297, pp. 842-857) last year and attracted criticism from both inside and outside of the dietary supplements industry.
The authors admit that this report contained errors and corrections were subsequently published in JAMA (2008, Vol. 299, pp. 765-766). "The present version of the review incorporates all these corrections," they state.
Bjelakovic and collaborators from the University of Nis in Serbia, and Ospedale V. Cervello in Palermo, followed the Cochrane Collaboration method for meta-analysis and systematically reviewed 67 randomised clinical trials including 232,550 participants, and focusing on beta-carotene, vitamin A, vitamin C, vitamin E, and selenium supplements versus placebo.
Seven hundred and forty seven trials were excluded for several reasons, including no mortality in the study groups (405 trials), the studies were not randomised trials (69 trials), they did not fulfil inclusion criteria (245 trials), or the studies are ongoing (four).
Bjelakovic and co-workers report no reduction in mortality, and note that 13.1 per cent of the participants randomised to antioxidant supplements died, compared to 10.5 per cent randomised to placebo or no intervention.
"The findings of our review show that if anything, people in trial groups given the antioxidants beta-carotene, vitamin A, and vitamin E showed increased rates of mortality. There was no indication that vitamin C and selenium may have positive or negative effects. So regarding these antioxidants we need more data from randomised trials," said Bjelakovic.
"The bottom line is that current evidence does not support the use of antioxidant supplements in the general healthy population or in patients with certain diseases."
The reviewers highlighted several possible explanations or mechanisms behind the potentially detrimental effects of antioxidant supplements, noting that elimination of free radicals may interfere with some essential defensive mechanisms, including programmed cell death (apoptosis), detoxification, and phagocytosis.
"Better understanding of mechanisms and actions of antioxidants in relation to a potential disease is needed," they added.
Dr. Bjelakovic was contacted by NutraIngredients.com and asked to comment on the exclusion of the 405 death-free trials, and to contextualise why most of the trials included in the meta-analysis tested for secondary prevention, looking at how a nutrient works in diseased populations, instead of primary prevention studies in healthy populations. No response was received by NutraIngredients.com in time for publication.
The dietary supplements industry has responded strongly to the review, with the Council for Responsible Nutrition (CRN), an industry association, releasing a statement that read: "Although [the authors] have updated their meta-analysis, by handpicking additional studies and correcting a litany of minor mistakes made in previous versions, it is for all intents and purposes not a new study, nor is it truly new information.
"In fact, it appears to be a systematic attempt by the authors to publish work that supports their own pre-determined conclusions about antioxidants and the way they should be regulated."
John Hathcock, Ph.D., senior vice president, scientific and international affairs, CRN, was quick to draw attention to the exclusion criteria employed by the researchers.
"With nearly 750 studies to choose from, it's interesting that they chose to include only 67 studies - less than nine percent of the total clinical trials on antioxidants that are available," said Dr. Hancock. "Moreover, the possible 750 clinical trials do not even account for other sources of evidence, such as observational studies, which were not considered by the authors at all. It is their exclusions, not the inclusions, where the fault lies."
"The conclusions one can reach from this meta-analysis are very limited."
When the meta-analysis was published initially in JAMA, Meir Stampfer, a professor of nutrition and epidemiology at the Harvard School of Public Health who was not connected to the meta-analysis, told the Associated Press that the studies reviewed were too different to be able to pool them together.
"This study does not advance our understanding, and could easily lead to misinterpretation of the data," Stampfer told the AP.
Similar comments were forthcoming from the UK natural health industry association, the Health Food Manufacturers' Association (HFMA). A spokesperson stated that the review was "systematically flawed."
"The analysis focused on one broad category of study, then evaluated just 67 of the 748 studies that could be included in the review. Therefore, the paper's conclusions are drawn on less than nine per cent of available evidence. In no way can this review be considered comprehensive," said the spokesperson.
"Antioxidant supplements cannot be expected to undo a lifetime of unhealthy living, but combined with good lifestyle choices, can play an important role in promoting overall health and wellbeing."
Pointing out the practicalities
Andrew Shoa, Ph.D., CRN's vice president, scientific and regulatory affairs said: "It really comes down to whether or not this meta-analysis should mean anything to consumers or scientists. And from a practical standpoint, it doesn't mean much.
"We maintain that healthy consumers who are using antioxidant supplements in the manner that they were meant to be used-as complements to, not in place of-other healthy lifestyle habits, can continue to feel confident in the benefits these supplements provide.
"For those consumers who are seriously ill with cancer, heart disease, etc., they should talk with their doctor about everything they put into their bodies."
Source: Cochrane Database of Systematic Reviews
2008, Issue 2. Art. No.: CD007176. DOI: 10.1002/14651858.CD007176.
"Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases"
Authors: G. Bjelakovic, D. Nikolova, L.L. Gluud, R.G. Simonetti, C. Gluud