A vast body of epidemiological studies has linked increased dietary intake of antioxidants from fruits and vegetables to reduced risks of a range of diseases including cancer, cardiovascular disease and diabetes.
However, when such antioxidants have been extracted and put into supplements the results, according to the randomized clinical trials (RCTs), do not always produce the same benefits, and may even be harmful.
These observations have led to much negative publicity about antioxidant supplements, particularly the more well-known vitamin E and beta-carotene.
Indeed, an article published in the New Scientist in 2006, authored by Dr Lisa Melton from the London-based registered charity, the Novartis Foundation, concluded that antioxidant supplements "do little or nothing".
The RCTs
One of the most recent examples of the apparent failure of antioxidants to live up to the epidemiological promise was the antioxidant meta-analysis published in the prestigious Cochrane Systematic Review.
The analysis considered 67 randomised trials with antioxidant supplements and concluded that vitamins A and E, and beta-carotene may increase mortality risk by up to 16 per cent.
"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 lead author Goran Bjelakovic from the Copenhagen Trial Unit at the Copenhagen University Hospital in Denmark.
The meta-analysis was subsequently criticized for several reasons, including the exclusion of over 400 clinical trials because no deaths were reported.
At the time of the publication, the UK’s Health Food Manufacturers' Association (HFMA), an industry association, said the review was "systematically flawed".
Two other high profile clinical trials, the Beta-Carotene And Retinol Efficacy Trial (CARET) in the United States and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial in Finland, reported that beta-carotene, alone or in combination with vitamin E or retinyl palmitate, could increase the risk of lung cancer by 28 and 16 per cent, respectively, compared to placebo. However, the observations were limited to heavy smokers taking high doses of beta-carotene.
Furthermore, at the end of last year, results from two high-profile clinical trials reported that selenium and the vitamins C and E are ineffective against prostate cancer. Null results from the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and the Physicians' Health Study II were met with disappointment by many.
RCT design
In an editorial comment on the selenium studies in the Journal of the American Medical Association, Peter Gann, MD, ScD, from the University of Illinois at Chicago, said the results were "disappointing news".
Putting the issues in the context of the bigger picture of how studies are performed, Gann said: "...single-agent interventions, even in combinations, may be an ineffective approach to primary prevention in average-risk populations.”
The design of randomised clinical trials, following the drug- or evidence-based model has received much criticism.
In an earlier interview with NutraIngredients, Andrew Shao, PhD, vice president of scientific & regulatory affairs for the Council for Responsible Nutrition (CRN), a trade association, said: "The current drug-based approach used in RCTs may not be the best approach to assess the health benefits of antioxidants, or other nutrients for that matter, and that researchers need to rethink how to design and execute such trials."
"I do think more clinical trials are needed for antioxidants, but it is critical that they are designed and conducted to truly test the question(s) of interest, with the results interpreted and communicated appropriately,” added Dr Shao.
Others have echoed Dr Shao’s views. In a interview with NutraIngredients, Jeff Blumberg, professor of nutrition science and policy at Tufts University said: “I think that when we look the idea at a single gold standard, like the randomized clinical trial, for evaluating nutrients and foods and diets just doesn’t work.
“Sometimes it’s useful for answering for some very specific questions, but I think at other times we must go and use the approach that we have been using for the last generation or two, of looking at all of the research strategies and the information they can give us, from basic research using cell cultures and animal models, from clinical experience looking at how patients respond in the clinic, to observational studies of large populations followed for long times consuming different types of diets, as well as the intervention clinical trials.”
Understanding antioxidants
The criticisms of the drug-model for testing nutrients highlight fundamental issues with the understanding of antioxidants, and nutrients in general. Professor Blumberg added that it was important to understand how nutrients work.
“When we look at nutrients, nutrients are distributed throughout the body. Essential nutrients like vitamins and minerals have to be in every cell in every tissue in our body,” he said. “But in fact the body concentrates those nutrients in higher amounts in some tissues and in lower amounts in other tissues, it uses them in combination with other nutrients. They are designed in a system of synergies and networks.”
Tomorrow, NutraIngredients will look at the different forms of antioxidants, and how the sum may be stronger than the parts.
The Société Française des Antioxidantes will be hosting the 5th International Conference on Antioxidants 2009 with the title Controversies & Perspectives in Paris on June 10-11.