JAMA Publishes Meta-Analysis on Antioxidants Industry Responds

The Journal of the American Medical Association (JAMA) has published a 'Systematic Review and Meta-Analysis'1 examining the effect of antioxidant supplements on mortality in randomized clinical trials. The trials selected involved beta carotene, vitamin A, vitamin C (ascorbic acid), vitamin E, and selenium either singly or combined vs placebo or vs no intervention.(68 randomized trials with 232,606 participants).

The authors concluded that treatment with beta carotene, vitamin A, and vitamin E may increase mortality, while the roles of vitamin C and selenium need more scrutiny.

The International Alliance of Dietary Supplement-Food Associations (IADSA), Council for Responsible Nutrition (CRN) and Natural Products Association have all weighed in on this study. Predictably, mainstream media has been very quick on the uptake with sensational headlines the most extreme of which reads, “Vitamins Can Kill You”.

At issue in this case, is another meta-analysis, another examination of previously published research. As is the case with any meta-analysis, selection of included (and excluded) studies becomes quite important, with industry arguing that the researcher’s criteria predisposed the analysis to the ultimate results - a significant increase in mortality. Another consistent observation made of the study results, and one which actually did get mention in one of the Reuters stories, was the fact that many of the studies involved, not a normal healthy population where vitamin supplementation is suggested to preserve good health, but rather diseased populations with a variety of health issues.

In CRN’s response, Dr. Andrew Shao observes, “Combining secondary prevention and primary prevention trials and then making conclusions for the entire population is an unsound scientific approach,” said Dr. Shao. “Additionally, many of the treatment trials had limitations, including the expectation that a simple antioxidant vitamin could be expected to overturn serious illness, such as cancer or heart disease. These trials likely statistically skewed the results.”

The Natural Products Association’s vice president of scientific affairs Daniel Fabricant confirmed, ““Despite the authors’ contention, this analysis is assessing mortality of at-risk and diseased populations – versus a healthy population – in prevention trials. The risk of mortality must be attributed to the appropriate population studied, those with an existing health condition, which it isn't in this case. Instead, those findings are generalized to a healthy general population, which is wrong on many levels.”

The challenges of interpreting a meta-analysis can be considerable, and not only because of different population groups, disease states or endpoints. Durations, dosages and controls also vary widely so the interpretation is at best challenging, at worst, daunting. Dr. Shao notes, “While meta-analyses can be useful when the included studies are very similar in design and study population, this meta-analysis combined studies that differ vastly from each other in a number of important ways that compromise the results.” Also at question is the source of the antioxidant vitamins as the authors argue that their analysis and conclusions are based on synthetic antioxidants and "should not be translated to potential effects of fruits and vegetables".

Dr Alexander Schauss, Senior Director, Natural and Medicinal Products Research, AIBMR Life Sciences, Inc. is quite open in his assessment of this result. “In the simplest of terms: the JAMA paper is a carefully crafted example of meta-assassination. The JAMA authors disregarded countless studies that would have altered their conclusion.” Schauss continues, “It is unfortunate that statisticians working in the public health arena are misusing meta-analysis to draw such misguided conclusions. Do they really want the public to disregard the advice of the USDA, physicians, dieticians, and nutritionists, who have been urging the public to increase their intake of antioxidant-rich fruits, vegetables and nuts, to prevent chronic and degenerative diseases?”

As is frequently the case, in few instances is the current headline story placed in the context of a complete body of research, positive, negative and inconclusive. The fact that the latest study is exactly that – the latest, is frequently lost in the drive to sensationalize the current presentation of results. In IADSA’s response, Dr Derek Shrimpton, Scientific Advisor to the European Federation of Associations of Health Product Manufacturers, was quoted: “The paper proposes to overturn the conclusions of well conducted clinical trials in favour of conclusions drawn from a statistical analysis of all publications in the scientific literature on the subject irrespective of their merit.”

Dr. Schauss contributes, “How unfortunate that the authors disregarded a fundamental physiological fact: Oxidative stress must be countered by antioxidant activity in vivo for the human body to maintain its normal function and remain healthy. There exists a firm scientific foundation based on thousands of studies published in hundreds of peer review journals on the role of oxidative stress in the development of chronic and degenerative diseases. Many diseases that are contributing to the hundreds of billions of dollars being spent on health care costs are known to increase in severity due to the cumulative effect of free radical damage on biological molecules (DNA, proteins, lipids, etc.).”

Loren Israelsen, Executive Director of the United Natural Products Alliance (UNPA) predicts “This study will be dissected more carefully than a lab frog as the debate continues whether this is competent science, prejudicial in intent or an example of the difficulty in studying diseased people to find out what makes healthy people healthy.”

Perhaps most significant from an industry and potential health standpoint is the impact of these headlines on already baffled, blitzed and confused consumers currently, based on research, using these vitamins to support and maintain good health. Fabricant comments, “…what’s most troubling is that people who are safely and beneficially taking vitamins might stop, which may actually put their health at greater risk.” More optimistically, Israelsen counters, “It is counter intuitive and unconvincing to many consumers that anti oxidants will contribute to an earlier death”.

The full impact of this study will take some time to materialize. There is no doubt however that it places more strain on already challenged categories in the dietary supplements marketplace. It is also quite apparent, yet again, that industry's response, or even ability to generate positive stories is heavily outweighed by the appetitie for the sensational negative - regardless of the questions or concerns about study protocol or intent.

1 JAMA Vol. 297 No. 8, February 28, 2007

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