Antioxidants don't boost mortality risk, says meta-analysis re-analysis

Scientists led by Prof Hans Biesalski from the University of Hohenheim re-analyzed data from 66 randomized clinical trials, and found that 36 percent of the trials showed a positive outcome or that the antioxidant supplements were beneficial, 60 percent had a null outcome, while only four percent found negative outcome.

These findings are vastly different from 16 percent increase in mortality risk published in 2007 in the Journal of the American Medical Association​ (Vol. 297, pp. 842-857). The initial meta-analysis was led by Goran Bjelakovic from the Copenhagen Trial Unit at the Copenhagen University Hospital in Denmark.

Controversial​

The initial JAMA meta-analysis included 66 randomized trials with antioxidant supplements, including vitamins A, C and E, and beta-carotene. Over 400 clinical trials were excluded from the analysis because no deaths were reported.

Following criticism of the initial JAMA​ article (corrections were published in JAMA​, 2008, Vol. 299, pp. 765-766), the authors republished their meta-analysis in the prestigious Cochrane Systematic Review​.

Revisiting old data​

A team of internationally renowned antioxidant scientists has now re-analysed the data used by Bjelakovic et al​., and have come to a different set of conclusions.

Writing in Nutrients​, Prof Biesalski and his co-workers state: “With regard to the efficacy of antioxidant supplementation in the RCTs included in the meta-analysis by Bjelakovic et al., we find that the benefit of the intervention was statistically significant principally in those populations generally characterized at risk for micronutrient deficiencies, including those of vitamins C and E, selenium, and beta-carotene as well as other nutrients such as zinc that contribute to the antioxidant defense network. ​

“This relationship may suggest that dietary supplementation for the prevention or treatment of chronic diseases is likely to be most effective in those with inadequate intakes, though absent overt deficiency syndromes. ​

“Further, this relationship also suggests there is a threshold nutrient status above which additional intake via supplementation might provide no further benefit,”​ added the reviewers.

RCTs​

The reviewers also turn their attention to the challenges of studying antioxidant supplements using the randomized clinical trial approach. “The outcome of human studies on dietary antioxidants will depend on the initial status of the antioxidant defense network and oxidative stress in each subject, the dose(s) of the nutrient(s), and the concentration threshold for action of each nutrient. ​

“One of the major challenges in conducting RCTs to test the efficacy and safety of antioxidants (and other nutrients) as dietary supplements in reducing the risk of chronic disease, especially in primary prevention, is the need for very long durations of the intervention as we lack validated intermediary biomarkers of these conditions.”​

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Overdue​

The re-analysis was called “interesting and long overdue”​ by Andrew Shao, PhD, senior VP of scientific and regulatory affairs for the Council for Responsible Nutrition (CRN).

“This group of well respected antioxidant experts examined the same data, but in a very different context,” ​explained Dr Shao. “Rather than simply examining numbers to see if the risk for total mortality is increased (as Bjelakovic et al did) this group of experts examined the same studies to (a) see if there was any statistically significant benefits demonstrated and (b) if the effects (either benefit or harm) were biologically plausible. ​

“Aside from all the weaknesses and limitations from the previous meta-analysis, these are important questions that were never considered by Bjelakovic. Not surprisingly, they reach a different conclusion. ​

“This sheds some important light on the relevance (or lack thereof) of ‘all-cause mortality’, and that when examining the effects of antioxidants (or other nutrients) in humans, researchers should take into account both the benefits and risks and the biologic plausibility,”​ added Dr Shao.

Source: Nutrients​
2010, 2(9), 929-949; doi:10.3390/nu2090929
“Reexamination of a Meta-Analysis of the Effect of Antioxidant Supplementation on Mortality and Health in Randomized Trials”​
​Authors: H.K. Biesalski , T. Grune , J. Tinz , I. Zollner, J.B. Blumberg

The re-analysis is free to access. To read the full paper, please click here​.