New analysis underlines safety of antioxidant supplements

A reexamination of a controversial meta-analysis suggesting an antioxidant-mortality link leads to different conclusions.

A group of international nutrition experts rechecked a meta-analysis of selected randomized controlled trials (RCTs), which concluded that antioxidant supplements containing vitamins A, C and/or E, and/or beta-carotene were associated with an increased risk of all-cause mortality (1). The meta-analysis included over 60 RCTs and was discussed controversially after its publications in 2007 (2) and 2008 (3): none of the trials were designed to measure mortality as a primary objective. Furthermore, over 400 clinical trials were excluded from the analysis because no deaths were reported. The new evaluation of the studies based on their actual primary objective: measuring health benefits of antioxidant supplements. The reexamination showed that of the 66 RCTs 24 (36%) had a positive outcome (i.e., benefit), 39 (59%) had a null outcome, and only 3 (<5%) had a negative outcome (i.e., harm). These findings are vastly different from 16 percent increase in mortality risk published in the original meta-analysis.

The scientists commented that an assessment of potential risks from antioxidant supplementation, as attempted by the meta-analysis, needs to be placed in the context of a benefit/risk ratio. Suggesting causality between antioxidant supplements and mortality is precarious as the risk of mortality in any RCTs of nutrients can be influenced by multiple factors and substantially depends upon the nature of the study population, including parameters such as advanced age, severe disease status, toxicity of drug treatments, etc.

With regard to the efficacy of antioxidant supplementation in the RCTs included in the meta-analysis, the experts stated that the benefit of an intervention was statistically significant principally in those populations generally characterized as being at risk for micronutrient (antioxidant) deficiencies. 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, although not presenting with overt deficiency syndromes.

Moreover, the scientists suggested that the reasons for contradictory findings about antioxidant supplements’ benefits and risks are due to the design of most randomized controlled trials. Most trials conducted have not determined antioxidant levels, such as plasma levels of vitamins C and E, or oxidative stress levels at the beginning of the study and following supplementation. Without such data, it is impossible to know whether the supplementation had the intended effect of increasing antioxidant and/or decreasing oxidative stress levels in the subjects studied, they said. In addition, most of the studies were designed to test the efficacy of supplements with only one or two antioxidant nutrients in multifactorial diseases. Thus, the trials may not have fully benefited from the dynamic interrelationships between these nutrients and other components (e.g. additional micronutrients) of the antioxidant defense network.

1. Biesalski H. K. et al. Reexamination of a meta-analysis of the effect of antioxidant supplementation on mortality and health in randomized trials. Nutrients. 2010; 2:929–949.
2. Bjelakovic G. et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: Systematic review and meta-analysis. J. Am. Med. Assoc. 2007; 297:842-857.
3. Bjelakovic G. et al. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst. Rev. 2008.