Do antioxidant supplements increase mortality?

According to a new literature review, supplements containing antioxidants, such as beta-carotene, vitamin A and vitamin E, do not show significant effects in preventing mortality, but may increase mortality by up to 3%. Experts criticize that the analysis included trials using high micronutrient doses to prevent or even treat chronic diseases, which would not reflect typical daily usage.

The systematic review included 78 randomized controlled trials involving a total of 296,707 healthy participants or patients (mean age 63 years) with various diseases (such as gastrointestinal, cardiovascular, neurological, ocu-lar, dermatological or rheumatoid diseases) who took supplements with antioxidants (beta-carotene, vitamin A, vitamin C, vitamin E and selenium) or placebo for a mean duration of three years (1). The data analysis showed that the antioxidant supplements had no significant effect on mortality in primary and secondary prevention. Meta-analyses showed an increase of mortality risk for participants who used supplements with beta-carotene (+2.7%), vitamin E (+1.7%), vitamin C (+0.6%), vitamin A (+0.4%) and selenium (+0.3%).

The researchers concluded that their findings did not support the use of antioxidant supplements in the general population or in patients with various diseases to prevent mortality. A potentially increase in the risk of mortality could be associated with the intake of supplements containing beta-carotene and possibly vitamin E as well as high doses of vitamin A, but not those with vitamin C or selenium.

Experts commented that the review included trials that were set up very specifically, in which supplement doses and objectives did not reflect everyday situations. In reality, large parts of the adult population and in particular of the elderly do not even consume enough of the nutrients to reach the daily recommended intake levels, as shown in population-based surveys in Europe and the US. They pointed out that given the limitations of the meta-analysis, generalizations and hasty conclusions should be avoided so as not to mislead people who use supple-ments to fill nutrient gaps in their diet.

A recent meta-analysis based on 57 studies involving a total of 246,371 participants taking vitamin E containing supplements or placebo for a median of 2.6 years at doses up to 5,500 IU per day showed that vitamin E supplementation is associated with neither a reduction nor an increase in the risk of all-cause mortality (2). This finding differs from the current and two former published meta-analyses, both of which found small but significantly increases in risk of mortality for those taking supplemental vitamin E. According to the experts, one possible explanation for the different findings is the number of trials included. One analysis (3) included only 19 trials and appeared prior to the release of mortality data from several large, well-conducted trials (4–7) showing no significant effect of vitamin E in the prevention or therapy of complex multifactor diseases, such as cancer or mortality linked to cardiovascular diseases. The second analysis (8) reported on 51 trials but only found a significant increase in risk of mortality when a subset of 26 studies was considered. Also this analysis was completed prior to the publication of large trials providing mortality data (5-7).

1. Bjelakovic G. et al. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. Published online March 2012.
2. Abner E. L. et al. Vitamin E and All-cause Mortality: A Meta-Analysis. Current Aging Science. 2011.
3. Miller E. R. et al. Meta-analysis: High dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2004; 142:37–46.
4. Lee I. et al. Vitamin E in the primary prevention of cardiovascular disease and cancer. The Women's Health Study: A Randomized Controlled Trial. JAMA. 2005; 294:56–65.
5. Cook N. R. et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: Results from the Women's Antioxidant Cardiovascular Study. Arch Intern Med. 2007; 167(15):1610–1618.
6. Sesso H. D. et al. Vitamins E and C in the prevention of cardiovascular disease in men: The Physicians' Health Study II Randomized Controlled Trial. JAMA. 2008; 300(18):2123–2133.
7. Lippman S. M. et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2008; 301(1).
8. Bjelakovic G. et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: Sytematic review and metaanalysis. JAMA. 2007; 297:842–857.