High-Dose Vitamin E Increases All-Cause Mortality
Abstract & Commentary
Comment by Mary Elina Ferris, MD, Clinical Associate Professor, University of Southern California, and Associate Editor, Internal Medicine Alert.
Synopsis: A meta-analysis of 19 clinical trials found that vitamin E intake greater than the recommended 400 IU/day found a statistically significant relationship between increased dosage and all-cause mortality when compared to both controls and lower doses.
Source: Miller ER, et al. Ann Intern Med. 2005;142:37-46.
A comprehensive review of all clinical trials since 1966 involving men and non-pregnant women using vitamin E supplementation for more than one year compared to randomized controls were analyzed for all-cause mortality. Nineteen trials were included involving 136,000 participants. Nine of the trials involved vitamin E supplementation alone, and the 10 others had combinations with other vitamins and minerals. Dosages of vitamin E ranged up to 2000 IU/day with a median of 400 IU/day.
While vitamin E overall did not affect mortality, there was a dose-response relationship between higher vitamin E amounts and increased mortality. The average death risk across all trials was 1022 per 10,000 persons; the pooled risk difference comparing vitamin E with controls was 10 per 10,000 persons. For low-dosage vitamin E the risk was actually lower, while for vitamin E in doses greater than 400 IU/day the pooled risk difference was 39 per 10,000 persons.
Miller and colleagues note that the trials that tested high dosages involved adults with chronic disease, and some involved multivitamin combinations so the exact effect of vitamin E could not be isolated. Nonetheless, they still felt that the conclusions were compelling enough to recommend against high-dosage vitamin E supplementation.
Comment
The editorial that accompanies this article in the Annals of Internal Medicine is appropriately titled "Vitamin E Supplements: Good in Theory, but is the Theory Good?"1 Widespread belief in the benefit of antioxidants has led to vitamin E being the most widely used of this group, estimated to be taken by 22% of US adults older than 55 years of age.2 However, while both epidemiological evidence and laboratory experiments have supported a role for the oxidative process in the pathogenesis of many diseases, actual clinical trials of antioxidants have not shown a clear benefit. Nevertheless, the prevailing opinion has been that no harm would be done to take the supplements in the hope that morbidity could be prevented.
This new meta-analysis indicates that harm may actually ensue, particularly with doses higher than the recommended daily allowances. Miller et al’s conclusions may be criticized because 10 of the 19 trials in their analysis also included other supplements (particularly beta-carotene which has been shown to be harmful) which may confound the results. However, the fundamental fact that no real benefit has been proven from antioxidants, in addition to possible harm, should lead physicians to recommend against increased vitamin E supplementation at this time.
References
1. Greenberg ER. Ann Intern Med. 2005:142:75-76.
2. Millen AE, et al. J Am Diet Assoc. 2004:104:942-950.
A meta-analysis of 19 clinical trials found that vitamin E intake greater than the recommended 400 IU/day found a statistically significant relationship between increased dosage and all-cause mortality when compared to both controls and lower doses.
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