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Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality

Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E.

Ann Intern Med. 2005 Jan 4;142(1):37-46.

Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality

Search Strategy and Inclusion Criteria

We searched for all reports of clinical trials (with no language restrictions) that tested the effect of vitamin E supplementation in humans. We performed a MEDLINE search by using the Medical Subject Heading (MeSH) terms vitamin E, antioxidant vitamins, alpha tocopherol, tocopherol, and clinical trials. The search period was 1966 through August 2004. We complemented the MEDLINE search by searching the Cochrane database of randomized, controlled trials; reviewing the reference lists from original research, review articles, and previous meta-analyses; and reviewing the files of the investigators.


Nine of 19 trials used vitamin E alone, while the other 10 trials combined vitamin E with other vitamins or minerals. All but 3 trials were placebo-controlled and double-blind. Average follow-up ranged from 1.4 to 8.2 years. Vitamin E dosage varied between 16.5 and 2000 IU/d, with a median dosage of 400 IU/d.

Combined Effect of Vitamin E on All-Cause Mortality

Overall, vitamin E supplementation did not affect all-cause mortality. The pooled risk difference comparing vitamin E with control was 10 per 10 000 persons. However, there was significant heterogeneity of study results that was explained by differences in results between low-dosage (>400 IU/d) and high-dosage (<400 IU/d) vitamin E trials.
[Overzicht studies - figuur]
[Overzicht studies - tabel]

Many adverse effects

A recent meta-analysis that examined the effects of antioxidants, not specifically vitamin E, in preventing cancer noted a possible increase in all-cause mortality. However, in an accompanying comment, Forman and Altman cautioned that these mortality analyses were exploratory and incomplete. A strength of our paper is the systematic search for trials that presented mortality data.

Although vitamin E is considered relatively safe compared to other fat-soluble vitamins, an increase in mortality at high dosages of vitamin E is biologically plausible. In fact, some researchers warned against the longterm administration of mega-dosages of vitamin E because it could be associated with many adverse effects. In vitro studies have shown that vitamin E may have pro oxidant effects at high doses. In in vitro models, the pro-oxidant effect of vitamin E on low-density lipoproteins is related to the production of the tocopheroxyl radical, which can be inhibited by co-antioxidants such as vitamin C.

However, the trials that combined highdosage vitamin E with vitamin C showed increased mortality in the vitamin E groups, with the exception of the small Polyp Prevention Study (PPS). High dosages of vitamin E may displace other fat-soluble Antioxidants, disrupting the natural balance of antioxidant systems and increasing vulnerability to oxidative damage. Vitamin E may also inhibit human cytosolic glutathione S-transferases, which help detoxify drugs and endogenous toxins.

Vitamin E also has anticoagulant properties, possibly by interfering with vitamin K–dependent clotting mechanisms. In fact, the Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Study showed a statistically significant increased risk for hemorrhagic stroke among participants assigned to vitamin E.


On the basis of our study, high-dosage vitamin E supplementation is clearly unjustified. Policymaking bodies, which currently do not recommend antioxidant vitamin supplement use to the general population, should also caution the public against the use of high-dosage vitamin E supplementation. Current practice guidelines, however, recommend the use of vitamin E supplementation to delay the progression of Alzheimer disease. This recommendation may be premature until larger randomized, controlled clinical trials evaluate the efficacy and safety of high-dosage vitamin E supplementation in patients with Alzheimer disease.





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