Vitamin E 400 IU: What the Trials Found

What 400 IU means on a label

An international unit of vitamin E is defined against a chemical form, so 400 IU can be two different doses. For synthetic dl-alpha-tocopheryl acetate, 1 IU is 0.45 mg, so 400 IU is 180 mg. For natural-source d-alpha-tocopherol, 1 IU is 0.67 mg, so it's 268 mg. Most 400 IU capsules use the synthetic ester, which is cheaper and more stable than the free alcohol. The RDA is 15 mg, and the tolerable upper limit is 1,000 mg a day from supplements.

Twelve times the RDA, in one capsule.

The trial that started the run

The prostate hypothesis came from ATBC, a Finnish trial of 29,133 male smokers built to test lung cancer. Men took 50 mg of dl-alpha-tocopheryl acetate or placebo for five to eight years. Lung cancer, the endpoint the trial was designed around, didn't fall. Prostate cancer, a secondary endpoint, came out 32% lower.

One secondary endpoint in smokers sold a great many bottles.

SELECT

SELECT was built to confirm it, with 35,533 men at 427 sites and a 2x2 design: 400 IU of synthetic vitamin E a day, 200 mcg of selenium, both, or placebo. Supplements stopped in October 2008 after about 5.5 years, when it was clear the trial wouldn't hit its target. The 2011 analysis, with 1.5 more years of follow-up, counted 76 prostate cancers per 1,000 men on vitamin E against 65 on placebo over seven years, a hazard ratio of 1.17 (99% CI 1.004 to 1.36).

Overall mortality and the other cancer sites didn't differ, so the signal sat on the endpoint the trial was built around and pointed the wrong way.

The mortality meta-analysis

Miller and colleagues pooled 19 randomized trials with 135,967 participants in 2005. Doses ran from 16.5 IU to 2,000 IU a day, median 400 IU. Nine of the 11 trials testing 400 IU or more showed a positive risk difference for all-cause mortality. That pooled difference was 39 deaths per 10,000 people (95% CI 3 to 74, P = 0.035), against minus 16 per 10,000 below it. A dose-response model put the inflection above 150 IU a day. That 39 per 10,000 works out to one extra death for every 250 people.

Bjelakovic and colleagues searched wider two years later, covering 68 trials and 232,606 participants. Pooling everything gave RR 1.02 (95% CI 0.98 to 1.06), which is no real effect. The 47 low-bias trials gave RR 1.05 (95% CI 1.02 to 1.08), and vitamin E alone in those gave RR 1.04 (95% CI 1.01 to 1.07). The answer moved with the trial list.

Both analyses leaned on trials that enrolled people who were already ill.

The case against the case

Abner and colleagues pooled 57 trials with 246,371 participants in 2011 and got RR 1.00 (95% CI 0.98 to 1.02), with heterogeneity near zero and no dose relationship even at 5,500 IU a day. Their argument was about timing: both earlier analyses closed their searches before the mortality data from the Women's Health Study, the Physicians' Health Study II and SELECT were out.

Those trials are the counterweight. The Women's Health Study randomized 39,876 women to 600 IU of natural-source vitamin E on alternate days for 10.1 years. Major cardiovascular events came out at RR 0.93 (95% CI 0.82 to 1.05), total cancer at RR 1.01 (95% CI 0.94 to 1.08), and total mortality showed no significant difference. Cardiovascular death was 24% lower (RR 0.76, 95% CI 0.59 to 0.98), a secondary finding later trials didn't reproduce. The study was funded by the National Institutes of Health and, in part, by the Natural Source Vitamin E Association.

Food is a different product

A supplement is alpha-tocopherol. Food is a mixture of alpha and gamma tocopherols plus tocotrienols, and the liver's alpha-tocopherol transfer protein retains alpha over everything else. High alpha intake tends to push plasma gamma-tocopherol down, so a 180 mg capsule and 15 mg from food aren't the same intervention at different sizes.

Getting 15 mg from food isn't difficult. An ounce of almonds carries 7.3 mg, an ounce of sunflower seeds 7.4 mg, and a tablespoon of wheat germ oil around 20 mg.

That's the boring part of the evidence, and it's the part nobody argues about.

What 400 IU is worth

At 400 IU the mortality signal is small, inconsistent across analyses, and driven by trials in sick people. The prostate signal from SELECT is the strongest single finding, and it points toward harm in healthy men. Neither result supports 400 IU daily for prevention, and neither rules out a multivitamin with 30 IU.

High-dose vitamin E can increase bleeding risk, particularly on anticoagulant or antiplatelet medication, and surgeons generally want it stopped before elective surgery. That's a conversation with a clinician, not a label decision.

Frequently asked questions

Is 400 IU of vitamin E too much?

400 IU is 180 mg from the synthetic form and 268 mg from the natural one. The upper limit is 1,000 mg a day, so it's below the limit and twelve times the RDA.

Did the vitamin E trials show more deaths?

The 2005 and 2007 meta-analyses did, by roughly 4% relative. A 2011 analysis of 57 trials found no difference, and the large trials in healthy people didn't reproduce it.

Does vitamin E prevent prostate cancer?

The opposite showed up. In SELECT, 400 IU a day was associated with 17% more prostate cancers over seven years.

Can I get enough from food?

Yes. The RDA is 15 mg, and an ounce of almonds or sunflower seeds supplies about half of it.

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This article is for general information only and does not constitute medical advice. Statements about dietary supplements have not been evaluated by the Food and Drug Administration and are not intended to diagnose, treat, cure, or prevent any disease. Talk with your health care provider before using vitamin E supplements, especially if you take prescription medication or have a bleeding disorder.

Sources

• Miller ER et al., Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality, Ann Intern Med 2005
• Bjelakovic G et al., Mortality in randomized trials of antioxidant supplements for primary and secondary prevention, JAMA 2007
• Abner EL et al., Vitamin E and all-cause mortality: a meta-analysis, Curr Aging Sci 2011
• National Cancer Institute, SELECT trial results: questions and answers
• Lee IM et al., Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study, JAMA 2005
• NIH Office of Dietary Supplements, Vitamin E Fact Sheet for Health Professionals