The last year has not been a good one for vitamin E.
Once considered a wonder supplement, an inexpensive and harmless pill that might prevent heart disease, cancer and Alzheimer's, a flurry of recent clinical trials suggest it does none of those things.
Some even suggest there is a small chance it could have been harmful in higher doses.
Yet while the oily little capsule apparently can not keep people alive longer, it refuses to die, in part because in nearly every one of the recent negative studies some caveat or contradictory finding finding creates a glimmer of hope.
It also does not hurt that the dietary supplement industry continues to promote vitamin E and offers experts to refute some of new research.
"It does not go away," said Edgar Miller, a vitamin E researcher and associate professor of medicine at Johns Hopkins University. "Why does it keep selling when there are so many of these negative studies?"
The answer appears to be a combination of factors, including years of advancing laboratory, animal and epidemiological studies; heavy promotion by the dietary supplement industry; and, more recently, contradictory findings within studies showing no overall benefit.
The required daily amount is 22 IU (international units). Many recent clinical trials have ranged from 300 IU to 2,000 IU.
Recent clinical trials of high-dose vitamin E have led some researchers to speculate that vitamin E in megadoses may increase the oxidation of LDL cholesterol, the bad kind.
When cholesterol is oxidated, it contributes to coronary artery disease.
There is also some concern that high amounts of vitamin E may displace other beneficial anti-oxidants from that average person's diet.
Consider these recent studies: In November, a vitamin E bombshell was dropped by Johns Hopkins University researchers at an American Heart Association meeting.
They pooled 19 clinical trials of vitamin E involving 136,000 patients.
In 11 of the high-dose trials (400 IU or more), the risk of dying from any cause increased 4%, compared with people taking placebos.
Prior to that finding, vitamin E had been considered, at worst, harmless.
"People take anti-oxidants because they want to live longer," said Miller, an associate professor of medicine. "What we showed is you do not live longer."
However, the analysis also suggested that lower doses of vitamin E (less than 150 IU a day) were associated with about a 2% reduction in deaths.
Researchers acknowledged several potential shortcomings in their study.
For instance, they noted that several of the high-dose trials involved people with various chronic diseases and may not apply to healthy individuals.
They also said the small size of several of the trials in the analysis and inconsistent reporting of health events preceded a detailed look at the effect of various doses of the vitamin.
"It's a very flawed analysis," said Julie Buring, a professor of medicine at Harvard Medical School who recently presented her own vitamin E research.
She also said the 4% increased risk of death was not "clinically meaningful" and could be a chance finding.
Women's health study
On March 7, Boring and other Harvard scientists presented their own vitamin E study at the American College of Cardiology annual meeting.
Once again, the vitamin thread researchers a curve.
Analyzing data from the Women's Health Study, a trial involving 40,000 women who got either 600 IU of vitamin E every other day or a placebo, researchers found that it provided no overall cardiovascular benefit such as reduction in heart attacks or strokes.
However, an analysis of a subgroup of women over 65 found a 26% reduction in cardiovascular events.
Buring said that although the finding was "intriguing," it was not supported by previous research.
She added that it needs confirmation.
Adding even more confusion, the study found a statistically significant 24% reduction in cardiovascular deaths among all vitamin E users.
Buring also asked that finding because there was no overall reduction in strokes and heart attacks. She said it was possible that it was due to other cardiovascular causes such as arrhythmias or heart failure, but there was no reasonable biological explanation for that.
"People should look at that further, but it could be chance," she said.
Buring concluded that vitamin E was neither harmful nor beneficial in preventing cardiovascular disease.
About a week after the Women's Health Study, another controversial vitamin E finding was presented.
The study involved 9,500 people aged 55 and older with vascular disease or diabetes who were followed for an average of seven years.
It found that 400 IU of vitamin E a day provided no protection against cancer or major vascular events such as heart attacks or strokes.
In addition, the study found a disturbing 13% increase in heart failure cases and 21% increase in heart failure hospitalizations.
That was the first time that vitamin E had been associated with an increased risk of heart failure, said lead author Eva Lonn, a professor of medicine at McMaster University in Hamilton, Ontario.
"I am not convinced about the harm," Lonn added.
Indeed, a recent small study of heart failure patients taking a cholesterol-lowering statin drug suggested that vitamin E actually increased the statin's ability to improve blood vessel function and lower inflammation.
Lonn and the other researchers said a review of all heart failure events in large vitamin E clinical trials "is strongly recommended."
Confounding the heart failure finding was what appeared to be a statistically significant 28% reduction in lung cancer cases, although in a secondary analysis of the data the benefit seemed to disappear.
"The numbers are small," Lonn said. "We think it's a chance finding."
The researchers noted that other larger vitamin E trials showed no lung cancer benefit.
There still is some hope that vitamin E might help prevent Alzheimer's disease, although in May a clinical trial of 769 patients with mild cognitive impairment found it was of no benefit in delaying the progress to Alzheimer's.
In that trial, the patients took a mega dose 2,000 IU a day for up to three years, according to the findings in the New England Journal of Medicine.
Other vitamin E / Alzheimer's trials are ongoing.
The anti-oxidant vitamin enthusiasm of the 1990s is being tempered by clinical trials, according to a JAMA editorial that accompanies the Women's Health Study results.
"These hopes are now limited to modest expectations for specific disorders and there are concerns about adverse effects," the editorial said.