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Vitamin E Supplementation: What Should Health Professionals Tell Their Patients?
Joel Mason, M.D.

Dr. Mason reports no commercial conflict of interest.


Release Date: 07/10/2005
Termination Date: 07/10/2008

Estimated time to complete: 1 hour(s).

Albert Einstein College of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Albert Einstein College of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
 
Learning Objectives
Upon completion of this Cyberounds®, you should be able to:
  • Discuss the widespread use of vitamin E supplements in the U.S.
  • Describe the evidence regarding the potential benefits of vitamin E supplementation in the prevention of cardiovascular disease and cancer
  • Describe the evidence indicating that high doses of vitamin E supplements could feasibly produce harm.

 

Recently, there has been considerable media attention as to whether or not vitamin E supplementation is safe or efficacious. The attention has been largely driven by publication of two papers in medical science journals over the past year with regard to potential adverse health effects of vitamin E supplementation(10),(11). As a result, physicians and other health professionals have been deluged with questions from their patients about vitamin E and sales of vitamin E supplements have plummeted.

What is the scientific basis of the claims of benefits and harms conveyed by vitamin E supplements?

Why Vitamin E Supplements are Popular

Over the past two decades, some scientists have proposed a so-called 'oxidant theory of disease.'(12) This hypothesis contends that oxidative metabolism, and the free radicals that arise from it, constitute the core pathophysiologic mechanism underlying a number of chronic degenerative diseases including cancer and cardiovascular disease (CVD). This theory, furthermore, postulates that adequate, or even supraphysiologic, intake of anti-oxidant nutrients such as vitamins C, E, the carotenoids and selenium can protect against such damage. Amongst all of these possible benefits, the potential protective effects against CVD and cancer have been the two most extensively submitted to the test of randomized clinical trials (see Tables 1 and 2).

How Widespread is the Use of Vitamin E Supplements?

The daily use of dietary supplements, and in particular vitamin E, has grown to be a widespread habit. Most surveys performed in the past five years have observed regular intake (>5 times/week) among 25-50% of the adult population and, in almost all cases, the prevalence incrementally increases by age and with the presence of chronic degenerative diseases.(1) Commonly, these adults take daily doses of 400 mg or more.

Even among physicians, vitamin E supplementation for their personal consumption is a growing practice. Large nationally representative cohorts of physicians have demonstrated regular intake among approximately one-third of the physician respondents. In the past decade, vitamin E supplements have been very popular: 8% and 16% usage among male and female physicians respectively, and like the general population, in the majority of instances the dose is 400 mg or greater.(2),(3)

Not surprisingly, such widespread use has significant financial ramifications, with sales of vitamin supplements reportedly amounting to over 19 billion dollars in 2003.(13) This latter item is rather important since the opportunity for financial gains may alter the manner in which a manufacturer reports to the public the purported health benefits of its products.

A Perspective on the Doses Contained in Vitamin E Supplements

The growing acceptance of vitamin E as a useful nutritional supplement has been greatly enhanced by the apparent safety of the vitamin, with upper limits of safe intake set by the National Academy of Sciences at 1000 mg/day, or approximately seventy times the basal requirement of the vitamin. So, although the most commonly used dosage for single-nutrient vitamin E supplements is 400 mg or roughly 30-fold greater than the RDA, that level of supplementation is still less than half the purported upper limit of safe intake.

With such a wide array of benefits and with an apparent solid margin of safety, it is not surprising that large segments of the public, as well as health professionals, have adopted the same philosophy uttered recently by an investigator in cardiology, who said about high dose vitamin E: 'It can't hurt and might help, so why not take it?'(4).

So, just what do the studies with respect to presumed risk benefit for coronary heart disease and cancer show? And do they confirm the perspective expressed by this investigator?

Vitamin E Supplements and Cardiovascular Disease

Large, observational studies published in the latter part of the 1980s and early 1990s consistently observed a strong, inverse association between habitual vitamin E consumption and the risk of coronary heart disease, with risk reductions of 30-60%. For example, two of the most oft-quoted studies emerged from the Nurses Health Study and the Health Professionals Health Study at Harvard, in which habitual total vitamin E intake, vitamin E intake from multivitamins and intake from single-nutrient E supplements were assessed in a prospective cohort fashion. These studies demonstrated a remarkably strong decrease in risk associated primarily with the use of high doses of vitamin E but considerably weak effects of low doses of the vitamin.(5),(6) It was data such as this that drove investigators in this field towards a perception that large doses were likely to be the efficacious ones.

However, when these observational results were subjected to controlled interventions, the results were considerably different. Table 1 displays the large prospective, randomized, controlled trials (PRCTs) in which the potential benefits of vitamin E supplementation have been tested with the secondary prevention of cardiovascular disease as the primary outcome.

Table 1. Vitamin E in the Prevention of CVD: PRCTs Having CVD as Primary Endpoint.

Trial/ref n Primary or Secondary Vit E Dose Outcome
CHAOS
Lancet 1996
2000 secondary 400-800 mg ↓CV death and non-fatal MI, RR=0.53
GISSI-IV
Lancet 1999
11,324 secondary 300 N.S.
HOPE
NEJM 2000
160 secondary 400 N.S.
HATS
NEJM 2001
160 secondary 800 + C + β-carotene+Se N.S., ↓ Statin/niacin benefit
HPS
Lancet 2002
20,536 secondary 600 + C + β-carotene+Se N.S.
HOPE-TOO
JAMA 2005
4,732 secondary 400 1° endpt N.S. CHF, RR=1.13

Although the first of these trials, the CHAOS trial, provided some promising results, all the subsequent trials, including ones with sizably larger study populations, showed no benefit. Overall, these studies provided no compelling evidence for a consistent benefit of vitamin E in the secondary prevention of cardiovascular disease. Furthermore, observations from two of the trials raised concerns about potential adverse effects. In the HATS trial, where angiographic evidence of narrowing constituted the primary endpoint, the use of vitamin E supplements diminished the angiographic benefits obtained from the use of niacin and a statin drug. In the HOPE-TOO trial, the use of vitamin E supplements slightly, but significantly, increased the risk of congestive heart failure.

Nevertheless, the fact that at least one large trial, the CHAOS trial, saw substantial and significant benefits perhaps makes this topic ripe for a meta-analysis, which we shall come to shortly.

Vitamin E Supplements in Cancer Prevention

A parallel evolution in thought occurred regarding vitamin E's purported benefits in cancer prevention. Large, observational studies in the 1990s, such as one that was conducted as a cross sectional analysis of 10,000 women and men participating in the NHANES survey (National Health and Nutrition Examination Survey: a representative sampling of the U.S. population), observed what appeared to be a remarkably strong protective effect of vitamin E against lung cancers among those at risk -- smokers, but only those who were mild-to-moderate smokers.(7)

Further weight of evidence to the theory of antioxidant protection was attributed to the fact that there appeared to be synergism between high intakes of multiple antioxidant nutrients. In contrast to the epidemiologic literature on CVD, this study found no evidence of increasing protection against cancer with high intakes from supplemental E compared to vitamin E coming solely from the diet. The study results greatly influenced the dose of supplement chosen for cancer prevention trials.

However, as was the case with cardiovascular disease, when this concept of antioxidant protection against cancer was rigorously tested within the context of PRCTs, the results were not compelling (see Table 2).

Table 2. Vitamin E in the Prevention of Cancer: PRCTs Having Neoplasia as 1° Endpoint.

Trial/ref n Dose of Vit. E Type of Cancer Outcome
ATBC
NEJM 1994
29,133 50 mg/d lung cancer (1° outcome) N.S.
ATBC
Cancer Cuases Contr 2000
29,133 50 colorectal cancer N.S.
ATBC
Cancer Cuases Contr 2000
29,133 50 urinary tract cancer N.S.
ATBC
JNCI 1998
29,133 50 prostate cancer ↓32% incidence
Linxian
J Natl Cancer Inst 1993
29,584 60 + Se + β-carotene stomach ↓32% incidence

Precancerous lesions. PRCT trials in dysplastic lesions: 1 negative trial in ductal dysplasia of the breast and 5 negative trials in colorectal adenomas.

The largest trial by far was the ATBC trial: ~29,000 male, Finnish smokers were prospectively administered vitamin E, beta-carotene, both or a placebo and followed for nearly a decade. There was no protection against lung cancer, the primary endpoint, and neither was protection conveyed against colorectal or urinary tract cancers. A follow-up study did, however, observe some promising protection against prostate cancer, which is now being followed up with the SELECT trial (see below).

The Linxian trial in rural China also observed some benefit with a 'cocktail' of antioxidant supplements. However, this trial is perceived by most as questionably applicable to Western medicine since this trial was conducted in a population where deficiencies of several of the administered supplements are widespread. Thus, vitamin E supplements have not yet been proven to be efficacious in cancer prevention.

Vitamin E Supplementation for Infection Control in the Elderly

I'll briefly touch on just one other issue pertinent to potential benefits of vitamin E that has been the subject of PRCTs -- a modest decrease in the integrity of the immune system of the elderly. There is some evidence that this well-documented decline in immunoresponsiveness is mediated by activity of reactive oxygen species that can be quenched by free radical scavengers such as vitamin E. The decline has been demonstrated for various functions of the cell-mediated as well as the humoral arms of the immune system.

Some eight years ago, a randomized clinical trial demonstrated improvements in measures of both the humoral and cell-mediated immune responses in elderly subjects with vitamin E supplementation, the optimal dose of which appeared to be 200 mg/d.(8) Last year, these authors published a follow-up PRCT in which the subjects were institutionalized elderly, the intervention was 200 mg of vitamin E daily and the primary endpoint was respiratory infections. No decrease in pneumonia was observed over a one-year period. However, a modest, but significant, 15% decline in the risk of upper respiratory infections, primarily coryza (the common cold), was observed.(9)

Recent Meta-analyses

Two recent meta-analyses have reawakened concern over the use of high-dose vitamin E supplementation. The first analysis examined whether 14 PRCTs, where each tested if antioxidant supplements prevented gastrointestinal cancers, demonstrated a beneficial effect overall. No benefit was observed in cancer prevention, with the exception that selenium may have shown some modest benefit.(10) It is worth noting that a rigorous effort was made to exclude the problem of heterogeneity -- both in regard to the types of cancers and the particular supplements used in each trial -- and heterogeneity was not found to be a confounding factor. What raised concern was the fact that when the studies that were considered to be of the highest methodologic quality were examined, there was an increase in all-cause mortality of 6%.

Another meta-analysis encompassing 136,000 subjects published in 2005 made a concerted effort to examine the issue of the dose of vitamin E, which was not feasible in the prior meta-analysis. The 2005 study found a slow rise in all-cause mortality associated with vitamin E supplementation with increasing dose such that only daily doses exceeding 150 mg presented some risk.(11) At doses >400 mg/d, the increased risk of death was 39 per 10,000 individuals (p=0.035). Again, heterogeneity was examined rigorously and not found to be a confounding factor.

If we are to believe that vitamin E supplementation might somehow be harmful, one might rightfully ask whether there is scientific evidence to indicate pathways through which vitamin E could possibly present a harmful effect. This is quite speculative at present since the only documented adverse effect of vitamin E is to induce a coagulopathy, and that only is shown at extraordinarily high doses. Nevertheless, Table 3 outlines pathways through which vitamin E could possibly be harmful.

Table 3. Pathways Through Which Vitamin E Could Hypothetically Be Harmful?

  • Like most antioxidants/free-radical scavengers, it can have a pro-oxidant effect at high doses (e.g., ↑'s LDL oxidation at high doses in vitro)
  • May displace other fat-soluble nutrients (e.g., λ-tocopherol)
  • Inhibits glutathione S-transferases in vitro
  • Creates a coagulopathy by inhibiting vitamin K pathways

What Conclusions Are To Be Drawn?

A physician is forever confronted with the dilemma of treating patients with imperfect and incomplete information and this is certainly the case here. A reasonable conclusion, based on the information available to date, is that high doses of vitamin E (>100 mg/day) have not conclusively been shown to provide any benefit and feasibly might increase the risk of harm, albeit to a very small degree. Until further insights are acquired in this field, physicians should critically challenge themselves as to the precise rationale for suggesting vitamin E supplementation to any particular patient. If the physician, nevertheless, chooses to suggest supplementation, they might be serving their patients best by keeping that recommendation to <100 mg/day.

The multi-center SELECT trial is presently underway in North America and will examine, over a 7-year period, whether 400 mg of vitamin E per day, with or without selenium, is effective in preventing prostate cancer among 32,000 men. This trial will hopefully answer many of the concerns raised in this article.


Footnotes

1Shikany JM, Patterson R, Agurs-Collins T, et al. Antioxidant supplement use in the Women’s Health Inititative Participants. Preventive Medicine 2003;36: 379-387.
2Muntwyler J, Hennekens C, Manson J, et al. Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality. Archiv Int Med 2002;162: 1472-1476.
3Frank E, Bendich A, Denniston M. Use of vitamin-mineral supplements by female physicians in theUnited States. Am J Clin Nutr 2000;72: 969-975.
4Quoted in, Greenberg ER. Vitamin E supplements: good in theory, but is the theory good? Ann Int Med 2005; 142: 75-76.
5Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary heart disease in men. New Engl J Med 1993;328:1450-1456.
6Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary heart disease in women. New Engl J Med 1993;328:1444-1449.
7Yong L-C, Brown C, Schatzkin A, et al. Intake of vitamins E, C, and A and risk of lung cancer. Am J Epidemiol 1997;146: 231-243.
8Meydani S, Meydani M, Blumberg J, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects. J Am Med Assoc 1997;277: 1380-1386.
9Meydani S, Leka L, Fine B, et al. Vitamin E and respiratory tract infections in elderly nursing home residents. J Am Medical Assoc 2004;292: 828-836.
10Bjelakovic G, Nikolova D, Simonetti R, et al. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet 2004;364: 1219-1228.
11Miller E III, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: high dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142: 37-46.
12Willcox J, Ash S, Catignani G. Antioxidants and prevention of chronic disease. Crit Rev Food Sci Nutr 2004;44: 275-295.
13Supplemental Business Report. Nutrition Business Journal. San Diego, CA. 2003.