Jeffrey Blumberg

Invited Article
Unraveling the Conflicting Studies on Vitamin E and Heart Disease

Jeffrey Blumberg, Ph.D., F.A.C.N.
Tufts University, Boston, Massachusetts

Experimental studies suggest that dietary antioxidants like vitamins C and E may play an important role in the prevention and treatment of several chronic diseases, but recent conflicting reports of successes and failures in human studies are confusing scientists and consumers alike. For example, surveys of over 200,000 people in different communities around the world have provided compelling evidence that diets high in vitamin E and/or use of vitamin E supplements reduce the risk of heart disease. Although some clinical trials provide supporting data, the results from several large-scale trials do not confirm these observations. And, more recently, vitamin E has been implicated as having an adverse effect in the treatment of heart disease. Why are the results from surveys and trials so mixed?

Every research approach and each research study have inherent limitations. In considering the apparent contradiction between the outcome of the studies on vitamin E and heart disease, it is important to understand the difference between tests of primary and secondary prevention. Primary prevention is most often tested by following large populations of healthy people for many years and examining the incidence of new heart disease among people with differing intakes of vitamin E. In contrast, secondary prevention is tested over a few years in clinical trials with vitamin E supplements (and placebos) in patients with heart disease to determine whether their conditions worsen, e.g., with a subsequent heart attack.

Since many studies indicate strongly that vitamin E retards the formation of atherosclerotic plaque, which begins to develop in childhood and progresses throughout adulthood, vitamin E might be most effective in primary prevention. Nevertheless, some research does show that vitamin E may prevent rapid changes in blood vessel responsiveness and rupture of the plaque, suggesting that vitamin E could benefit patients with established disease. However, secondary prevention studies to assess clinical events and outcomes are frequently complicated not only by other conditions common among heart disease patients, such as diabetes and smoking, but also by the many drugs they are receiving along with the vitamin E supplement. The distinction between primary and secondary prevention is made even more complicated by the fact that the underlying biochemical mechanisms of action and the doses and time needed to accomplish them may be very different from one another.

Unfortunately, in part for reasons of cost and feasibility, all the large clinical trials thus far published have failed to test the basic premise underlying their hypothesis—the capacity of the antioxidant to reduce oxidative stress. Without some assessment of oxidative stress status in these trials, it is impossible to determine whether the supplement achieved its intended biochemical effect. Equally important, as none of these trials considered elevated oxidative stress as an eligibility criterion for study enrollment, it's impossible to determine whether an antioxidant intervention was even warranted for every subject. This situation is akin to testing the efficacy of a drug to lower blood pressure without first determining whether the patients in the study had hypertension.

It is always possible to question whether the dose or form (e.g., natural vs. synthetic) of vitamin E or the duration of the study was adequate to find a beneficial effect. It is also important to note that, to date, all the clinical trials of vitamin E and heart disease have not included any other antioxidants. Yet it is known that the dietary antioxidants, including vitamins C and E as well as the carotenoids and flavonoids, work together in a synergistic fashion. Several ongoing studies are now examining the effect of antioxidant "cocktails" on heart disease. For example, an on-going study of 520 people in Finland has found that, after three years, a combination of vitamins C and E is retarding atherosclerosis in men (but not women). In contrast, preliminary results from 20,000 people in Britain indicate that a combination of vitamins C and E and beta-carotene did not provide any benefit to patients with heart disease. Whether in healthy people or in patients with heart disease, more work must be done to find whether it is possible to determine in advance who will be responsive to the potential preventive or therapeutic effects of antioxidants. While diet, lifestyle factors, and patient characteristics will undoubtedly prove important in this quest, understanding the contribution of an individual's genes present another part of the solution.

Although decades of research have revealed that antioxidants are safe even in high doses, a recent clinical trial has shown that an antioxidant cocktail (800 IU vitamin E, 25 mg beta-carotene, 1,000 mg vitamin C, 100 µg selenium) reduced the efficacy of an established therapy with simvastatin (a lipid lowering drug) and niacin (a B vitamin) in patients with heart disease. Although the researchers found these results surprising and unexpected, some people have now concluded that the use of antioxidants could be hazardous in some circumstances. As noted above, every study has limitations and this study (with only 40 patients receiving the antioxidants and drug therapy) is no exception. No harm has been observed in any of the other studies of vitamin E and heart disease.

The promise of preventive and therapeutic nutrition holds a great deal of hope for promoting health and treating disease. Considering the challenges being faced in defining effective nutritional interventions, conclusions we reach today about the value of antioxidants and their application in our daily lives requires a thoughtful scientific judgment of all of the available evidence from basic research through clinical trials. In thinking about the value of vitamin E supplementation, particularly in primary prevention, it is important to appreciate not only its potential benefit in heart disease but also in a variety of other chronic diseases associated with oxidative stress, including age-related macular degeneration, Alzheimer’s disease, cancer, cataract, diabetes, Parkinson’s disease, and rheumatoid arthritis. Although research on heart disease represents the area of most extensive examination of vitamin E, provocative data on the prevention and treatment of these other conditions, even in the absence of definitive answers, suggest the widespread use of vitamin E supplements is not without a rational basis. Thus, it is relevant to note that the Tolerable Upper Intake Level (UL) of 1,000 mg daily (about 1,500 IU of natural vitamin E or 1,100 IU of synthetic vitamin E) established in 2000 by the Institute of Medicine allows for a reasonable range of self-prescribed supplement doses of vitamin E.

Last updated May, 2002

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