By Alan R. Gaby, M.D.
Several weeks ago, two studies that appeared in medical journals achieved widespread media attention and created concern among people who are using nutritional supplements. One study concluded that the use of multivitamins or of certain individual supplements was associated with small but statistically significant increases in the mortality rate. The other study found that taking vitamin E increased the incidence of prostate cancer. The discussion below explains why neither of these studies has changed my view that nutritional supplements are, for the most part, very safe.
Observational study: “adjusted” data and no proof of cause-and-effect
In one of the studies, 38,772 women (mean age, 62 years) from Iowa filled out a questionnaire three times over an 18-year period regarding dietary supplement use. During a total follow-up period of 22 years, the risk of dying from any cause was said to be 6% higher among women who took a multivitamin supplement than among women who did not take a multivitamin. In addition, the use of individual supplements of vitamin B6, folic acid, iron, magnesium, zinc, and copper were said to be associated with increased mortality rates.1
A potentially serious problem with this study is that the researchers did not report actual mortality rates. Instead they compared “adjusted” mortality rates between supplement users and nonusers, by adjusting for a wide range of factors including caloric intake, cigarette smoking, body mass index, blood pressure, educational level, diabetes, use of hormone-replacement therapy, physical activity, and intake of fruits and vegetables. For each of these factors, the supplement users were in the “healthier” category (for example, less diabetes, less obesity, more physical activity, fewer smokers, and higher intake of fruits and vegetables), and would therefore have been expected to have lower mortality rates than the nonusers. Consequently, the mortality rate of the supplement users was presumably adjusted upward, when compared with the mortality rate of the nonusers. Epidemiology is a relatively crude and inexact science, and it is quite possible that the researchers “over-adjusted” the data, making the mortality rate among supplement users look higher than it really was. When the researchers adjusted the data only for age and caloric intake, there was no statistically significant difference in mortality rate between supplement users and nonusers, a point that was not mentioned in the media coverage of this study.
Another weakness of the study is that it was observational in nature. In contrast to randomized controlled trials, observational studies cannot prove cause-and-effect. There have been a number of instances in the history of medical research in which the results of observational studies were eventually contradicted by randomized controlled trials. For example, numerous observational studies suggested that the use of hormone-replacement therapy by postmenopausal women prevents heart disease, but subsequent randomized controlled trials demonstrated that hormone-replacement therapy either has no effect or actually increases the risk of heart disease.
One of the many potential sources of error in observational studies is what is known as “confounding by indication,” which in the present study would denote a failure to adjust for why the participants were taking nutritional supplements. To be sure, the supplement users were healthier than the nonusers according to the various parameters that the researchers measured. However, the supplement users may have been less healthy than nonusers according to a number of parameters that were not measured. Reasons that people might take nutritional supplements include recurrent migraines, asthma, persistent fatigue, recurrent infections, joint pains, or a family history of heart disease or other diseases. Some of these indications for supplement use may be associated with an increased risk of mortality.
Because of these weaknesses, the new study does not negate previous research demonstrating that vitamins and minerals can have a wide range of health benefits. One exception: the use of iron supplements by people who are not iron-deficient or who carry a gene for iron overload could have adverse consequences.
Vitamin E and prostate cancer: does the type of vitamin E matter?
In the other study, 35,533 men were randomly assigned to receive 400 IU per day of vitamin E (in the form of alpha-tocopherol) or placebo for an average of 5.5 years, and the men were then followed for a total of approximately 7 years. During that time, the incidence of prostate cancer was significantly higher by 17% in the vitamin E group than in the placebo group.2
Although the study was well designed from a technical standpoint, it suffers from an important weakness, in that the type of vitamin E used was not the same as the vitamin E that occurs in food. Vitamin E is found in food in 4 different forms: alpha-, beta-, gamma-, and delta-tocopherol. However, as is the case with most vitamin E research, the men in this study were given only alpha-tocopherol. Early research suggested that most, if not all, of the biological activity of vitamin E is due to alpha-tocopherol, but it is now known that at least one of the other components-gamma-tocopherol-has important functions. Furthermore, treatment with large doses of alpha-tocopherol has been shown to deplete gamma-tocopherol, potentially upsetting the natural balance of the different forms of vitamin E in the body. “Mixed tocopherols,” on the other hand, a supplement that contains all four types of vitamin E, would not be expected to cause such an imbalance.
In a previous study, both alpha-tocopherol and gamma-tocopherol inhibited the growth of human prostate cancer cells in vitro, but gamma-tocopherol was the more potent of the two.3 In another study, higher blood levels of alpha-tocopherol and gamma-tocopherol were each associated a lower risk of developing prostate cancer, but the protective effect of gamma-tocopherol was greater than that of alpha-tocopherol.4
Clinical trials that used alpha-tocopherol in doses lower than 400 IU per day did not find an adverse effect on prostate cancer incidence. In a double-blind study of male smokers, compared with placebo, supplementation with 50 IU per day for 5-8 years significantly decreased the incidence of prostate cancer by 32%.5 In a double-blind study of male physicians, supplementation with 200 IU per day (400 IU every other day) for 8 years resulted in a nonsignificant 3% decrease in prostate cancer incidence, compared with placebo.6 Thus, the effect of alpha-tocopherol on prostate cancer appears to be dose-related: protective at low doses (50 IU per day), neutral or modestly protective at intermediate doses (200 IU per day), and harmful at high doses (400 IU per day).
The totality of the evidence suggests that alpha-tocopherol has a protective effect against prostate cancer. However, when alpha-tocopherol is given by itself in large doses (such as 400 IU per day or more), it depletes gamma-tocopherol, which could more than negate any beneficial effect that alpha-tocopherol might have. If that is the case, then taking vitamin E in the form of mixed tocopherols would not be expected to increase prostate cancer risk, and might even help prevent prostate cancer. Further research is needed to examine that possibility.
Dr. Sara Knuth, ND
401 29th St, Suite 101
Oakland, CA 94609