In this issue of American Family Physician, Adams and colleagues discuss potential clinical uses of antioxidant vitamin supplementation. Interest in dietary antioxidant vitamins has been growing over the past few decades with the recognition that oxidative processes can damage cell membranes and DNA. An overabundance of oxidant formation has been proposed to play a role in the development of several diseases, including atherosclerosis, cancer, Parkinson's disease, Alzheimer's disease and morbid obesity. The pathologic effect of oxidation has been most specifically identified in atherosclerosis. It is now accepted that oxidation of low-density lipoprotein (LDL) cholesterol plays a central role in the formation, proliferation and rupture of atherosclerotic plaques.^2,3

Epidemiologic studies have also supported a role for dietary antioxidant vitamins, most notably ∂-tocopherol (vitamin E), ascorbic acid (vitamin C) and β-carotene, in disease prevention. Multiple studies have reported decreased rates of cancer and cardiac disease in populations with high consumption of fruits and vegetables.⁴ Studies focusing more specifically on antioxidants have confirmed that the more antioxidants a population consumes in their food, the lower the rate of cancer and cardiovascular disease.⁴

Both the epidemiologic and basic research on antioxidants has raised exciting possibilities concerning their clinical use. Enthusiasm was particularly high for vitamin E supplementation after the 1993 reports of the Nurse's Health Study⁵ and Health Professionals Follow-up Study.⁶ These prospective observational studies reported a significantly decreased risk of major coronary artery disease among both women⁵ and men⁶ who took vitamin E supplements for at least two years during four to eight years of follow-up.

Unfortunately, association does not prove causation, and subsequent randomized controlled trials of antioxidant supplementation have not shown as much benefit as hoped. Supplementation with β-carotene was found to actually increase lung cancer and coronary artery disease mortality among cigarette smokers in the Alpha-Tocopherol Beta-Carotene (ATBC) Cancer Prevention Study⁷ and Beta-Carotene and Retinal Efficacy (CARE) trial⁸ The Physicians Health Study⁹ found no benefit from β-carotene supplementation after 12 years of follow-up. There have been no prospective studies showing decreased risk of cardiovascular disease or cancer with vitamin C supplementation.

Results of the two major prospective randomized placebo-controlled trials of vitamin E supplementation have been mixed. The Cambridge Heart Antioxidant Study (CHAOS)¹⁰ was a secondary prevention trial in patients with coronary artery disease demonstrated on angiography. Patients who received vitamin E supplements had significantly lower rates of major cardiovascular events, including nonfatal myocardial infarction, but actually had more fatal myocardial infarctions and greater overall mortality during a median follow-up of 2.6 years.¹⁰

The ATBC trial¹¹ reported no benefit with vitamin E supplementation in primary prevention of cardiac events or mortality in smokers, or in secondary prevention among patients with previous myocardial infarction.¹² As in the CHAOS trial, there was a nonsignificant increase in all-cause mortality with vitamin E supplementation in patients with previous myocardial infarction.

What could be the reasons for the discrepancy between observational and randomized trials? All observational studies, no matter how well-controlled, have a problem with self-selection. People who eat more vegetables and fruit and take antioxidant supplements may also have other healthier living habits. In addition, the benefits of consuming fruits and vegetables may be the result of a combination of nutrients, including antioxidants.¹³ Antioxidants may need to work synergistically with other nutrients to be beneficial. In this way, the effective dosage of antioxidant vitamin supplementation may be dependent on the presence or absence of other nutrients and the overall nutritional state of the individual. Certainly, the optimal dosages of specific antioxidant vitamin supplements are unknown.

Antioxidant supplements may be beneficial. However, at this time, the proper formulation, combination and dosage remain unknown. The trials involving β-carotene that revealed increased mortality with supplementation are sobering reminders that prospective clinical trials need to be completed before making recommendations for supplementation. Until these trials are completed, it is most prudent to advise patients to obtain antioxidants in the form that has a proven benefit: in whole fruits and vegetables.