What Vitamins Should I Be Taking, Doctor?
Walter C. Willett, M.D., Dr.P.H., and Meir J. Stampfer, M.D., Dr.P.H.     NEJM 2001;345:1819

Medical teaching has been that, in generally healthy persons, nutritional needs can be readily met by diet alone.  Public interest in vitamin supplements is enormous, with 30 percent of the population of the United States currently using such supplements.Political pressures have led to a highly unregulated industry with limited control by the Food and Drug Administration over marketing and quality.

Because foods contain many nutrients, distinguishing among the effects of various nutrients in the same foods can be difficult. For example, the observation that high-dose beta carotene supplementation in smokers did not reduce the risk of lung cancer and may even have increased risk highlights the potential dangers of extrapolating from epidemiologic studies of food consumption (the consumption of fruits and vegetables, in this case) to concentrated forms of a single chemical. Epidemiologic studies of vitamin-supplement use per se are more directly relevant, but careful statistical adjustment for other lifestyle factors is essential because users of supplements may have healthier behavior in general than nonusers. We briefly review the potential effects of commonly used vitamins, recognizing that the relevant literature is far greater than what can be cited here.

Folic Acid

Several epidemiologic studies have found that periconceptional folic acid supplementation is associated with a substantially reduced risk of neural-tube defects. In a randomized trial, a high-dose folic acid supplement reduced the incidence of recurrent neural-tube defects by 70 percent. A randomized trial of a multivitamin that included folic acid (800 g daily) in pregnant women without a history of an affected pregnancy was stopped early because of a clear benefit. This is the only definitively proven benefit of a multivitamin.

Although this relation has not been tested in randomized trials, substantial evidence suggests that low folic acid intake increases the risk of cardiovascular disease and several types of cancer. Higher intake of folic acid is associated with a lower risk of colon cancerand breast cancer, particularly among persons who are at increased risk because of daily alcohol consumption. Also, a polymorphism in the gene for methylenetetrahydrofolate reductase (which is involved in folate metabolism) has been associated with an increased risk of colon cancer in some studies, providing additional evidence that the relation between low folic acid intake and an increased risk of colon cancer is causal. Alcohol interferes with folate absorption and metabolism, perhaps accounting for increased folate requirements among drinkers.

The optimal folic acid intake remains uncertain. An intake of 400 g per day minimizes blood homocysteine levels in most people, but more may be needed to reduce the risk of cancer. Although an intake of 400 g of folate per day may be achieved by eating natural foods, the average American intake from these sources is about 200 g per day. Since 1998, the food-fortification program in the United States has been adding about 100 g per day. Thus, most people in this country still consume less than 400 g per day, and users of multivitamins still have lower homocysteine levels than nonusers.

Vitamin B6

Vitamin B6 intake below the U.S. recommended daily allowance (RDA) of 2 mg is associated with an increased risk of coronary disease, but it is unclear whether this association is independent of folic acid intake.

Vitamin B12

Low blood levels of vitamin B12 (serum cobalamin level, <258 pmol per liter), caused primarily by reduced absorption in elderly persons with low gastric acidity, are also associated with higher blood homocysteine levels.Twelve percent of elderly persons may have inadequate vitamin B12 stores. The consequences of marginal vitamin B12 status remain unclear, but they may include increased risks of vascular disease and cancer.Crystalline vitamin B12, the form that is used in supplements, does not require gastric acid for absorption, so a multivitamin can ensure that intake is adequate for most people.

Vitamin D

Sun exposure alone can provide adequate vitamin D, but in the northern United States, ultraviolet radiation during the winter is insufficient to minimize the risk of osteoporosis and fractures.Among patients admitted to a Boston hospital, 57 percent were deficient in vitamin D.  Reasonable evidence suggests that many Americans would benefit from supplemental vitamin D to reach the RDA of 400 IU, and double this amount may be desirable for some persons. A vitamin D intake of up to 2000 IU per day is believed to be safe.

Vitamin A

Because vitamin A helps regulate cell differentiation, higher intakes could potentially reduce the risk of cancer. However, blood levels are tightly controlled, and greater intake in well-nourished persons has only a minimal effect on these levels. Both intake and blood levels of vitamin A have generally been shown to be unrelated to the risk of cancer.Supplemental beta carotene, a vitamin A precursor, has consistently failed to reduce the risk of cancer in randomized trials.

Multivitamin Preparations

The most common supplements are multivitamins that typically include the RDA of thiamin, riboflavin, niacin, folic acid, and vitamins A, C, B6, B12, D, K, and E. Few studies have evaluated the effects of multivitamins per se rather than specific components of them. In prospective studies, the daily use of a multivitamin has been associated with a lower risk of coronary disease,colon cancer,and breast cancer, particularly among regular consumers of alcohol.In a randomized trial involving elderly persons, a multivitamin–multimineral combination reduced the number of days of illness due to infections by half.A similar supplement reduced the incidence of stroke, primarily among men, in a nutritionally deficient population in China.These results must be replicated in other settings.

Vitamin E Supplements

Vitamin E supplements, most of which contain 200 to 800 IU, lead to intakes far greater than the RDA of 30 IU and well beyond those attainable by diet. High doses of vitamin E block the oxidative modification of low-density lipoprotein cholesterol and have additional effects that might reduce the risk of coronary disease.However, the value of vitamin E for the prevention of cardiovascular disease is controversial. In prospective, observational studies involving persons without known cardiovascular disease, the use of vitamin E supplements for two or more years — most commonly at a dose of 400 IU per day — has been associated with a 20 to 40 percent reduction in the risk of coronary disease.The long-term benefits of vitamin E supplementation for primary prevention remain unclear.

It has also been hypothesized that vitamin E supplements reduce the risk of cancer. No benefit has been found in terms of the risk of breast cancer, and data on the risk of colon cancer are mixed.The randomized Alpha-Tocopherol Beta Carotene Cancer Prevention Study found an unexpected, significant reduction in the incidence of prostate cancer but not in the incidence of other types of cancer. Because many cancer sites were examined, this may represent a chance finding. Sparse evidence suggests that vitamin E may slow the progression of Alzheimer's disease.

Vitamin C Supplements

Little evidence supports the existence of a benefit of vitamin C supplementation beyond the range of the typical diet in the United States or the current RDA of 90 mg for men and 75 mg for women (35 mg higher for smokers), and minimal effects might be expected from supplementation because tissues become saturated at about these levels of intake.Many studies have found an association between a low dietary intake of vitamin C and an increased risk of stomach cancer,but the effects of vitamin C supplements have not been specifically evaluated. Even long-term supplementation with vitamin C was not associated with a lower risk of breast cancer. Fewer data are available on associations with other types of cancer, but there is no compelling evidence of a benefit.

Few of the many possible associations between specific vitamins and specific diseases have been examined in randomized clinical trials. The evidence that folic acid reduces the risk of coronary disease and of colon cancer is strong, although not definitive. The Food and Nutrition Board of the Institute of Medicine notes that there has been no resolution of the question regarding the effect of antioxidant vitamins on the risk of chronic disease.

Conclusions and Recommendations

Given the greater likelihood of benefit than harm, and considering the low cost, we conclude that a daily multivitamin that does not exceed the RDA of its component vitamins makes sense for most adults. Substantial data suggest that higher intakes of folic acid, vitamin B6, vitamin B12, and vitamin D will benefit many people, and a multivitamin will ensure an adequate intake of other vitamins for which the evidence of benefit is indirect.A multivitamin is especially important for women who might become pregnant; for persons who regularly consume one or two alcoholic drinks per day; for the elderly, who tend to absorb vitamin B12 poorly and are often deficient in vitamin D; for vegans, who require supplemental vitamin B12; and for poor urban residents, who may be unable to afford adequate intakes of fruit and vegetables.

Many multivitamins also include essential minerals, although the doses of some of these minerals, such as calcium, are well below the RDA. Although we have not discussed minerals here, there is less evidence supporting the existence of a benefit for mineral supplements, with the exception of the additional iron required by some premenopausal women. A vitamin pill is no substitute for a healthful lifestyle or diet, because foods contain additional important components, such as fiber and essential fatty acids. In particular, a vitamin supplement cannot begin to compensate for the massive risks associated with smoking, obesity, or inactivity. We also believe that vitamin E supplements are reasonable for most middle-aged and older Americans who are at increased risk for coronary disease. Evidence is still accruing, but even assuming a low probability that vitamin E will eventually be proved efficacious (and we view the probability as fairly high), the likelihood of a benefit would still outweigh the very low probability of harm. We would offer a vitamin E supplement in a dose of 400 IU as an option. Finally, although we do not recommend additional vitamin supplements at present, the relevant evidence remains far from complete.
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