The Efficacy and Safety of Multivitamin and Mineral Supplement Use To Prevent Cancer and Chronic Disease in Adults.

Multivitamin and mineral supplements are the most commonly used dietary supplements in the United States. According to the National Health and Nutrition Examination Survey 1999–2000, 35% of adults reported recent use of multivitamin supplements. Most persons use multivitamin and mineral supplements to ensure adequate intake and to prevent or mitigate diseases. The commonly used over-the-counter multivitamin and mineral supplements contain at least 10 vitamins and 10 minerals.

Many chronic diseases share common risk factors, including cigarette smoking, unhealthy diet, sedentary lifestyle, and obesity. Important underlying mechanisms for these factors to increase risk for disease include oxidative damage, inflammation, and 1-carbon metabolism. Numerous in vitro studies and animal studies have suggested favorable effects of several vitamins and minerals on these processes and on angiogenesis, immunity, cell differentiation, proliferation, and apoptosis.

The U.S. Food and Nutrition Board has established tolerable upper intake levels for several nutrients. An upper intake level is defined as the highest level of daily nutrient intake that is likely to pose no risk for adverse effects to almost all persons in the general population. The strength of the evidence used to determine an upper intake level depends on data availability. Hence, an update of the data on adverse effects will help researchers to evaluate the appropriateness of upper intake levels.

Discussion

In the Linxian and SU.VI.MAX studies, the types of vitamin and mineral supplements overlapped and the doses were similar (1 to 2 times the U.S. Recommended Daily Allowance). The efficacy for cancer prevention differed somewhat but had similar implications. Whereas the multivitamin and mineral supplements used in the Linxian trial reduced the mortality rate from cancer by 21% in women and 7% in men, the efficacy of the supplement use in the SU.VI.MAX study in reducing cancer incidence was evident only in men. This sex-dependent efficacy may be attributed to the different nutritional status of the study samples: The Linxian sample had generally poor nutritional status, and men in the SU.VI.MAX study had suboptimal antioxidant status compared with women. Findings from these trials corroborated those of some observational studies that suggest benefits of fruits and vegetables on cancer prevention. However, these trials were not designed to test whether supplementation with multivitamins and minerals can replace a balanced, healthful diet in prevention of chronic disease.

The lack of benefits from supplementation in women in the SU.VI.MAX study might have been due to a threshold effect for those who had adequate dietary intake. However, women in the SU.VI.MAX study were on average 5 years younger than men, and the cardiovascular events in women were only 22.6% of the events in men. Hence, the study may have had insufficient statistical power to test for sex-specific efficacy. Furthermore, an important limitation of the SU.VI.MAX study (as well as several other studies in our review) was that participants often were permitted to use vitamin or mineral supplements other than the assigned study supplements, and data on self-selected supplement use were not reported. Most studies also did not provide information on such factors as medication use, which could have modified the effects of the nutrients. These limitations were rarely discussed in the literature. Because many nutrients share common mechanisms of action, self-selected supplement use may attenuate the net efficacy, if any, of the nutritional supplements under investigation. This conjecture is supported by the findings from the Women’s Health Study that 40% of the participants used multivitamin and mineral supplements in addition to the study supplements (vitamin E or placebo), and the relative risk for major cardiovascular disease in those receiving vitamin E compared with those receiving placebo was 0.88 in women who did not use multivitamin supplements and 1.02 among women who used supplements. Because multivitamin and mineral supplements are widely used by the general public in the United States, particularly among middle-aged or older persons, it would be difficult now to recruit persons representative of the general population into large-scale randomized, controlled trials of multivitamin and mineral supplementation.

For cataract prevention, AREDS was the largest study, and the findings were internally consistent in showing no benefit of use of multivitamin and mineral supplements. Whereas REACT found a deceleration in cataract progression in the U.S. study site, similar benefits were not seen in the United Kingdom study site. With respect to prevention of age-related macular degeneration, a high dose of vitamin E (400 IU) and zinc (2 times the upper intake level) was used in AREDS, and the benefit on preventing the progression to advanced age-related macular degeneration was limited to persons at high risk for advanced disease.

The implications of data on total mortality are uncertain. Total mortality is relevant to chronic disease prevention because it may provide a clue to potential harms. However, the risk for death should be considered on the basis of plausible biological mechanisms and the evidence on the effects of the nutrients on specific disorders. Because of the great heterogeneity across studies, we did not calculate an aggregate estimate for total mortality rate for the trials that reported such data. The 9% reduction in risk for total mortality by multivitamin and mineral supplements in the Linxian trial probably resulted from reductions in the rates of death from stomach cancer and stroke. Similarly, the reduced total mortality rate among men in the SU.VI.MAX study may have reflected the 31% reduction in the incidence of cancer.

During our review process, we identified 2 studies that addressed changes in cognitive performance by daily use of a mixture of vitamins and minerals for 6 months or daily use of combined folic acid (800 µg), vitamin B6 (3 mg), and vitamin B12 (500 µg) for 4 months. No improvement in cognition was found. These studies, however, were subject to several limitations, such as uncertain clinical significance, short-term supplementation, the lack of a gold standard test, and training and learning of the cognitive tests.

Marked heterogeneity is found in the literature on the questions addressed in this review, in terms of differences in study design (for example, factorial design), targeted study sample (differing cultural, lifestyle, and genetic backgrounds), chemical forms and doses of supplements, and specific outcome measures. This heterogeneity made it difficult to synthesize results across studies and inappropriate to perform quantitative synthesis (such as meta-analysis). The differences in study samples were particularly problematic because no study has examined the efficacy of multivitamin and mineral supplements in prevention of cancer or cardiovascular disease in the general U.S. population. It is therefore difficult to determine whether the results of studies in China and France can be applied to the United States.

We did not include observational studies on the associations between multivitamin/mineral supplement use and risk for chronic diseases. Extensive confounding variables that a linear combination of the variables in regression models may not fully take into account can seriously compromise the internal validity of observational studies. In addition, in previous observational studies, validated tools were not developed for collecting accurate information on the various compositions and doses of commercially available multivitamin and mineral supplements.

Furthermore, survey questionnaires used in observational studies often were not updated in a timely manner to capture the changes in compositions and doses within a product, and participants may have had errors and recall bias in reporting supplement use. Although previous observational studies did not show consistent evidence for or against a benefit of multivitamin and mineral supplements in prevention of cardiovascular disease, the inconsistency might have been primarily due to measurement errors and confounding variables. We therefore considered it important to focus primarily on the strongest source of evidence: randomized, controlled trials.

The potential adverse effects of multivitamin and mineral supplements have not been systematically determined in well-designed randomized, controlled trials. Because of uncertainties regarding design (for example, doses and outcome monitoring) and ethical constraints, such studies may never be performed. A few adverse effects of nutrients in multivitamin preparations may be interpreted as common responses in the general population because they occurred with certain consistency in different primary prevention trials. Examples include skin yellowing with sustained consumption of [beta]-carotene; increases in serum triglyceride levels with vitamin A supplementation; and minor bleeding, particularly epistaxis, with vitamin E supplementation. However, there was no consistent evidence to suggest that vitamin E supplementation results in more serious bleeding events, such as hemorrhagic stroke. With the caveat that available data are limited, a general conclusion is that consumption of multivitamin supplements for prolonged periods appears to be safe. In addition, some studies confirmed the adverse effects used to define the tolerable upper intake level, such gastrointestinal symptoms or diarrhea with vitamin C use. Although the tolerable upper intake level for this nutrient was set at 2 g/d, these symptoms could have occurred with a daily dose of 750 mg. A tolerable upper intake level represents a probability of a nutrient at a threshold level causing an adverse event in the general population, and the probability may vary with subgroups and different circumstances.

Case reports are subject to serious methodologic limitations. As a result, the overall strength of the evidence from case reports is weak. To date, data from case reports have been rarely used. In a previous systematic review of case reports of drug adverse effects, 83% of suspected adverse reactions were not further evaluated in confirmatory studies, and adverse effect alerts were not systematically incorporated into published drug reference information. In view of the rapidly increasing number of persons who choose to use dietary supplements, and given that many food products are fortified with several nutrients, the dietary intake of certain nutrients in the United States may well be greater than the Recommended Daily Allowances. Hence, it is important to study the level of intake among consumers. A systematic reporting and tracking system for adverse events would facilitate such studies.

It remains unproven that a balanced, healthful diet is superior to multivitamin and mineral supplement use. Because of feasibility and availability of resources, most randomized, controlled trials had approximately 5 years of follow-up, and some followed participants for only 2 to 3 years; however, chronic disease may take 10 to 20 years or longer to develop. It is unknown whether persons should take multivitamin and mineral supplements for a lifetime or during certain life stages to obtain benefits. To date, no published randomized, controlled trials have examined the efficacy of the commonly used over-the-counter multivitamin supplements, and the optimal compositions and doses of multivitamin and mineral supplements have not been systematically tested. Future research should be directed toward developing valid in vivo biomarkers that predict disease risk and measuring those biomarkers in randomized, controlled trials to guide the search for optimal composition and doses of multivitamin and mineral supplements. Additional research is also needed to examine how efficacy may vary by age, sex, duration of supplementation, adherence to intervention regimens, dietary patterns, and genetic polymorphisms. More attention should be given to nutrient–nutrient interactions and to controlling for co-interventions and use of medications and other dietary supplements.

In summary, data are scarce on the efficacy and safety of multivitamin and mineral supplement use in primary prevention of chronic disease in the general adult population. Evidence accumulated to date suggests potential benefits of multivitamin and mineral supplements in the primary prevention of cancer in persons with poor nutritional status or suboptimal antioxidant intake. However, the applicability of the findings to use of commercially available supplements by the general U.S. population is limited by differences in study sample and in the compositions and doses of the supplements. The evidence also indicates that multivitamin and mineral supplementation has no significant effect in the primary prevention of hypertension, cardiovascular disease, and cataracts but may slow progression of age-related macular degeneration among persons at high risk for advanced stages of the disease.

Our findings have important implications for clinical practice and public health policy. When people ask about the need for multivitamin and mineral supplements, clinical practitioners should be aware that although supplements are unlikely to have serious adverse effects, it remains unclear whether supplementation is efficacious in preventing cancer, cardiovascular disease, or other major chronic diseases and conditions in the general U.S. adult population.

Clinical practitioners may need to consider other factors, such as pregnancy, for which folic acid supplementation is beneficial in preventing birth defects, and other special nutritional needs when making recommendations about use of multivitamin and mineral supplements. For public health policymakers, our conclusion is that the strength of evidence is insufficient to support the presence or the absence of a benefit from routine use of multivitamin and mineral supplements by adults in the United States for primary prevention of cancer, cardiovascular disease, hypertension, cataracts, or age-related macular degeneration, and that there are no data from randomized, controlled trials on the efficacy of multivitamin and mineral supplement use for preventing type 2 diabetes mellitus, Parkinson disease, dementia, hearing loss, osteoporosis, osteopenia, rheumatoid arthritis, osteoarthritis, nonalcoholic steatohepatitis, chronic renal insufficiency, chronic nephrolithiasis, HIV infection, hepatitis C, tuberculosis, or chronic obstructive pulmonary disease.