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The Efficacy and Safety of Multivitamin and Mineral Supplement Use To Prevent Cancer and Chronic Disease in Adults: A Systematic Review for a National Institutes of Health State-of-the-Science Conference FREE

Han-Yao Huang, PhD, MPH; Benjamin Caballero, MD, PhD; Stephanie Chang, MD; Anthony J. Alberg, PhD, MPH; Richard D. Semba, MD, MPH; Christine R. Schneyer, MD; Renee F. Wilson, MSc; Ting-Yuan Cheng, MSc; Jason Vassy, MPH; Gregory Prokopowicz, MD, MPH; George J. Barnes II, BA; and Eric B. Bass, MD, MPH
[+] Article and Author Information

From the Bloomberg School of Public Health and the School of Medicine, Johns Hopkins University, Baltimore, Maryland.


Disclaimer: The authors are responsible for the content of this article, including any clinical or treatment information. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or of the U.S. Department of Health and Human Services.

Acknowledgments: The authors thank Steven Bressler for assistance with the literature searching and database management; Gabriel Lai, Karran Phillips, Konstantinos K. Tsilidis, and Amina Chaudhry for assistance with article reviewing and data entry; and Brenda Zacharko for her editorial assistance.

Grant Support: The study was requested and funded by the National Institutes of Health and conducted by the Johns Hopkins Evidence-based Practice Center, under contract no. 290-02-0018 to the Agency for Healthcare Research and Quality.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Han-Yao Huang, PhD, MPH, Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, E-6144, Baltimore, MD 21205-2223; e-mail, hyhuang@jhsph.edu.

Current Author Addresses: Dr. Huang: Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, E-6144, Baltimore, MD 21205-2223.

Dr. Caballero: Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, E2041, Baltimore, MD 21205.

Dr. Chang: Department of Medicine, Johns Hopkins School of Medicine, 1830 Building, Room 8040, 600 North Wolfe Street, Baltimore, MD 21287-1824.

Dr. Alberg: Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, P.O. Box 250955, Charleston, SC 29425.

Dr. Semba: Department of Ophthalmology, Johns Hopkins School of Medicine, 550 North Broadway, Suite 700, Baltimore, MD 21205.

Dr. Schneyer: Division of Endocrinology, Johns Hopkins University School of Medicine, 1830 Building, Room 333, 600 North Wolfe Street, Baltimore, MD 21287.

Ms. Wilson: Evidence-based Practice Center, Bloomberg School of Public Health, Johns Hopkins University, 1830 East Monument Street, Room 8061, Baltimore, MD 21287.

Mr. Cheng: Department of Epidemiology, P.O. Box 1032, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205.

Mr. Vassy: Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205.

Dr. Prokopowicz: Department of Medicine, Johns Hopkins School of Medicine, 601 North Caroline Street, JHOC 7157, Baltimore, MD 21287.

Mr. Barnes: Evidence-based Practice Center, Bloomberg School of Public Health, Johns Hopkins University, 1830 East Monument Street, Room 8063, Baltimore, MD 21287.

Dr. Bass: Evidence-based Practice Center, Bloomberg School of Public Health, Johns Hopkins University, 1830 East Monument Street, Room 8068, Baltimore, MD 21287.


Ann Intern Med. 2006;145(5):372-385. doi:10.7326/0003-4819-145-5-200609050-00135
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Multivitamin and mineral supplements are the most commonly used dietary supplements in the United States (1). According to the National Health and Nutrition Examination Survey 1999–2000, 35% of adults reported recent use of multivitamin supplements (1). 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 (27). 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 (810).

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 (11). 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.

We performed a systematic review to synthesize the published literature on 1) the efficacy of multivitamin and mineral supplements and certain commonly used single vitamin or mineral supplements in the primary prevention of cancer and chronic disease in the general adult population and 2) the safety of multivitamin and mineral supplements and certain commonly used single vitamin or mineral supplements in the general population of adults and children (12). The review was done for a National Institutes of Health State-of-the-Science Statement for health care providers and the general public. This report is from the systematic review and focuses on 2 questions: What is the efficacy determined in randomized, controlled trials of multivitamin and mineral supplements (each at a dose less than the upper intake level) in the general adult population for the primary prevention of cancer and chronic diseases or conditions, and what is known about the safety of multivitamin and mineral supplement use in the general population of adults and children, on the basis of data from randomized, controlled trials and observational studies?

We defined “multivitamin and mineral supplements” as any supplements that contain 3 or more vitamins or minerals without herbs, hormones, or drugs. We defined the general population as community-dwelling persons who do not have special nutritional needs. (Examples of persons with special nutritional needs are those who are institutionalized, hospitalized, pregnant, or clinically deficient in nutrients.) A disease or condition was defined as chronic if it persists over an extended period, is not easily resolved, often cannot be cured by medication (although symptoms may be controlled or ameliorated with medication), frequently worsens over time, causes disability or impairment, and often requires ongoing medical care (13). The following chronic diseases were considered: breast cancer, colorectal cancer, lung cancer, prostate cancer, gastric cancer, or any other cancer (including colorectal polyps); myocardial infarction, stroke, hypertension, or other cardiovascular diseases; type 2 diabetes mellitus; Parkinson disease, cognitive decline, memory loss, or dementia; cataracts, macular degeneration, or hearing loss; osteoporosis, osteopenia, rheumatoid arthritis, or osteoarthritis; nonalcoholic steatohepatitis; chronic renal insufficiency or chronic nephrolithiasis; HIV infection, hepatitis C, or tuberculosis; and chronic obstructive pulmonary disease.

We focused on primary prevention trials in adults because primary prevention is the main purpose of multivitamin supplement use in the general adult population (14). Primary prevention was defined as an action taken to prevent the development of a disease in persons who are well and do not have the disease in question (15). Using this definition, we included studies for prevention of chronic disease (for example, cardiovascular disease) in persons with risk factors (for example, type 2 diabetes mellitus or hypertension) for that disease. We also included studies for prevention of malignant disorders (such as colon cancer) in persons with selected precursors of disease (such as polyps). We did not include studies in persons with carcinoma in situ or similar malignant conditions.

Literature Sources

We searched the MEDLINE, EMBASE, and Cochrane databases, including Cochrane Reviews and the Cochrane Central Register of Controlled Trials, for articles published from 1966 through February 2006. Additional articles were identified by searching references in pertinent articles, querying experts, and hand-searching the tables of content of 15 relevant journals published from January 2005 through February 2006.

Search Terms and Strategies

We developed a core strategy for searching MEDLINE, accessed through PubMed, that was based on analysis of the Medical Subject Heading terms and text words of key articles identified a priori. This strategy formed the basis for the strategies developed for the other databases (see the complete evidence report for additional details) (12).

Inclusion and Exclusion Criteria

We focused on trials that ascertained clinical end points. Biomarker data were considered if data were presented in a way that permitted ascertainment of incident cases of chronic disease. Because users of multivitamin supplements were more likely than nonusers to be women, to be older, to have higher levels of education, to have a healthier lifestyle (more physical activities, more fruit and vegetable intake, and less likely to be smokers), and to more frequently use nonsteroidal anti-inflammatory drugs (1, 16), residual confounding would limit the internal validity of observational studies. Hence, for assessment of efficacy, we focused on data from randomized, controlled trials as the strongest source of evidence. However, for assessment of safety, we included data from randomized, controlled trials and observational studies in adults and children to minimize the risk for missing any potential safety concerns.

An article was excluded if it was not written in English; presented no data in humans; included only pregnant women, infants, persons 18 years of age or younger (except if a study of persons ≤ 18 years of age presented data on the safety of multivitamin and mineral supplements), patients with chronic disease, patients receiving treatment for chronic disease, or persons living in long-term care facilities; studied only nutritional deficiency; did not address the use of supplements; did not address the use of supplements separately from dietary intake; did not cover any pertinent diseases; or was an editorial, commentary, or letter. Each article underwent title review, abstract review, and assessment of inclusion or exclusion by paired reviewers. Differences in opinion were resolved through consensus adjudication. Article review, organization, and tracking were performed by using Web-based SRS, version 3.0 (TrialStat! Corp., Ottawa, Ontario, Canada).

Assessment of Study Quality

Each eligible article was reviewed by paired reviewers who independently rated its quality according to 5 domains: the description of how study participants were representative of the source population (4 items), bias and confounding (12 items), descriptions of study supplements and supplementation (1 item), adherence to treatment and follow-up (7 items), and statistical analysis (6 items). Reviewers assigned a score of 0 (criterion not met), 1 (criterion partially met), or 2 (criterion fully met) to each item. The score for each quality domain was the proportion of the maximum score available in each domain. The overall quality score of a study was the average of the 5 scores for the 5 domains. The quality of each study in each domain was classified as good (score ≥ 80%), fair (score of 50% to 79%), or poor (score < 50%).

For data on adverse effects, causality was evaluated with respect to temporal relationship, lack of alternative causes, dose–response relationship, evidence of increased circulating levels of the nutrient under investigation, disappearance of adverse effects after cessation of supplement use, and response to rechallenge.

Data Extraction

Paired reviewers abstracted data on study design, participant characteristics, study supplements, and results. Data abstraction forms were completed by a primary reviewer and were verified for completeness and accuracy by a second reviewer.

Evidence Grading

We graded the quantity, quality, and consistency of the evidence on efficacy by adapting an evidence grading scheme recommended by the Grading of Recommendations Assessment, Development and Evaluation Working Group (17). The strength of evidence was classified into 1 of 4 categories: high (further research is very unlikely to change our confidence in the estimates of effects), moderate (further research is likely to greatly affect our confidence in the estimates of effects and may change the estimates), low (further research is very likely to greatly affect confidence in the estimates of effects and is likely to change the estimates), or very low (any estimate of effect is very uncertain).

Role of the Funding Source

This article is based on research conducted at the Johns Hopkins Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (contract no. 290-02-0018), Rockville, Maryland, in response to a task order requested by the National Institutes of Health Office of Medical Applications of Research. We are responsible for the content of this article, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or of the U.S. Department of Health and Human Services.

After title review, we identified 3710 potentially eligible articles through abstract review. After full text review, 64 articles met the inclusion and exclusion criteria. Of these, 7 articles from randomized, controlled trials contained only efficacy data, 5 articles from randomized, controlled trials contained both efficacy and safety data, and 3 articles from case reports contained only safety data. The remaining articles on the efficacy and safety of single-nutrient supplements are not included in this report.

Efficacy

Our search identified 12 articles that addressed the efficacy of multivitamin and mineral supplements in the primary prevention of cancer, cardiovascular disease, hypertension, cataracts, or age-related macular degeneration. Data for other chronic diseases and conditions were lacking. Designed vitamin and mineral combinations, but not the one-a-day type of multivitamin supplements available on the U.S. market, were used in these studies.

The 12 articles presented results from 5 randomized, controlled trials published from 1993 to 2005: the Linxian General Population Trial in China (1822); the SUpplémentation en VItamines et Minéraux AntioXydants (SU.VI.MAX) study in France (2325); the Multicenter Ophthalmic and Nutritional Age-Related Macular Degeneration Study (MONMD) in the United States (26); the Roche European American Cataract Trial (REACT) in the United States and United Kingdom (27); and the Age-Related Eye Disease Study (AREDS) in the United States (2829). A total of 47 289 persons were included in these trials. Table 1 shows trial design, study supplements, participant characteristics, loss to follow-up, and self-selected supplement use.

Table Jump PlaceholderTable 1.  Characteristics of Randomized, Controlled Trials on the Efficacy of Multivitamin and Mineral Supplement Use in Primary Prevention of Chronic Disease*
Study Quality

Inclusion and exclusion criteria were clearly defined in most trials. The study quality was good in terms of randomization, double masking, ascertainment of trial end points, adherence, and use of an intention-to-treat Continued on page 377 approach in statistical analyses. However, the articles generally lacked descriptions of whether the allocation sequence was concealed and whether observers independently evaluated outcomes. The articles also gave little information about previous and concomitant use of supplements and medications that could have modified the efficacy of the study supplements. No article reported on the success of blinding and the extent of unintended crossover. Overall, study quality was fair for the studies of cancer, cardiovascular disease, cataracts, and age-related macular degeneration and poor for the studies on hypertension (Table 2).

Table Jump PlaceholderTable 2.  Quality of Randomized, Controlled Trials on the Efficacy of Multivitamin and Mineral Supplements in Primary Prevention of Chronic Disease*
Cancer

The Linxian trial examined the incidence of and mortality from all cancer, esophageal cancer, stomach (cardia and noncardia) cancer, esophageal and gastric cardia cancer, and other cancer (18). After 5.25 years of follow-up, supplementation had no significant effect on these end points (Appendix Table 1). The only exceptions were reductions in the incidence of gastric cancer (relative risk, 0.84 [95% CI, 0.71–1.00]), mortality rate from cancer (relative risk, 0.87 [95% CI, 0.75–1.00]), and mortality rate from stomach cancer (relative risk, 0.79 [95% CI, 0.64–0.99]) in the groups receiving β-carotene, α-tocopherol, and selenium, with or without other nutrients, compared with the groups receiving vitamin and mineral combinations with no β-carotene, α-tocopherol, and selenium (Figure 1) (18), and a lower mortality rate from noncardia stomach cancer in those receiving retinol and zinc (relative risk, 0.59 [95% CI, 0.37–0.93]) (18). The reduction in the mortality rate from cancer was greater in women than in men (relative risk, 0.79 [95% CI, 0.64–0.98] and 0.93 [95% CI, 0.77–1.12], respectively) and in persons younger than 55 years of age than in those 55 years of age or older (relative risk, 0.71 [95% CI, 0.55–0.92] and 0.94 [95% CI, 0.80–1.11], respectively) (19). In the substudy in which participants underwent endoscopic examination at the end of the trial, supplementation with β-carotene, α-tocopherol, and selenium had no significant effect on dysplasia or early cancer of the esophagus or stomach, although the odds ratios were generally in the protective direction (20) (Appendix Table 1).

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Figure 1.
Relative risk for cancer with use of multivitamin and mineral supplements.

The lines represent 95% CIs, the midpoints of the lines represent the relative risk estimates, and the size of the boxes represents the relative size of the study sample. SU.VI.MAX = SUpplémentation en VItamines et Minéraux AntioXydants. *Vitamin E + selenium + β-carotene + zinc + vitamin C. † Vitamin E + selenium + β-carotene.

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The SU.VI.MAX study reported no benefit of use of antioxidant supplements for cancer prevention in women (relative risk, 1.04 [95% CI, 0.85–1.29]) but a reduction in the risk for cancer in men (relative risk, 0.69 [95% CI, 0.53–0.91]) (Appendix Table 1, Figure 1) (23). In this study, women were younger than men and generally had a healthier lifestyle, as suggested by higher serum levels of β-carotene and vitamin C and fewer smokers (23). A reduction in the risk for prostate cancer by use of antioxidant supplements was observed in men with a normal baseline level of prostate-specific antigen (≤3 µg/L) (hazard ratio, 0.52 [95% CI, 0.29–0.92]) but not in those with elevated levels (24).

Cardiovascular Disease

The Linxian trial reported a lower risk for death from stroke in persons receiving β-carotene, selenium, α-tocopherol, retinol, and zinc (relative risk, 0.71 [95% CI, 0.50–1.00]) but did not find significant effects of other nutrient combinations (21) (Appendix Table 2). Hemorrhagic and ischemic stroke were not distinguished, but other data sources showed that approximately two thirds of the strokes were ischemic in this sample (30). In the SU.VI.MAX study, no significant difference in the incidence of ischemic cardiovascular disease was noted between randomized groups in men and women (23) (Appendix Table 2).

Hypertension

At the end of the Linxian trial, participants receiving β-carotene, selenium, and α-tocopherol had a higher prevalence of isolated diastolic hypertension (relative risk, 1.23 [95% CI, 1.06–1.43]) but not isolated systolic hypertension or both types of hypertension (21) (Appendix Table 2). The prevalence of isolated diastolic hypertension was lower in participants receiving riboflavin, niacin, vitamin C, and molybdenum than in participants who received placebo (relative risk, 0.68 [95% CI, 0.50–0.94]), but the prevalence of hypertension in other randomized groups did not differ from that in the placebo group (21). In the SU.VI.MAX trial, the risk for hypertension did not differ between the antioxidant group and the placebo group (25) (Appendix Table 2).

Total Mortality Rate

Overall, data on total mortality pointed to either no increased risk or lower risk in the groups that used multivitamin and mineral supplements (Figure 2). In the Linxian trial, the total mortality rate was lower among persons who received β-carotene, selenium, and α-tocopherol (relative risk, 0.91 [95% CI, 0.84–0.99]) but not other nutrient combinations (18, 21). In AREDS, a statistically nonsignificant increase in total mortality rate was seen among participants receiving antioxidants compared with those not receiving antioxidants (relative risk, 1.06 [99% CI, 0.84–1.33]) (28). However, when analysis was limited to participants with age-related macular degeneration categories 2, 3, and 4, the total mortality rate was lower in the groups receiving zinc combined with antioxidants (relative risk, 0.87 [99% CI, 0.60–1.25]) (29). The SU.VI.MAX study showed a lower total mortality rate among men receiving antioxidants and zinc compared with men receiving placebo (relative risk, 0.63 [95% CI, 0.42–0.93]), but no risk reduction in women (relative risk, 1.03 [95% CI, 0.64–1.63]), whereas the Linxian trial reported no differences by sex or age (19). In REACT, 9 deaths occurred in the antioxidant group (among 81 participants) and 3 deaths occurred in the placebo group (among 77 participants) (27). The causes of death in the antioxidant group were esophagitis, sudden death, aneurysm, pulmonary fibrosis, cancer, and coronary thrombosis, whereas the causes of death in the placebo group were cancer and coronary thrombosis (27).

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Figure 2.
Relative risk for all-cause mortality with use of multivitamin and mineral supplements.

The lines represent 95% CIs, the midpoints of the lines represent the relative risk estimates, and the size of the boxes represents the relative size of the study sample. AREDS = Age-Related Eye Disease Study; SU.VI.MAX = SUpplémentation en VItamines et Minéraux AntioXydants. *Vitamin E + selenium + β-carotene + zinc + vitamin C. † Vitamin E + selenium + β-carotene. ‡ Vitamin E + vitamin C + β-carotene.

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Cataracts and Age-Related Macular Degeneration

In the Linxian trial, supplementation with combined α-tocopherol, selenium, and β-carotene had no effect on nuclear cataract, cortical cataract, or posterior subcapsular cataract (22) (Appendix Table 3). In the MONMD study, distance visual acuity decreased in the placebo group but was unchanged in the multivitamin group (P = 0.03). The multivitamin group also had slightly better M-print visual acuity and fewer scotoma in left eyes (P = 0.07) after 12 months of supplementation but did not differ from the placebo group in several other cataract measurements (26) (Appendix Table 3).

In REACT, the primary measure for estimating the effect on cataract formation was the change from baseline in the percentage pixel opaque in the anteriorly focused retroillumination image. At the end of the second year, there was a small positive effect on the percentage pixel opaque in both the U.S. and United Kingdom groups. After the third year, the positive effects were greater in the U.S. group but not the United Kingdom group. Unfavorable changes in secondary outcomes (posterior subcapsular cataract, nuclear cataract, cortical cataract, and nuclear color) were smaller in the active supplement group, but none differed significantly from the placebo group (27) (Appendix Table 3).

In AREDS, no appreciable effects of antioxidant supplementation were found on development or progression of cataract or visual acuity loss after 6 years of follow-up (28) (Appendix Table 3). The odds ratio for developing advanced macular degeneration was 0.75 (95% CI, 0.55–1.03) in participants who received zinc alone, 0.80 (95% CI, 0.59–1.09) in those who received antioxidants alone, and 0.72 (95% CI, 0.52–0.98) in those who received combined zinc and antioxidants, compared with placebo (29). When participants with extensive small drusen, nonextensive intermediate-sized drusen, or pigment abnormalities were excluded, the odds ratio for progression to advanced age-related macular degeneration was 0.76 (95% CI, 0.55–1.05) in those who received antioxidants alone and 0.66 (95% CI, 0.47–0.91) in those who received combined zinc and antioxidants (29). The odds ratio of having at least moderate visual acuity loss was 0.73 (95% CI, 0.54–0.99) among participants who received antioxidants plus zinc, but this finding was not statistically significant for other groups (29) (Appendix Table 3).

Strength of Evidence

Taking into consideration the quantity, quality, and consistency of evidence, we concluded that the strength of evidence on the efficacy of multivitamin/mineral supplementation in the general adult U.S. population was very low for primary prevention of cancer, cardiovascular disease, and hypertension and low for cataract and age-related macular degeneration (Table 3).

Table Jump PlaceholderTable 3.  Grade of the Evidence on the Efficacy of Multivitamin and Mineral Supplements in Primary Prevention of Chronic Disease*
Safety

Eight articles reported on the adverse effects of multivitamin and mineral supplements from 4 randomized, controlled trials and 3 case reports (2629, 3134) (Appendix Table 4). The randomized, controlled trials met only 2 of the 6 causality criteria: temporal relationship and evidence of supplement use. Overall, no consistent pattern of increased adverse events was evident. In the MONMD study, “a few cases of diarrhea” were reported that the authors attributed to use of ascorbic acid (750 mg/d) (26). In REACT, the frequency of reported side effects did not differ between the antioxidants and placebo groups (27). In AREDS, skin yellowing was more frequently reported by the antioxidant group than the placebo group (8.3% compared with 6.1% [P = 0.001] in the cataract study and 8.3% compared with 6.0% [P = 0.008] in the age-related macular degeneration study) (2829). In a feasibility trial in China, participants received combinations of retinol, 25 000 IU; β-carotene, 50 mg; α-tocopherol, 800 IU; and selenium, 400 μg. Such symptoms as broken nails and skin yellowing were reported to be generally improved in the groups receiving multivitamin and mineral supplements (31).

One case report documented the occurrences of rash with an excessive dose of niacin (240 mg, of which 40 mg was from multivitamin supplements) (32). This report showed a dose–response relationship, recurrence after rechallenge, and symptom disappearance after discontinuation of challenge; provided evidence on supplement use; and discussed a lack of alternative cause (32). The other 2 reports did not address any of the causality criteria (3334) (Appendix Table 4).

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 (18, 20, 2324). 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 (23). Findings from these trials corroborated those of some observational studies that suggest benefits of fruits and vegetables on cancer prevention (35). 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 (23). 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 (95% CI, 0.75–1.03) in women who did not use multivitamin supplements and 1.02 (95% CI, 0.84–1.25) among women who used supplements (36). 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 (28). 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 (29).

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 (18, 21). 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 (23).

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 (3738). 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 (39), 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 β-carotene (4041); increases in serum triglyceride levels with vitamin A supplementation (42); 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 (36, 43). 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 (26). 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 (44). 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.

Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF.  Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999-2000. Am J Epidemiol. 2004; 160:339-49. PubMed
CrossRef
 
Breimer LH.  Molecular mechanisms of oxygen radical carcinogenesis and mutagenesis: the role of DNA base damage. Mol Carcinog. 1990; 3:188-97. PubMed
 
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL.  Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989; 320:915-24. PubMed
 
Selhub J, Bagley LC, Miller J, Rosenberg IH.  B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000; 71:614S-620S. PubMed
 
Ames BN, Shigenaga MK.  Oxidants are a major contributor to aging. Ann N Y Acad Sci. 1992; 663:85-96. PubMed
 
Granger DN, Vowinkel T, Petnehazy T.  Modulation of the inflammatory response in cardiovascular disease. Hypertension. 2004; 43:924-31. PubMed
 
Duthie SJ, Narayanan S, Brand GM, Pirie L, Grant G.  Impact of folate deficiency on DNA stability. J Nutr. 2002; 132:2444S-2449S. PubMed
 
Diaz MN, Frei B, Vita JA, Keaney JF Jr.  Antioxidants and atherosclerotic heart disease. N Engl J Med. 1997; 337:408-16. PubMed
 
Reddy BS.  Micronutrients as chemopreventive agents. IARC Sci Publ; 1996; 221-35. PubMed
 
Kelloff GJ, Boone CW, Steele VE, Fay JR, Lubet RA, Crowell JA. et al.  Mechanistic considerations in chemopreventive drug development. J Cell Biochem Suppl. 1994; 20:1-24. PubMed
 
Institute of Medicine of the National Academies.  Dietary reference intakes: vitamins. Available athttp://www.iom.edu/Object.File/Master/7/296/webtablevitamins.pdfAccessed 31 May 2006.
 
Huang HY, Caballero B, Chang S, Alberg AJ, Semba RD, Schneyer CR, et al.  Multivitamin/Mineral Supplements and Prevention of Chronic Disease. Evidence Report/Technology Assessment No. 139. Prepared by the Johns Hopkins University Evidence-based Practice Center under contract no. 290-02-0018. AHRQ publication no. 06-E012. Rockville, MD: Agency for Healthcare Research and Quality; 2006. Available athttp://www.ahrq.gov/clinic/evrptpdfs.htm#multivitAccessed 31 May 2006.
 
National Center for Chronic Disease Prevention and Health Promotion.  Grantmakers in Health. Addressing Chronic Disease at Its Roots. Issue Brief No. 19. Available athttp://www.gih.org/usr_doc/Healthy_Behaviors_Issue_Brief.pdfAccessed 31 May 2006.
 
Sloan E.  How and why do we use supplements? A National Institutes of Health State-of-the Science Conference on Multivitamin/Mineral Supplements and Chronic Disease Prevention. Bethesda, MD: U.S. Department of Health and Human Services; 2006; 25-8.
 
Gordis L.  Epidemiology. 2nd ed. Philadelphia: Saunders; 2000.
 
White E, Patterson RE, Kristal AR, Thornquist M, King I, Shattuck AL. et al.  VITamins And Lifestyle cohort study: study design and characteristics of supplement users. Am J Epidemiol. 2004; 159:83-93. PubMed
 
Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S. et al.  Grading quality of evidence and strength of recommendations. BMJ. 2004; 328:1490. PubMed
 
Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ. et al.  Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst. 1993; 85:1483-92. PubMed
 
Blot WJ, Li JY, Taylor PR, Guo W, Dawsey SM, Li B.  The Linxian trials: mortality rates by vitamin-mineral intervention group. Am J Clin Nutr. 1995; 62:1424S-1426S. PubMed
 
Wang GQ, Dawsey SM, Li JY, Taylor PR, Li B, Blot WJ. et al.  Effects of vitamin/mineral supplementation on the prevalence of histological dysplasia and early cancer of the esophagus and stomach: results from the General Population Trial in Linxian, China. Cancer Epidemiol Biomarkers Prev. 1994; 3:161-6. PubMed
 
Mark SD, Wang W, Fraumeni JF Jr, Li JY, Taylor PR, Wang GQ. et al.  Do nutritional supplements lower the risk of stroke or hypertension? Epidemiology. 1998; 9:9-15. PubMed
 
Sperduto RD, Hu TS, Milton RC, Zhao JL, Everett DF, Cheng QF. et al.  The Linxian cataract studies. Two nutrition intervention trials. Arch Ophthalmol. 1993; 111:1246-53. PubMed
 
Hercberg S, Galan P, Preziosi P, Bertrais S, Mennen L, Malvy D. et al.  The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med. 2004; 164:2335-42. PubMed
 
Meyer F, Galan P, Douville P, Bairati I, Kegle P, Bertrais S. et al.  Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trial. Int J Cancer. 2005; 116:182-6. PubMed
 
Czernichow S, Bertrais S, Blacher J, Galan P, Briançon S, Favier A. et al.  Effect of supplementation with antioxidants upon long-term risk of hypertension in the SU.VI.MAX study: association with plasma antioxidant levels. J Hypertens. 2005; 23:2013-8. PubMed
 
Richer S.  Multicenter ophthalmic and nutritional age-related macular degeneration study—part 2: antioxidant intervention and conclusions. J Am Optom Assoc. 1996; 67:30-49. PubMed
 
Chylack LT Jr, Brown NP, Bron A, Hurst M, Kopcke W, Thien U. et al.  The Roche European American Cataract Trial (REACT): a randomized clinical trial to investigate the efficacy of an oral antioxidant micronutrient mixture to slow progression of age-related cataract. Ophthalmic Epidemiol. 2002; 9:49-80. PubMed
 
 A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001; 119:1439-52. PubMed
 
 A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001; 119:1417-36. PubMed
 
Shi FL, Hart RG, Sherman DG, Tegeler CH.  Stroke in the People's Republic of China. Stroke. 1989; 20:1581-5. PubMed
 
Xuan XZ, Schatzkin A, Mao BL, Taylor PR, Li JY, Tangrea J. et al.  Feasibility of conducting a lung-cancer chemoprevention trial among tin miners in Yunnan, P.R. China. Cancer Causes Control. 1991; 2:175-82. PubMed
 
Grouhi M, Sussman G.  Pseudoallergic toxic reaction. Ann Allergy Asthma Immunol. 2000; 85:269-71. PubMed
 
Gulati R, Bhargava P, Mathur NK.  Fixed drug eruption due to multi-vitamin multi-mineral preparation as part of familial polysensitivity. J Assoc Physicians India. 1999; 47:253. PubMed
 
Ohtake T, Kobayashi S, Negishi K, Moriya H.  Supplement nephropathy due to long-term, high-dose ingestion of ascorbic acid, calcium lactate, vitamin D and laxatives. Clin Nephrol. 2005; 64:236-40. PubMed
 
Key TJ, Schatzkin A, Willett WC, Allen NE, Spencer EA, Travis RC.  Diet, nutrition and the prevention of cancer. Public Health Nutr. 2004; 7:187-200. PubMed
 
Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE. et al.  Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA. 2005; 294:56-65. PubMed
 
Lewerin C, Matousek M, Steen G, Johansson B, Steen B, Nilsson-Ehle H.  Significant correlations of plasma homocysteine and serum methylmalonic acid with movement and cognitive performance in elderly subjects but no improvement from short-term vitamin therapy: a placebo-controlled randomized study. Am J Clin Nutr. 2005; 81:1155-62. PubMed
 
Wolters M, Hickstein M, Flintermann A, Tewes U, Hahn A.  Cognitive performance in relation to vitamin status in healthy elderly German women—the effect of 6-month multivitamin supplementation. Prev Med. 2005; 41:253-9. PubMed
 
Morris CD, Carson S.  Routine vitamin supplementation to prevent cardiovascular disease: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2003; 139:56-70. PubMed
 
Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR. et al.  Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996; 334:1145-9. PubMed
 
Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH.  Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study. J Natl Cancer Inst. 1999; 91:2102-6. PubMed
 
Omenn GS, Goodman GE, Thornquist M, Brunzell JD.  Long-term vitamin A does not produce clinically significant hypertriglyceridemia: results from CARET, the beta-carotene and retinol efficacy trial. Cancer Epidemiol Biomarkers Prev. 1994; 3:711-3. PubMed
 
Leppälä JM, Virtamo J, Fogelholm R, Huttunen JK, Albanes D, Taylor PR. et al.  Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers. Arterioscler Thromb Vasc Biol. 2000; 20:230-5. PubMed
 
Loke YK, Price D, Derry S, Aronson JK.  Case reports of suspected adverse drug reactions—systematic literature survey of follow-up. BMJ. 2006; 332:335-9. PubMed
 

Figures

Grahic Jump Location
Figure 1.
Relative risk for cancer with use of multivitamin and mineral supplements.

The lines represent 95% CIs, the midpoints of the lines represent the relative risk estimates, and the size of the boxes represents the relative size of the study sample. SU.VI.MAX = SUpplémentation en VItamines et Minéraux AntioXydants. *Vitamin E + selenium + β-carotene + zinc + vitamin C. † Vitamin E + selenium + β-carotene.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Relative risk for all-cause mortality with use of multivitamin and mineral supplements.

The lines represent 95% CIs, the midpoints of the lines represent the relative risk estimates, and the size of the boxes represents the relative size of the study sample. AREDS = Age-Related Eye Disease Study; SU.VI.MAX = SUpplémentation en VItamines et Minéraux AntioXydants. *Vitamin E + selenium + β-carotene + zinc + vitamin C. † Vitamin E + selenium + β-carotene. ‡ Vitamin E + vitamin C + β-carotene.

Grahic Jump Location

Tables

Table Jump PlaceholderTable 1.  Characteristics of Randomized, Controlled Trials on the Efficacy of Multivitamin and Mineral Supplement Use in Primary Prevention of Chronic Disease*
Table Jump PlaceholderTable 2.  Quality of Randomized, Controlled Trials on the Efficacy of Multivitamin and Mineral Supplements in Primary Prevention of Chronic Disease*
Table Jump PlaceholderTable 3.  Grade of the Evidence on the Efficacy of Multivitamin and Mineral Supplements in Primary Prevention of Chronic Disease*

References

Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF.  Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999-2000. Am J Epidemiol. 2004; 160:339-49. PubMed
CrossRef
 
Breimer LH.  Molecular mechanisms of oxygen radical carcinogenesis and mutagenesis: the role of DNA base damage. Mol Carcinog. 1990; 3:188-97. PubMed
 
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL.  Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989; 320:915-24. PubMed
 
Selhub J, Bagley LC, Miller J, Rosenberg IH.  B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000; 71:614S-620S. PubMed
 
Ames BN, Shigenaga MK.  Oxidants are a major contributor to aging. Ann N Y Acad Sci. 1992; 663:85-96. PubMed
 
Granger DN, Vowinkel T, Petnehazy T.  Modulation of the inflammatory response in cardiovascular disease. Hypertension. 2004; 43:924-31. PubMed
 
Duthie SJ, Narayanan S, Brand GM, Pirie L, Grant G.  Impact of folate deficiency on DNA stability. J Nutr. 2002; 132:2444S-2449S. PubMed
 
Diaz MN, Frei B, Vita JA, Keaney JF Jr.  Antioxidants and atherosclerotic heart disease. N Engl J Med. 1997; 337:408-16. PubMed
 
Reddy BS.  Micronutrients as chemopreventive agents. IARC Sci Publ; 1996; 221-35. PubMed
 
Kelloff GJ, Boone CW, Steele VE, Fay JR, Lubet RA, Crowell JA. et al.  Mechanistic considerations in chemopreventive drug development. J Cell Biochem Suppl. 1994; 20:1-24. PubMed
 
Institute of Medicine of the National Academies.  Dietary reference intakes: vitamins. Available athttp://www.iom.edu/Object.File/Master/7/296/webtablevitamins.pdfAccessed 31 May 2006.
 
Huang HY, Caballero B, Chang S, Alberg AJ, Semba RD, Schneyer CR, et al.  Multivitamin/Mineral Supplements and Prevention of Chronic Disease. Evidence Report/Technology Assessment No. 139. Prepared by the Johns Hopkins University Evidence-based Practice Center under contract no. 290-02-0018. AHRQ publication no. 06-E012. Rockville, MD: Agency for Healthcare Research and Quality; 2006. Available athttp://www.ahrq.gov/clinic/evrptpdfs.htm#multivitAccessed 31 May 2006.
 
National Center for Chronic Disease Prevention and Health Promotion.  Grantmakers in Health. Addressing Chronic Disease at Its Roots. Issue Brief No. 19. Available athttp://www.gih.org/usr_doc/Healthy_Behaviors_Issue_Brief.pdfAccessed 31 May 2006.
 
Sloan E.  How and why do we use supplements? A National Institutes of Health State-of-the Science Conference on Multivitamin/Mineral Supplements and Chronic Disease Prevention. Bethesda, MD: U.S. Department of Health and Human Services; 2006; 25-8.
 
Gordis L.  Epidemiology. 2nd ed. Philadelphia: Saunders; 2000.
 
White E, Patterson RE, Kristal AR, Thornquist M, King I, Shattuck AL. et al.  VITamins And Lifestyle cohort study: study design and characteristics of supplement users. Am J Epidemiol. 2004; 159:83-93. PubMed
 
Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S. et al.  Grading quality of evidence and strength of recommendations. BMJ. 2004; 328:1490. PubMed
 
Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ. et al.  Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst. 1993; 85:1483-92. PubMed
 
Blot WJ, Li JY, Taylor PR, Guo W, Dawsey SM, Li B.  The Linxian trials: mortality rates by vitamin-mineral intervention group. Am J Clin Nutr. 1995; 62:1424S-1426S. PubMed
 
Wang GQ, Dawsey SM, Li JY, Taylor PR, Li B, Blot WJ. et al.  Effects of vitamin/mineral supplementation on the prevalence of histological dysplasia and early cancer of the esophagus and stomach: results from the General Population Trial in Linxian, China. Cancer Epidemiol Biomarkers Prev. 1994; 3:161-6. PubMed
 
Mark SD, Wang W, Fraumeni JF Jr, Li JY, Taylor PR, Wang GQ. et al.  Do nutritional supplements lower the risk of stroke or hypertension? Epidemiology. 1998; 9:9-15. PubMed
 
Sperduto RD, Hu TS, Milton RC, Zhao JL, Everett DF, Cheng QF. et al.  The Linxian cataract studies. Two nutrition intervention trials. Arch Ophthalmol. 1993; 111:1246-53. PubMed
 
Hercberg S, Galan P, Preziosi P, Bertrais S, Mennen L, Malvy D. et al.  The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med. 2004; 164:2335-42. PubMed
 
Meyer F, Galan P, Douville P, Bairati I, Kegle P, Bertrais S. et al.  Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trial. Int J Cancer. 2005; 116:182-6. PubMed
 
Czernichow S, Bertrais S, Blacher J, Galan P, Briançon S, Favier A. et al.  Effect of supplementation with antioxidants upon long-term risk of hypertension in the SU.VI.MAX study: association with plasma antioxidant levels. J Hypertens. 2005; 23:2013-8. PubMed
 
Richer S.  Multicenter ophthalmic and nutritional age-related macular degeneration study—part 2: antioxidant intervention and conclusions. J Am Optom Assoc. 1996; 67:30-49. PubMed
 
Chylack LT Jr, Brown NP, Bron A, Hurst M, Kopcke W, Thien U. et al.  The Roche European American Cataract Trial (REACT): a randomized clinical trial to investigate the efficacy of an oral antioxidant micronutrient mixture to slow progression of age-related cataract. Ophthalmic Epidemiol. 2002; 9:49-80. PubMed
 
 A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001; 119:1439-52. PubMed
 
 A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001; 119:1417-36. PubMed
 
Shi FL, Hart RG, Sherman DG, Tegeler CH.  Stroke in the People's Republic of China. Stroke. 1989; 20:1581-5. PubMed
 
Xuan XZ, Schatzkin A, Mao BL, Taylor PR, Li JY, Tangrea J. et al.  Feasibility of conducting a lung-cancer chemoprevention trial among tin miners in Yunnan, P.R. China. Cancer Causes Control. 1991; 2:175-82. PubMed
 
Grouhi M, Sussman G.  Pseudoallergic toxic reaction. Ann Allergy Asthma Immunol. 2000; 85:269-71. PubMed
 
Gulati R, Bhargava P, Mathur NK.  Fixed drug eruption due to multi-vitamin multi-mineral preparation as part of familial polysensitivity. J Assoc Physicians India. 1999; 47:253. PubMed
 
Ohtake T, Kobayashi S, Negishi K, Moriya H.  Supplement nephropathy due to long-term, high-dose ingestion of ascorbic acid, calcium lactate, vitamin D and laxatives. Clin Nephrol. 2005; 64:236-40. PubMed
 
Key TJ, Schatzkin A, Willett WC, Allen NE, Spencer EA, Travis RC.  Diet, nutrition and the prevention of cancer. Public Health Nutr. 2004; 7:187-200. PubMed
 
Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE. et al.  Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA. 2005; 294:56-65. PubMed
 
Lewerin C, Matousek M, Steen G, Johansson B, Steen B, Nilsson-Ehle H.  Significant correlations of plasma homocysteine and serum methylmalonic acid with movement and cognitive performance in elderly subjects but no improvement from short-term vitamin therapy: a placebo-controlled randomized study. Am J Clin Nutr. 2005; 81:1155-62. PubMed
 
Wolters M, Hickstein M, Flintermann A, Tewes U, Hahn A.  Cognitive performance in relation to vitamin status in healthy elderly German women—the effect of 6-month multivitamin supplementation. Prev Med. 2005; 41:253-9. PubMed
 
Morris CD, Carson S.  Routine vitamin supplementation to prevent cardiovascular disease: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2003; 139:56-70. PubMed
 
Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR. et al.  Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996; 334:1145-9. PubMed
 
Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH.  Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study. J Natl Cancer Inst. 1999; 91:2102-6. PubMed
 
Omenn GS, Goodman GE, Thornquist M, Brunzell JD.  Long-term vitamin A does not produce clinically significant hypertriglyceridemia: results from CARET, the beta-carotene and retinol efficacy trial. Cancer Epidemiol Biomarkers Prev. 1994; 3:711-3. PubMed
 
Leppälä JM, Virtamo J, Fogelholm R, Huttunen JK, Albanes D, Taylor PR. et al.  Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers. Arterioscler Thromb Vasc Biol. 2000; 20:230-5. PubMed
 
Loke YK, Price D, Derry S, Aronson JK.  Case reports of suspected adverse drug reactions—systematic literature survey of follow-up. BMJ. 2006; 332:335-9. PubMed
 

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