Chapter  139:  Multivitamin/Mineral Supplements and Prevention of Chronic Disease

Introduction

The Johns Hopkins University Evidence-based Practice Center (EPC) reviewed and synthesized the published literature on four Key Questions:

• 1

  What is the efficacy of multivitamin/mineral supplement use in the prevention of chronic disease for the general adult population?

• 2

  What is the safety of multivitamin/mineral supplementation in the general population of adults and children?

• 3

  What is the efficacy of single nutrients or functionally related nutrient pairs in preventing chronic disease in the general adult population?

• 4

  What is the safety of single nutrients or functionally related nutrient pairs in the general population of adults and children?

Multivitamin/mineral supplements are the most commonly used nutritional supplements in the United States. Most multivitamin/mineral supplements contain at least 10 vitamins or minerals with a wide range of doses. Many individuals use multivitamin/mineral supplements for prophylactic or disease-mitigating purposes.

Chronic disease is estimated to account for 35 million deaths worldwide. Cardiovascular disease and cancer comprise a major proportion of chronic diseases in both developed and developing countries. Other than cardiovascular disease and cancer, obesity-related diseases such as type 2 diabetes, end-stage renal disease, and osteoarthritis are also becoming significant public health problems. Many of these chronic diseases share common risk factors and underlying pathologic mechanisms that may be modified by nutrients. Examples include reduction of oxidative damage by antioxidants, DNA methylation regulated by folate and B vitamins, bone metabolism regulated by vitamin D and calcium, and cell differentiation, proliferation, and growth regulated by retinol, calcium, and vitamin D.

The biological effects of a nutrient are heavily dependent on its bioavailability. Key factors determining the bioavailability of micronutrients are the chemical form in which the nutrient is presented to the intestinal absorptive surface, the presence of other competing chemicals in the intestinal lumen, the concentration of food constituents (such as phytates and other chelating agents) that bind to the nutrient and make it unavailable for absorption, intestinal transit time, and enzyme activity. A nutrient may affect not only the absorption of other nutrients, but also the transport, tissue uptake, function and metabolism of other nutrients. Hence, concurrent ingestion of several nutrients may result in synergistic, antagonistic, or threshold effects as compared to a single nutrient. The efficacy of a single nutrient or multiple nutrients should be considered separately unless no interactive or threshold effects can be found.

The United States Food and Nutrition Board has established the tolerable upper intake levels (ULs) for several nutrients. By definition, a UL is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population. Since the time when ULs were determined, several large-scale randomized controlled trials of vitamin/mineral supplementation have been completed. An update of the data on adverse effects/events will help to evaluate the appropriateness of the ULs.

Methodology

Our EPC established a team and a work plan to develop this evidence report. The project consisted of recruiting technical experts, formulating and refining the specific questions, performing a comprehensive literature search, summarizing the state of the literature, constructing evidence tables, synthesizing the evidence into a report, and submitting the report for peer review. The investigative team has strong expertise in nutrition, medicine, chronic disease epidemiology, clinical trial methodology, HIV infection, ophthalmology, and gerontology. In addition, the investigators have extensive experience in conducting research projects specific to vitamins and minerals in the general population, children, and the elderly.

We defined multivitamin/mineral supplements as any supplements containing 3 or more vitamins and/or minerals without herbs, hormones, or drugs, each at a dose less than the UL determined by the Food and Nutrition Board. The general population is defined as community-dwelling individuals who do not have special nutritional need (e.g., not institutionalized, hospitalized, pregnant, or clinically deficient in nutrients). For efficacy, we considered data from randomized controlled trials. For safety, we considered data from randomized controlled trials and observational studies.

We used a systematic approach for searching the literature to minimize the risk of bias in selecting articles for inclusion in the review. In this systematic approach, we had to be very specific about defining the eligibility criteria for inclusion in the review. The systematic approach was intended to help identify gaps in the published literature."

To enhance our understanding of the efficacy of multivitamin/mineral supplements in preventing chronic disease, we also considered evidence on the efficacy and the safety of individual vitamins and minerals that are often included in multivitamin/mineral supplements. The individual or functionally-related paired nutrients considered for efficacy issues were calcium, folic acid, vitamin B6, vitamin B12, vitamin D, vitamin E, vitamin C, vitamin A, iron, zinc, magnesium, vitamin B1, vitamin B2, niacin, calcium/vitamin D, calcium/magnesium, folic acid/vitamin B12, and folic acid/vitamin B6. The nutrients considered for safety issues were calcium (with or without vitamin D), folic acid, vitamin D, vitamin E, vitamin A, iron, selenium, and β-carotene.

The following chronic diseases were considered: (a) breast cancer, colorectal cancer, lung cancer, prostate cancer, gastric cancer, or any other malignancy; (b) myocardial infarction, stroke; (c) type 2 diabetes mellitus; (d) Parkinson's disease, dementia; (e) cataracts, macular degeneration, hearing loss; (f) osteoporosis, osteopenia, rheumatoid arthritis, osteoarthritis; (g) non-alcoholic steatorrheic hepatitis, non-alcoholic fatty-liver disease; (h) chronic renal insufficiency, chronic nephrolithiasis; and (i) HIV infection, hepatitis C, tuberculosis, and (j) chronic obstructive pulmonary disease.

Results

The literature search process identified 11,324 citations potentially relevant to the Key Questions. We excluded 849 duplicate citations. In the title review process, we excluded 6,863 citations because they clearly did not pertain to the Key Questions. In the abstract review process, we excluded 3,163 citations that did not meet one or more of the eligibility criteria. Using the article inclusion/exclusion form, we then excluded an additional 386 articles that did not meet one or more of the eligibility criteria. That left a total of 63 articles eligible for inclusion in the review of one or more of the Key Questions.

Results from this systematic review indicated a paucity of data from randomized controlled trials that specifically address the efficacy of multivitamin/mineral supplement use in the prevention of chronic disease in the general population of the United States. The data were on the efficacy of designed combinations of vitamins and minerals; none of the trials used one-a-day multivitamins prevailing on the market in the United States. Data on cancer and cardiovascular outcomes came from the Linxian General Population Trial in China and the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) trial in France. The Linxian trial documented that supplementation with combined β-carotene, vitamin E and selenium supplements at doses 1 to 2 times the United States Recommended Daily Allowance (RDA) for 5 years had 13 percent to 21 percent reductions in gastric cancer incidence, gastric cancer mortality, and total cancer mortality in a poorly nourished Chinese population. The reduction in cancer mortality was stronger in women than in men. There were no significant effects on total cancer incidence and cerebrovascular mortality. The SU.VI.MAX study in a French population documented a 31 percent reduction in overall cancer risk by use of vitamin C, vitamin E, β-carotene, selenium, and zinc at doses 1–2 times the RDAs for 8 years in men but not in women. A 12 percent reduction in prostate cancer risk, particularly a 48 percent risk reduction in those with normal prostate specific antigen levels at baseline, was found in men receiving active supplements compared to men receiving placebo. There was no significant effect of the combined antioxidants on ischemic cardiovascular disease incidence. In this trial, men had lower serum levels of vitamin C and β-carotene than women at baseline.

Multivitamin/mineral supplement use for 3 to 6 years had no significant benefits in preventing cataract in 3 trials in the United States (also in the United Kingdom in one trial) and the Linxian trial. In the Age-Related Eye Disease Study (AREDS), high-dose zinc (10 times the RDA) alone or combined with antioxidants (5 to 15 times the RDAs) had beneficial effects on age-related macular degeneration only in those with intermediate age-related macular degeneration in one or both eyes, or those with advanced age-related macular degeneration in one eye.

Overall, data on total mortality rates pointed to either no increased risk or lower risk in the groups with multivitamin/mineral supplement use. Total mortality was 9 percent lower among those who received β-carotene, selenium, and vitamin E in the Linxian trial; there was no sex- or age-difference in the relative risks. In AREDS, total mortality was 6 percent higher in the group receiving antioxidants compared to the group receiving no antioxidants, but the increase was not statistically significant. Among the participants at high risk for age-related macular degeneration, total mortality was 13 percent to 20 percent lower in the groups receiving zinc alone or zinc combined with antioxidants. In the SU.VI.MAX study, a sex-difference was documented for the relative risk of total mortality among those receiving antioxidants and zinc compared to those receiving placebo. In the REACT, the total mortality rate was not calculated. There were 9 deaths in the antioxidant group, whereas 3 deaths occurred in the placebo group.

Daily supplementation with β-carotene of 20 mg, 30 mg or 50 mg was not protective against malignancies, cardiovascular disease outcomes, diabetes mellitus, cataract or age-related maculopathy. Supplementation with β-carotene with or without vitamin A increased the incidence of lung cancer in persons with asbestos exposure or in smokers, and was associated with increased mortality. To date, there has been no randomized controlled trial that assessed the efficacy of vitamin A alone in preventing chronic disease. Studies in selected populations (nutritionally inadequate, smokers, or asbestos exposure) showed no benefit of combinations of vitamin A and zinc or vitamin A and β-carotene for the prevention of stroke mortality, esophageal or gastric cancer incidence, cardiovascular mortality, or all-cause mortality.

Vitamin E supplements (synthetic α-tocopherol 50 mg or 300 IU per day, natural vitamin E 500 IU, or natural source vitamin E, 600 IU per day) have been studied for primary prevention of cancer, cardiovascular disease, cataract, and age-related eye disease. The evidence predominantly comes from the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) study and the Women's Health Study (WHS). There was a lack of effects of vitamin E in the prevention of these diseases, except for a 32 percent reduction in prostate cancer incidence, a 41 percent reduction in the prostate cancer mortality, and a 22 percent reduction in colorectal cancer in smokers in the ATBC study, and decreased cardiovascular deaths (primarily sudden death) in the WHS participants, particularly in those aged 65 years or older. The findings on hemorrhagic stroke were conflicting between the ATBC trial and the WHS; the former found a higher risk with use of low-dose α-tocopherol supplements but the latter found a lower risk with use at a high dose.

Two previous systematic reviews reported that supplementation with folic acid at a daily dose of 0.75 mg or 30 mg, alone or in combination with vitamin B12 and/or vitamin B6 for 5–12 weeks, had no significant effects on cognitive function in 5 small randomized controlled trials. Combined vitamin B2 and niacin supplement use for 5 years had no significant effects on cerebrovascular mortality, total mortality, total cancer incidence, esophageal or gastric dysplasia/cancer incidence, or esophageal or gastric cancer mortality in a poorly nourished population in China.

In a study in persons with a history of non-melanoma skin cancer, supplementation with selenium of 200 mcg per day had no effect on cardiovascular outcomes, but had protective effects on total mortality and incidence of lung, colorectal, and prostate cancers. Another study in China found a significantly reduced risk for liver cancer in those who used selenium supplements of 200 mcg/day for two years.

Due to the substantial amount of efficacy data on calcium/vitamin D and osteoporosis, we reviewed systematic review articles supplemented with updated data from recent randomized controlled trials and data from randomized controlled trials that met our inclusion criteria, but were not included in previous systematic reviews. The previous systematic reviews reported that supplementation with calcium has short-term (particularly within one year) benefit on retaining bone mineral density in postmenopausal women, and a possible effect in preventing vertebral fractures. The reviews also indicated that combined vitamin D₃ (700–800 IU/day) and calcium (1000 mg/day) may reduce the risk of hip and other non-vertebral fractures in populations with low levels of vitamin D and/or calcium. Recent published data from the Women's Health Initiative (WHI) trial were consistent with these systematic reviews in showing a 1.06 percent higher hip bone density (p<0.02) and a 12 percent non-significant lower risk for hip fracture in postmenopausal women after receiving calcium carbonate (500 mg twice a day) and vitamin D₃ (200 IU twice a day) for an average of 7 years as compared to women receiving a placebo. In this trial, participants were allowed to have self-selected use of multivitamin supplements as well as calcium and vitamin D supplements up to 1000 mg and 600 IU per day, respectively, and thus the WHI participants had higher intake of calcium (an average of 1150 mg per day) than the general population (761 mg per day). The WHI trial found no benefit of calcium and vitamin D supplementation in preventing colorectal cancer incidence.

For data on safety, we identified 10 studies using multivitamin/mineral preparations and 24 studies using single nutrients. Doses were usually 2 to 10 times the RDA. Overall, there was no consistent pattern of increased adverse effects in the active group compared with the placebo group, with the exception of changes in skin color, which was common in studies in which β-carotene was part of the multivitamin preparation. In the few studies where mortality was compared between active and control groups, no significant adverse effect of multivitamin/mineral supplementation on this outcome was found.

Supplementation with β-carotene with or without vitamin A increased the incidence of lung cancer in persons with asbestos exposure or in smokers. Vitamin A supplementation moderately increased serum triglyceride levels. Calcium supplementation increased the risk of kidney stones. Vitamin E supplementation was associated with an increased incidence of epistaxis but was not associated with an increased risk of more serious bleeding events, such as hemorrhagic stroke. Iron supplementation was found to reduce weight gain in iron-sufficient, non-anemic children in a small randomized controlled trial. More recent trials have not clarified this issue because they targeted deficient populations and/or included other micronutrients in the intervention formulation.

Future Research

In vitro studies and animal models have helped us to understand the function of nutrients under a controlled environment. However, these types of studies often have over-simplified the sophistication of the human body. There is a gap in our knowledge of how specific nutrients work in vivo to prevent disease. Future research should be directed toward filling the gap by developing valid in vivo biomarkers and applying them in the settings of randomized controlled trials to examine how nutrients influence the body's physiological function and pathological processes, and how multiple nutrients work in concert to do so. Identifying an optimal dose in dose-response studies is critical to guide the design of future large-scale randomized controlled trials when the conduct of the trials is considered worthwhile.

Nutritional research has adopted a reductionist approach that emphasizes the role of individual nutrients in physiologic function or disease process. In view of the complex pathological processes of chronic diseases, the idea of using a single nutrient or a few nutrients to modify disease risk carries considerable optimism. The design and conduct of several large-scale randomized controlled trials on antioxidants was derived from epidemiological data that showed a lower risk of chronic disease (predominantly cancer and cardiovascular disease) in those who had higher circulating levels or dietary intake of some micronutrients. Because of residual confounding and measurement errors in dietary assessment, dietary data from observational studies can be better examined by patterns of food consumption with a multivariate approach, rather than by ranking of specific nutrient intake with a univariate approach.

We have found that many studies did not report study participants' self-selected supplement use before and during the trial participation, and allowed self-selected supplement use during the trial. Similarly, there was a lack of information on other variables that might have modified the effects of study supplements. Furthermore, collective study findings also may not apply to every individual. Additional research should be done, particularly in existing randomized controlled trials, to examine how efficacy may vary by age, time since trial enrollment to diagnosis, self-selected supplement use, dietary patterns, disease history, medication use, and/or genetic polymorphisms.

With many food products being fortified with several nutrients, Americans' dietary intake of certain nutrients may well be above the RDAs. Hence, it is important to study the level of intake among consumers and assess how nutrient fortification may influence the public's health. An adverse event reporting system needs to be in place to facilitate this type of research.

For policy making, research should be conducted to estimate the cost-effectiveness and the risk/benefit profile of multivitamin/mineral supplement use or more generally, dietary supplement use, in the general population. Such research should also consider subpopulations for which these parameters may differ.

Purpose

Multivitamin/mineral supplements are the most commonly used nutritional supplements in the United States.¹ Scientific evidence on the efficacy and safety of supplement use will serve as the basis for us to identify knowledge gaps and inform the general public's practice and future research. This report synthesizes the published literature on the efficacy and the safety of multivitamin/mineral supplements in the prevention of chronic disease for the general population of adults, and on the efficacy and the safety of certain commonly-used single vitamin or mineral supplements in the general population of adults and children. The content of this report will be used by the National Institutes of Health (NIH) in preparing a State-of-the-Science Statement for health care providers and the general public.

Specific Aims

The specific aims of this review are to synthesize evidence in the literature for addressing the following Key Questions:

• 1

  What is the efficacy determined in randomized controlled trials of multivitamin/mineral supplements (defined as 3 or more vitamins and/or minerals without herbs, hormones, or drugs), each at a dose less than the tolerable upper intake level (UL) determined by the Food and Nutrition Board, in the general adult population^* for prevention^† against the development of one or more of the following chronic diseases or conditions^‡?

  • a

    Oncologic: breast cancer, colorectal cancer, lung cancer, prostate cancer, gastric cancer, or any other malignancy (including colorectal polyps)

  • b

    Cardiovascular: myocardial infarction, stroke

  • c

    Endocrine: type 2 diabetes mellitus

  • d

    Neurologic: Parkinson's disease, cognitive decline, memory loss, dementia

  • e

    Age-related sensory loss: cataracts, macular degeneration, hearing loss

  • f

    Musculoskeletal: osteoporosis, osteopenia, rheumatoid arthritis, osteoarthritis

  • g

    Gastroenterologic: non-alcoholic steatorrheic hepatitis, non-alcoholic fatty-liver disease

  • h

    Renal: chronic renal insufficiency, chronic nephrolithiasis

  • i

    Infectious: HIV infection, hepatitis C, tuberculosis

  • j

    Pulmonary: chronic obstructive pulmonary disease

• 2

  What is known about the safety of use of multivitamin/mineral supplements (as defined in question 1) in the general population of adults and children, based primarily on data from randomized controlled trials and observational studies?

• 3

  What is the efficacy determined in randomized controlled trials of supplementation with the single nutrients or functionally related nutrient pairs listed below, each at a dose less than the UL determined by the Food and Nutrition Board, in the general adult population for prevention against the development of one or more of the chronic diseases or conditions listed above for question 1?

  • a

    calcium

  • b

    folic acid

  • c

    vitamin B6

  • d

    vitamin B12

  • e

    vitamin D

  • f

    vitamin E

  • g

    vitamin C

  • h

    vitamin A

  • i

    iron

  • j

    zinc

  • k

    magnesium

  • l

    vitamin B1

  • m

    vitamin B2

  • n

    niacin

  • o

    calcium/vitamin D

  • p

    calcium/magnesium

  • q

    folic acid/vitamin B12

  • r

    folic acid/vitamin B6

• 4

  What is known about the safety of use of the following single nutrients in the general population of adults and children, based primarily on data from randomized controlled trials and observational studies?

  • a

    calcium (with or without vitamin D)

  • b

    folic acid

  • c

    vitamin D

  • d

    vitamin E

  • e

    vitamin A

  • f

    iron

  • g

    selenium

  • h

    β-carotene

Use of Multivitamin/mineral Supplements in the United States

Multivitamins are the most commonly used dietary supplements in the United States.¹ Multivitamin/mineral pills typically include at least 10 vitamins, and 10 minerals. They generally contain 100 percent of the Recommended Daily Allowance (RDA) for those micronutrients for which there are recommendations, except for calcium and certain other minerals, which are too bulky to include more than a fraction of the RDA. Recently, variation in the formulation of multivitamin/mineral supplements has occurred. Many of these supplements contain two to six times the RDA. Often, formulations of B vitamins are 10 to 20 times the RDA. According to the National Health and Nutrition Examination Survey (NHANES) 1999-2000, 35 percent of adults reported use of multivitamin/mineral supplements in the month prior to the survey.¹ Commercials have widely promoted dietary supplements. In 2005, 20.3 billion dollars were spent on purchases of dietary supplements in the United States.² Many individuals use vitamins/minerals supplements for prophylactic or disease-mitigating purposes. Whether long-term use is efficacious and safe warrants rigorous scientific evaluation.

Chronic Disease

Chronic disease is estimated to account for 35 million deaths worldwide.³ Cardiovascular disease and cancer comprise a major proportion of chronic diseases in both developed and developing countries.⁴ Other than cardiovascular disease and cancer, obesity-related diseases such as type 2 diabetes, end-stage renal disease, osteoarthritis and non-alcoholic steatorrheic hepatitis are also becoming significant public health problems.^{5, 6} The prevalence and incidence of these diseases may rapidly increase in the near future in the United States because the prevalence of obesity has increased from 23 percent to 30 percent during the 1990s.⁷ At the same time, the population is gradually aging, and age-related degenerative diseases/conditions claim enormous health and economic tolls. Age-related cataract is the leading cause of blindness, accounting for about 42 percent of all blindness globally.⁸ Approximately one in five people over age 65 live with age-related macular degeneration, and adults with advanced macular degeneration have a markedly reduced quality of life and need for assistance with activities of daily living.⁹ The incidence of dementia also increases exponentially with age.¹⁰ Alzheimer disease accounts for more than half of dementia cases.¹¹

Common Pathologic Mechanisms of Chronic Diseases

The etiology of most chronic diseases is multifaceted. However, many chronic diseases share common risk factors and underlying pathologic mechanisms. Cigarette smoking/tobacco use, sedentary lifestyle, unhealthy (high calorie, low fruit/vegetable intake) diet, and obesity are well established as major risk factors of several chronic diseases. Cigarette smoke is a rich source of oxidants (free radicals and reactive oxygen, nitrogen and chlorine species), whereas a diet low in fruits and vegetables contains a low amount of antioxidants. Substantial evidence from in vitro experiments, animal models and epidemiological observational studies suggests that oxidative stress, a result of an imbalance between oxidative and reductive potential in favor of the former, may play an important role in the initiation, promotion, and progression of cardiovascular disease (in particular, ischemic heart disease and stroke), cancer, and several degenerative diseases/conditions, such as age-related cataract, age-related macular degeneration and cognitive decline.¹²–¹⁹ Oxidative damage to lipids by free radicals initiates and propagates chain reactions that may be intercepted by antioxidants or otherwise lead to development of atherosclerosis and mutagenesis.^{12, 20} Oxidative damage to DNA causes formation of DNA adducts, double strand breaks, single strand breaks, aberrations and instability of chromosomes, and genomic instability, all of which may result in mutagenesis and carcinogenesis.²¹ Oxidative damage to proteins may affect enzyme expression and impair critical cellular signaling, leading to alterations in cell function.²²

It is well known that sedentary lifestyle, excessive caloric intake, and lack of physical activities lead to obesity, and obese individuals have higher levels of inflammation, a key process of host responses to infections and an important risk factor of cardiovascular disease and many cancers and chronic conditions.^{23, 24} Inflammatory responses can induce the generation of free radicals and reactive species that cause oxidative stress and further exacerbate disease processes.²⁵

In addition to oxidative damage and inflammation, one-carbon metabolism has been implicated to be important in several chronic diseases, particularly cardiovascular disease, renal failure, neurological dysfunction, and cancer. An important step in one-carbon metabolism is the synthesis/metabolism of methionine. Methionine is a precursor of S-adenosylmethionine (SAM), a universal methyl donor to DNA, RNA, protein, phospholipids, neurotransmitters and hormones. Hypermethylation in the promoter regions of tumor suppressor genes and chromosome aberrations due to global hypomethylation may lead to oncogenesis.^{26, 27} In methionine synthesis, an intermediate molecule is homocysteine, which has been found to be associated with increased risk of coronary artery disease, stroke, peripheral vascular disease, cognitive impairment, dementia, depression, osteoporotic fractures, and functional decline.²⁸

Other pathways by which chronic disease develops may or may not be modifiable by vitamins/minerals. Examples of these factors include but are not limited to genetic susceptibility, growth factors, and capacity of detoxification.

Possible Mechanisms of Action of Vitamins and Minerals in Chronic Disease Prevention

Multivitamin/mineral supplements often contain vitamin A, β-carotene, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B6 (pyridoxine), vitamin B12 (cyanocobalamin), vitamin C, vitamin D, vitamin E, folic acid, niacin, calcium, iron, zinc, magnesium, and selenium. These nutrients have numerous biological effects and have garnered considerable research interest in their potential as chemo-preventive agents for the prevention of chronic disease.

As described previously, a common process of chronic disease is oxidative damage by free radicals or reactive species. Multiple systems work in concert to protect the human body from oxidative damage. Endogenous enzymatic antioxidants, such as copper- and zinc-, or manganese-containing superoxide dismutase, selenium-dependent glutathione peroxidase, and catalase, can catalyze radical- and peroxide-quenching reactions. Nonenzymatic antioxidants include but are not limited to vitamin C, vitamin E, bilirubin, urate, flavanoids, and certain carotenoids (e.g., β-carotene and lycopene). In addition, metal-binding proteins can quench iron and copper ions which, if free, can catalyze oxidative reactions.²⁹

Folate, vitamin B6, and vitamin B12 influence methylation by supplying methyl groups and are essential for nucleotide synthesis, DNA synthesis, and DNA repair.³⁰ Folate and B vitamins maintain normal brain function through the methylation of neurotransmitters, phospholipids and myelin.³¹ They are also essential in homocysteine metabolism because irreversible transsulfuration and the re-methylation of homocysteine rely on coenzymes derived from vitamin B6, vitamin B12, and folate. A previous meta-analysis indicated that daily supplementation with folic acid of 0.5–5 mg and vitamin B12 of approximately 0.5 mg would reduce blood homocysteine concentrations by up to one-third, whereas vitamin B6 did not have a significant additional effect.³² However, whether a reduction in homocysteine leads to decreased risk for clinical outcomes awaits evidence from randomized controlled trials.

In addition to anti-oxidation and regulation of methylation, vitamins and minerals may have inhibitory effects on inflammation (γ-tocopherol, zinc, and vitamin A) and angiogenesis (α-tocopherol, vitamin A, vitamin C, vitamin D). Some may also regulate cell differentiation, proliferation, and apoptosis (vitamin A, α-tocopherol, vitamin D, calcium) and enhance immunity (vitamin A, zinc, vitamin E, vitamin C, calcium).³³–⁴⁰ Vitamin C may be useful in the prevention or management of osteoarthritis through collagen synthesis,⁴¹ and vitamin D may prevent the progression of osteoarthritis by impairing bone's response to the pathophysiological process of the disease.⁴² Magnesium and calcium are important in regulating blood pressure.^{43, 44} Calcium may also have beneficial effects on cholesterol levels and body weight, and may shield the contact of carcinogen with bowel mucosa by forming insoluble chemical complexes with bile acid and fat.^{45, 46} Several meta-analyses have addressed the effects of calcium and/or vitamin D supplementation on bone density, osteoporosis, fractures, and falls.⁴⁷–⁵² The evidence has led the Food and Drug Administration (FDA) to authorize health claims in the labeling of calcium supplements for the benefits in osteoporosis prevention. The 2004 United States Surgeon General's Report on Bone Health and Osteoporosis has clearly stated the importance of calcium and vitamin D in maintaining healthy bones and preventing osteoporosis.⁵³ However, intake of vitamin D and calcium from food source has been generally inadequate in American adults; only 4 percent of individuals of age greater than 51 years meet the Adequate Intake level of vitamin D,⁵⁴ and the average calcium intake in American adults was estimated to be 761mg per day, below the Recommended Dietary Allowance for adults (1,000–1,200 mg).⁵⁵

Factors that Affect the Efficacy and Safety of Vitamin/mineral Supplement Use in Chronic Disease Prevention

Perturbation of metabolism and other physiologic function often occurs in persons with established chronic disease. Accordingly, evaluation of the efficacy and safety of multivitamin/mineral supplement use should be made separately for primary versus secondary prevention. In addition to individuals' health status, several factors may affect the efficacy and the safety of vitamin and/or mineral supplement use in chronic disease prevention, such as individuals' nutritional status, bioavailability of nutrients, nutrient-nutrient interaction, chemical forms and doses of supplements, timing and duration of supplement use, among others.

Age, sex, race, genetic susceptibility, geographic location, smoking, diet, physical activity, obesity, and sunlight exposure are important factors because they affect individuals' baseline nutritional levels and may modify the efficacy and safety of supplement use. Geographical location is also relevant because dietary intake of selenium depends on the selenium content of the soil where plants are grown or animals are raised. In addition, ecological studies have linked areas with increased selenium levels to lower rates of lung, colorectal, bladder, esophageal, pancreas, breast, ovarian, and cervical cancers.⁵⁶

After a nutrient is ingested, its biological effects are heavily determined by the bioavailability, i.e., the absorbable fraction that affects the biological effects of the nutrient by modulating the amount of the nutrient entering the body. Key factors determining the bioavailability of a micronutrient are the chemical form in which the nutrient is presented to the intestinal absorptive surface, the presence of other competing chemicals the concentration of food constituents (such as phytates and other chelating agents) that bind to the nutrient and make it unavailable for absorption, intestinal transit time, and enzyme activity. For example, synthetic vitamin E has approximately 50 percent the bioavailability of natural vitamin E, and use of α-tocopherol can reduce the bioavailability of other forms of vitamin E,⁵⁷ after competing for the uptake into very low-density lipoproteins (VLDL) by α-tocopherol transfer protein in the liver. Hence, factors influencing the bioavailability of a nutrient are important to consider when assessing the effects of multiple micronutrient preparations.

One nutrient may affect the absorption, transport, tissue uptake, function and metabolism of other nutrients. Accordingly, the concurrent ingestion of several nutrients may result in synergistic, antagonistic, or threshold effects as compared to a single nutrient. Hence, the efficacy of a single nutrient vs. multiple nutrients should be considered separately unless no interactive or threshold effects can be found. Examples of nutrient-nutrient interactions include vitamin B12 and selenium modification of host's responses to inadequate dietary intake of folic acid. An excessive intake of folic acid may obscure vitamin B12 deficiency.⁵⁸ Zinc regulates the absorption, transport and utilization of vitamin A.⁵⁹ Calcium and vitamin D are inter-related metabolically in bone and intestine.

The chemical form of a nutrient may also determine its effects. For example, rather than an antioxidant effect, α-tocopheryl succinate has anti-proliferative effects in in vitro settings. Doses of supplements and duration of use are directly relevant to the efficacy, particularly for lipid soluble vitamins that can be accumulated in the tissue for a long-term.

The Tolerable Upper Intake Levels of Daily Nutrient Intake

The United States Food and Nutrition Board established tolerable ULs for several nutrients. By definition, a UL is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population.⁶⁰ A UL is determined by the following steps: (1) hazard identification based on in vitro experiments, animal studies, and/or human studies, (2) dose-response assessment to identify the no-observed-adverse-effect level (NOAEL) or lowest-observed-adverse- effect level (LOAEL), which is then weighed with an uncertainty factor (UF) to derive the UL. In the case where toxicity data are unavailable from children, an extrapolation from the ULs determined for adults is made based on body weight difference. The strength of the evidence for determining a UF varies and therefore the choice of a UF has leeway of subjectivity. The UL of vitamin E for adults is determined primarily based upon its hemorrhagic effects in rats.⁶⁰ The UL of iron, zinc, and selenium was determined based on gastrointestinal symptoms, reduced copper status, and hair and nail brittleness and loss, respectively.⁶⁰ Since the time when ULs were determined, several large-scale randomized controlled trials of vitamin/mineral supplementation have been completed. An update on the data regarding adverse effects will help to evaluate the appropriateness of ULs.

Federal Regulation of Vitamin/mineral Supplements

The United States FDA regulates dietary supplements under the Dietary Supplement Health and Education Act (DSHEA) of 1994 which states that supplements containing ingredients marketed prior to the enactment of DSHEA are not subject to pre-market burden on proof of safety. Many vitamins and minerals, such as vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, calcium, and magnesium, with established nutritional function, fall into this category and have been grandfathered as Generally Recognized As Safe (GRAS).^{61, 62} However, the determination of GRAS was primarily based on experts' opinions or a history of safe use before January 01, 1958 when the Food Additives Amendment to Food, Drug, and Cosmetic Act was enacted. A lack of high-quality data before 1958 is conceivable when an adverse event reporting system was not in place.

Conceptual Framework

Figure 1. Conceptual framework for the prevention of (more...)

   Figure 1. Conceptual framework for the prevention of chronic diseases and conditions with vitamin/mineral supplements (circled numbers represent the key questions addressed in this systematic review)

Figure 1

Recruitment of Technical Experts and Peer Reviewers

At the beginning of the project, we recruited a panel of internal and external technical experts to give input on key steps including the selection and refinement of the questions to be examined. The panel included two internal technical experts from the Johns Hopkins University who have strong expertise in various aspects of the efficacy and/or safety of multivitamins/minerals and evidence-based medicine, and external experts who have strong expertise in nutritional research (see Appendix A ^a). In addition to this panel of technical experts, we recruited a few additional experts to serve as peer reviewers of the evidence report, as described further in the section on Peer Review.

Key Questions

We worked with the technical experts and representatives of OMAR and the Agency for Healthcare Research and Quality (AHRQ) to develop the Key Questions that are presented in the Specific Aims section of Chapter 1 (Introduction). We expanded the preliminary questions to include functionally related nutrient pairs, tuberculosis, hepatitis C, and pulmonary disease, and limited the questions involving efficacy to randomized controlled trials. The Key Questions focus on the efficacy of multivitamins/minerals (and specific single nutrients and functionally related pairs) in the prevention of chronic diseases and conditions as well as the safety of multivitamin/minerals and specific nutrients.

Literature Search Methods

Searching the literature included the steps of identifying reference sources, formulating a search strategy for each source, and executing and documenting each search. Additionally, we searched for medical subject heading (MeSH) terms that were relevant to the specific nutrients and diseases specified in Key Question 1 to help develop the search strategy. We used a systematic approach for searching the literature to minimize the risk of bias in selecting articles for inclusion in the review. In this systematic approach, we had to be very specific about defining the eligibility criteria for inclusion in the review. The systematic approach was intended to help identify gaps in the published literature. We used a systematic approach for extracting data from the studies to minimize the risk of bias in how we extracted data from eligible studies. By creating standardized forms for data extraction, we sought to maximize consistency in identifying all pertinent data available for synthesis.

Organization and tracking of literature search

Figure 2. Summary of literature search and review process (more...)

   Figure 2. Summary of literature search and review process (number of articles )

The results of the searches were downloaded and imported into ProCite^® version 5 (ISI ResearchSoft, Carlsbad, CA). From ProCite, the articles were uploaded to SRS 3.0. We used the duplication check feature in SRS 3.0. This feature allowed us to scan for exact article duplicates, author/title duplicates, and title duplicates. Additionally, this database was used to store citations in portable document format (PDF) and to track the search results at title review, abstract review, article inclusion/exclusion, and data abstraction levels (Figure 2). A list of excluded articles is presented in Appendix D ^a

Title Review

After the electronic databases were searched, citations were downloaded into ProCite, and uploaded to the SRS 3.0 tracking system. The study team scanned all titles. Two independent reviewers conducted title scans in a parallel fashion. For a title to be eliminated at this level, both reviewers had to indicate that it was ineligible. If the two reviewers did not agree on the eligibility of an article, it was automatically promoted to the next level (see Appendix E ^a, Title Review Form). The title review phase was designed to capture as many studies as possible reporting on the efficacy of single nutrients, related nutrient pairs, and multivitamins/minerals in the primary prevention of chronic diseases and conditions as well as the safety of multivitamins/minerals and a specified set of nutrients. All titles that were thought to address the above efficacy and or safety issues were promoted to the abstract review phase.

Abstract Review

Article Inclusion/Exclusion

Because of the broad array of potentially eligible articles obtained at the abstract review phase, full articles initially selected for review underwent another independent parallel review by investigators to determine if they should be included for full data abstraction. At this phase of review, investigators determined which of the Key Questions each article addressed, and what type of protocol was used in the study (see Appendix E, Article Inclusion/Exclusion Form). If articles were still deemed to have applicable information, they were included in the final article review. Differences in opinions regarding article inclusion or exclusion were resolved through consensus adjudication.

Article Review/Data Abstraction

The purpose of the article review was to confirm the relevance of each article to the research questions, to determine methodological characteristics pertaining to study quality, and to collect evidence that addressed the research questions. Articles eligible for full review could address one or more of the Key Questions. If reviewers determined that an article addressed both efficacy and safety, multiple data abstraction forms were used. We used a systematic approach for extracting data from the studies to minimize the risk of bias in how we extracted data from eligible studies. By creating standardized forms for data extraction, we sought to maximize consistency in identifying all pertinent data available for synthesis.

Each article underwent double review by study investigators for full data abstraction and assessment of study quality. For all data abstracted from studies, we used a sequential review process. In this process, the primary reviewers completed all data abstraction forms. The second reviewer confirmed the first reviewer's data abstraction forms for completeness and accuracy. Reviewer pairs were formed to include personnel with both clinical and methodological expertise. A third reviewer re-reviewed a random sample of articles marked as “ineligible” by the first two reviewers to ensure consistency in the classification of the articles. Reviewers were not masked to the articles' authors, institution, or journal. In most instances, data were directly abstracted from the article. If possible, relevant data were also abstracted from figures. Differences in opinion were resolved through consensus adjudication. For assessments of study quality, each reviewer independently judged study quality and rated items on quality assessment forms. (see Appendix E, Data Abstraction Review Forms)

For all articles containing original data, reviewers extracted information on general study characteristics such as study design, study period and follow up, study participants, sample size, and prior supplement use (see Appendix E, Data Abstraction Review Forms). Data abstracted to the “Arm” forms (see Appendix E, Data Abstraction Review Forms) included: placebo or intervention; nutrients studied; chemical form; dose; units; frequency of use; timing of use; and duration of use.

For studies addressing efficacy (Key Question 1 and/or 3), an outcomes form for efficacy (see Appendix E, Data Abstraction Review Forms) was filled out to obtain the information on study outcomes and adverse effects, and the results from subgroup analyses. Additionally, a specific study quality form was filled out (quality forms were filled out independently) to assess: representativeness of the study population; bias and confounding; description of study supplements/supplementation; adherence and completeness of follow up; statistical analysis; and conflict of interest (see Appendix E, Data Abstraction Review Forms).

Reviewers used an outcomes form to abstract data from articles addressing safety (Key Questions 2 and/or 4) on adverse effects/events and criteria for causality (see Appendix E, Data Abstraction Review Forms).

We also abstracted data from systematic reviews that specifically applied to our Key Questions. This included systematic reviews of calcium and/or vitamin D only, and reviews of studies other than calcium and/or vitamin D only (see Appendix E, Data Abstraction Review Forms).

All information from the article review process was entered into the TrialStat database by the individual completing the review. Reviewers entered comments into the system whenever applicable. The TrialStat database was used to maintain and clean the data, as well as to create detailed evidence tables and summary tables (see Appendix F and Summary Tables).

Quality Assessment

Article quality was assessed differently for different types of studies: efficacy studies (randomized controlled trials only); safety studies; and systematic reviews. The dual, independent review of article quality judged articles on several aspects of each study type's external and internal validity. Quality assessment of studies addressing efficacy included: (1) the representativeness of the study population (description of the study population and where it was drawn, and how well the participants' characteristics were described); (2) bias and confounding (whether this was controlled for in the study design and reported on in the study); (3) description of supplements/supplementation; (4) description of adherence to study protocols and follow up (flow of patients through the study over time, loss to follow up, and participant withdrawal); (5) statistical analysis; and (6) conflict of interest.

Quality assessment of studies addressing safety considered: (1) temporal relationships between timing of supplement use and adverse events (how this was reported); (2) dose-response relationship; (3) whether adverse effects disappeared after supplement use ceased; (4) serum levels of supplements; (5) whether an alternative cause for the adverse event was investigated: and (6) whether the adverse event re-occurred if the supplement was used again.

The quality of each systematic review was assessed using a different set of criteria: (1) whether the question being addressed by the review was clearly stated; (2) comprehensiveness of search methods used and described in the report; (3) whether inclusion/exclusion criteria were clearly defined and appropriate; (4) whether analyses were conducted to measure variability in efficacy; (5) whether study quality was assessed and done appropriately (using validated instruments); (6) whether differences in how outcomes were reported and analyzed across studies were taken into consideration; (7) whether the study methodology was reproducible; and (8) whether conclusions were supported by the data presented.

For each study, we assigned a rating of high, medium or low quality for each domain of study quality based on whether the score for that domain was designated High (80–100%), Medium (50–79%), or Low (0–49%) quality.

Data Synthesis

For each Key Question, we created a set of detailed evidence tables containing all information extracted from eligible studies. The investigators reviewed the tables and eliminated items that were rarely reported. Investigators used the resulting versions of the evidence tables to prepare the text of the report and selected summary tables.

Data Entry and Quality Control

Initial data were abstracted by investigators and entered directly into Web-based data collection forms using; SRS^® 3.0 (TrialStat! Corporation, Ottawa, Ontario, Canada). After a second reviewer reviewed data, adjudicated data were re-entered into Web-based data collection forms by the second reviewer. Second reviewers were generally more experienced members of the research team, and one of their main priorities was to check the quality and consistency of the first reviewers' answers. In addition to the second reviewers checking the consistency and accuracy of the first reviewers, a senior investigator examined all reviews to identify problems with the data abstraction. If problems were recognized in a reviewer's data abstraction, the problems were discussed at a meeting with the reviewers. In addition, research assistants used a system of random data checks to assure data abstraction accuracy.

Grading of the Evidence

At the completion of our review, we graded the quantity, quality and consistency of the best available evidence addressing Key Questions 1 and 3 by adapting an evidence grading scheme recommended by the GRADE Working Group.⁶³ We applied evidence grades to bodies of evidence on each type of nutrient for each major type of outcome. We considered the strength of the study designs with randomized controlled trials considered best, followed by non-randomized controlled trials, observational studies, and case reports. We considered at least two randomized controlled trials reporting on a specific outcome to constitute a body of evidence pertaining to that outcome. If an outcome was evaluated by at least two randomized controlled trials as well as observational studies and case reports, our evidence grade was based only on the randomized controlled trials evaluating that outcome. If an outcome was evaluated by one or no randomized controlled trials, our evidence grade was based on the single randomized controlled trial in addition to the best available non-randomized controlled trial or the best available observational studies (cohort studies considered best, followed by cross-sectional studies and studies with pre-post observational design). We reported the number of studies within the category of best available evidence to assess the quantity of evidence. We also assessed the quality and consistency of the best available evidence, including assessment of limitations to individual study quality (using individual quality scores), certainty regarding the directness of the observed effects in studies, precision and strength of findings, and availability (or lack thereof) of data to answer the Key Question. We classified evidence bodies pertaining to each Key Question into four basic categories: (1) “high” grade (indicating confidence that further research is very unlikely to change our confidence in the estimated effect in the abstracted literature); (2) “moderate” grade (indicating that further research is likely to have an important impact on our confidence in the estimates of effects and may change the estimates in the abstracted literature); (3) “low” grade (indicating further research is very likely to have an important impact on confidence in the estimates of effects and is likely to change the estimates in the abstracted literature); and 4) “very low” grade (indicating any estimate of effect is very uncertain).

Peer Review

Throughout the project, feedback was sought from the technical experts through ad hoc and formal requests for guidance. A draft of the completed report was sent to the technical experts and peer reviewers, as well as to the representatives of the NIH and AHRQ. In response to the comments of the technical experts and peer reviewers, revisions were made to the evidence report, and a summary of the comments and their disposition has been submitted to AHRQ.

Overall Results of the Literature Search

Figure 2

Key Question 1

What is the Efficacy Determined in Randomized Controlled Trials of Multivitamin/mineral Supplement Use (Defined as 3 or More Vitamins and/or Minerals Without Herbs, Hormones, or Drugs), Each at a Dose Less Than the UL Determined by the Food and Nutrition Board, in the General Adult Population for Prevention Against the Development of one or More Chronic Diseases or Conditions?

Results of literature search for Key Question 1

Table 1

Number of articles by key questions and disease categories (more...)

Table 1

Number of articles by key questions and disease categories

			KQ 3 (N= 44)							KQ 4 (N = 24)
	KQ 1(N = 11)	KQ 2(N = 10)	β-carotene (N = 20)	Vitamin A (N = 7)	Vitamin E (N = 12)	Vitamin B2 and niacin (N = 3)	Selenium (N = 6)	Vitamin D/ calcium (systematic reviews) (N= 6)	Vitamin D/ calcium (RCTs) (N=5)	β-carotene (N= 13)	Vitamin E (N = 7)	Other nutrients (N = 6)
Cancer	2		14	2	8	1	5		1
Cardiovascular disease	2		10	2	4	1	2
Cataract	4		1	1	2	1
Age-related macular degeneration	2				1
Bone mineral densisty								3	2
Fracture prevention								5	1
Total mortality	4		3	2	4	1	1			5	3	1
Hospitalization		2									1
General illness		1								4	4	2
Yellowing of skin		5								4
Anemia		1								1	1
Genitourinary		1
Circulation		1								2	1
Gastrointestinal		3								1	4	1
Cardiovascular		2								2	2	1
Renal		1										2
Psychiatric										1

Numbers within the table may exceed total numbers in each category; nutrients may have more than one effect.

KQ = key question; Other nutrients include: Vitamin B2, selenium, zinc, and niacin

Our literature search identified 11 articles from randomized controlled trials that addressed the efficacy of multivitamin/mineral supplements in the primary prevention of cancer, cardiovascular disease, cataract and age-related macular degeneration. Data for other diseases were lacking (Table 1). These studies used designed vitamin/mineral combinations, but not the one-a-day type of multivitamin supplements available on the United States market.

The 11 articles documented results from 5 randomized controlled trials published from 1993 to 2005, including (1) the Linxian General Population Trial in China,^{64 65 66 67 68}, (2) the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study in France,^{69 70} (3) the Multi-center Ophthalmic and Nutritional Eye-Related Macular Degeneration Study (MONMD) in United States veterans,⁷¹ (4) the Roche European American Cataract Trial (REACT) in the United States and United Kingdom,⁷² and (5) the Age-Related Eye Disease Study (AREDS) in the United States.⁷³

Similarity and heterogeneity in study design among trials

Table 2

Summary of randomized controlled trials on multivitamin/mineral (more...)

Table 2

Summary of randomized controlled trials on multivitamin/mineral supplements and chronic disease prevention

Study name/ Study design	Study Site/ year	Sample Size	Characteristics of Study Population	Study design Randomized groups	Doses (RDA)	Supplementation Period	Self-selected supplement use	Statistically significant and statistically non-significant findings, RR (95% CI) Comment
Linxian General Population Trial 6466	Linxian, China	29,584	age 44–60	Groups of placebo, AB, AC, AD, BC, BD, CD, ABCD where	≈1–2 x RDAs	5.25 years	Not reported	SIGNIFICANT:
Fractional factorial trial	1986-91		55% women	A: Retinol palmitate 10,000 IU + Zinc oxide 45 mg,			(Prior supplement users were ineligible for trial enrollment)	(1) In the groups receiving β-carotene, vitamin E and selenium: gastric cancer incidence 0.84 (0.71–1.00), Cancer mortality 0.87 (0.75–1.00), stomach cancer mortality 0.79 (0.64–0.99), total mortality 0.91 (0.84–0.99)
			nutritionally deprived	B: Riboflavin 5.2 mg + Niacin 40 mg,				(2) in the groups receiving retinol and zinc: non-cardia stomach cancer mortality 0.59 (0.37–0.93)
			low intake of fresh fruits, meat, and other animal products	C: Ascorbic acid 180 mg + Molybdenum Yeast complex 30 µg,				(3) in the groups receiving retinol, zinc, β-carotene, vitamin E and selenium: Stroke death 0.71 (0.50–1.00)
			low circulating levels of micro-nutrients, but overt clinical deficiencies were not common	D: β-carotene 15 mg + Selenium yeast 50 µg + α-tocopherol 60 mg				NON-SIGNIFICANT:
								(1) No effects of A, B, or C on: Total mortality, stroke death, esophageal cancer mortality, esophageal/ gastric cardia mortality, gastric cancer mortality, cancer mortality, total cancer incidence, gastric cancer incidence, esophageal cancer incidence, esophageal/ gastric cardia cancer incidence
								(2) No effect of D on: Stroke death, esophageal cancer mortality, esophageal/ gastric cardia mortality, total cancer incidence, esophageal cancer incidence, esophageal/ gastric cardia cancer incidence
								(3) no effects of AB, AC, AD, BC, BD, CD, or ABCD on: Stroke deaths (except for AD group), total mortality
Linxian General Population Trial - end-of-trial endo-scopy survey68	Linxian, China	391	Mean age: 53	Groups of placebo, AB, AC, AD, BC, BD, CD, ABCD where	≈1–2 x RDAs	Endo-scopy done at the end of the trial	Not reported	SIGNIFICANT;
	1991		45% women	A: Retinol palmitate 10000 IU + Zinc oxide 45 mg,				None
			younger, more men, more smokers, more alcohol use compared to the total trial participants	B: Riboflavin 5.2 mg + Niacin 40 mg,				NON-SIGNIFICANT:
				C: Ascorbic acid 180 mg + Molybdenum Yeast complex 30 µg,				No effects of A, B, C, or D on: Dysplasia and cancer in the esophagus and stomach cancer in the esophagus and stomach
				D: β-carotene 15 mg + Selenium yeast 50 µg + α-tocopherol 60 mg				COMMENT:
								Overall prevalence of dysplasia and cancer was extraordinarily high, 15%. Small sample size.
Linxian General Population Trial - end-of trial cataract study65	Linxian, China	5,390	age 45–74	Groups of placebo, AB, AC, AD, BC, BD, CD, ABCD where	≈1–2 x RDAs	Eye exams done at the end of the trial	Not reported	SIGNIFICANT:
	1985-91		55% women	A: Retinol palmitate 10000 IU + Zinc oxide 45 mg,			(Prior supplement users were ineligible for trial enrollment)	(1) in the groups receiving riboflavin and niacin: prevalence of nuclear cataract in those aged 65–74, OR (95% CI) = 0.45 (0.31–0.46)
				B: Riboflavin 5.2 mg + Niacin 40 mg,				(2) in the groups receiving riboflavin and niacin: prevalence of posterior subcapsular cataract in those aged 45–74, OR (95% CI) = 2.64 (1.31–5.35)
				C: Ascorbic acid 180 mg + Molybdenum Yeast complex 30 µg,				NON-SIGNIFICANT:
				D: β-carotene 15 mg + Selenium yeast 50 µg + α-tocopherol 60 mg				(1) no effects of A, C, or D on the prevalence of nuclear cataract, cortical cataract, and posterior subcapsular cataract
								(2) no effects of B on the prevalence of nuclear cataract In those aged 55–64
SU.VI.MAX69,70	France	12741	62% women	Vit C 120mg+ vit E 30mg+ β-carotene 6mg+ selenium 100µg+ zinc 20mg	≈ 1–2 x RDAs	7.5 years	Not reported	SIGNIFICANT:
Parallel-arm design	1994-2002		Mean(SD) age:	vs. Placebo	(vitamin E: chemical forms not specified)		(Regular users of any of the vitamins and minerals provided in the study were ineligible for trial enrollment.)	Men: total cancer incidence 0.69 (0.53–0.91) total mortality 0.63 (0.42–0.93) prostate cancer in men with PSA<3 µg/L 0.52 (0.2–-0.92)
			women: 46.6 (6.6);
			men: 51.3 (4.7)
		5141 (men)	Mean (SD) age:			8 years		NON-SIGNIFICANT:
			51.3 (4.6)					Men & women: Ischemic cardio-vascular disease
								Women: cancer incidence, total mortality
								Men: Prostate cancer for those with PSA ≥ 3 µg/L or the subgroups by age, smoking, BMI, and serum levels of β-carotene, vitamin C, α-tocopherol, selenium, and zinc no effect on circulating PSA and IGF levels
								COMMENT:
								Well-designed
								Men had lower serum levels of β-carotene and vitamin C at baseline.
								Cardiovascular events in women were only 22.6% of the events in men.
								Information on prior or concomitant supplement use was not reported.
REACT72	US UK	297	Mean (SD) age:	β-carotene 18mg + vit C 750mg + all-rac α-tocopherol acetate 600 mg, 3 divided doses per day	Vit C: 10x RDA for women	3 years	Not reported	SIGNIFICANT:
Parallel-arm design	1990-1995		UK: 67.55 (8.47)	vs. Placebo	≈8x RDA for men		(Regular users of any vitamin supplement were ineligible for trial enrollment.)	Anterior % pixel opaque (primary endpoint):
			US: 64.2 (8.49)		all-rac α-toco-pherol acetate: 40x RDA			Mean (95% CI) Placebo: baseline 5.0 (1.4), last 8.3 (2.2),
								Mean change from baseline: 3.3 (1.4);
								Supplement: baseline 5.7 (1.6), last 7.3(2.0),
								Mean change from baseline: 1.7 (1.0);
								Difference from placebo: -1.6 (p=0.048)
								NON-SIGNIFICANT:
								Retro data posterior % pixel opaque (secondary endpoint):
								Retro data posterior % pixels opaque, retro data anterior pupil diameter, retro data posterior pupil diameter, nuclear color, nuclear cataract, posterior subcapsular cataract, cortical cataract
								COMMENT:
								After 3 years, the positive effects were greater in the U.S. group (% pixel opaque = 0.389 vs. 2.517 in the vitamin vs. placebo group, p=0.0001), but not the UK group
AREDS - cataract73	U.S. (11- center trial)	4596	Median age: 56	β-carotene 15 mg + vit C 500 mg + vit E 400 IU	Vit C: 6.6x RDA	6.3 years	55% of trial participants who had prior vitamin/mineral supplement use were enrolled and supplied with Centrum.	SIGNIFICANT:
Parallel-arm design	1992-2001			vs. Placebo	Vit E: chemical form not specified		Additionally, 13% of trial participants chose to take Centrum.	None
					Zinc: 10x RDA			NON-SIGNIFICANT:
								Total lens event, nuclear event, cortical event, posterior sub-capsular event, cataract surgery, severe lens event, loss of visual acuity, total mortality
								COMMENT:
								The study had the strengths in documenting key aspects of the study conduct, including details on withdrawal, compliance and dropout.
								The major limitations are the option of multivitamin use (66% of the study participants) and self-selected use of non-study supplements (20% of participants) that contain at least one of the study nutrients.
								Data on how the self-selected supplement use distributed across randomized groups and AMD categories were not reported.
AREDS - age-related macular degeneration75		3509	Median age: 69	Groups of placebo, A, B, C where				SIGNIFICANT:
2 by 2 factorial design				A: β-carotene 15 mg+ vit C 500 mg+ vit E 400 IU				(1) zinc vs. no zinc: Progression to advanced AMD (among participants in AMD categories 3&4), OR (99% CI) = 0.79 (0.62–0.99) Neovascular AMD OR (99% CI) = 0.76 (0.58–0.98)
				B: zinc 80 mg as zinc oxide + copper 2mg as cupric oxide				(2) zinc vs. placebo Progression to advanced AMD (among participants in AMD categories 3&4), OR (99% CI) = 0.71 (0.52–0.99)
				C: β-carotene 15 mg+ vit C 500 mg+ vit E 400 IU+ zinc 80 mg as zinc oxide + copper 2mg as cupric oxide				(3) Antioxidants + zinc vs. placebo: Progression to advanced AMD (among participants in AMD categories 3&4; 2&3&4), OR (99% CI) = 0.66 (0.47–0.91); 0.72 (0.52–0.98) Loss of visual acuity score of ≥15 letters from baseline(among participants in AMD categories 3&4), OR (99% CI) = 0.73 (0.54–0.99) Risk of neovascular AMD(among participants in AMD categories 3&4), OR (99% CI) = 0.62 (0.43–0.90)
								NON-SIGNIFICANT:
								(1) No effects of A or B on: Progression to advanced AMD (among participants in AMD categories 2&3&4) Loss of visual acuity score of ≥15 letters from baseline(among participants in AMD categories 3&4)
								(2) No effects of A, B, or C on: Loss of visual acuity score of >=15 letters from baseline (among participants in AMD categories 2&3&4) Central geographic atrophy(among those in AMD categories 3,4)
								(3) No effects of A on: Progression to advanced AMD (among participants in AMD categories 3&4) Neovascular AMD
MONMD71,74	U.S.	71	Veterans	β-carotene 20,000IU + vit E 200IU + vit C 750mg + citrus bioflavonoid complex 125mg+ quercitin 50 mg + rutin 50 mg+ biberry extract 5 mg+ zinc picolinate 12.5 mg+ selenium50mcg+ taurine 100mg+ N-acetyl cysteine 100 mg+ l-glutathione 5mg + vit B2 25mg+ Chromium 100 mcg	Vitamin E: 6.6x RDA	18 months	Not reported	SIGNIFICANT:
Parallel-arm design	1992-2001			vs. Placebo	Vit C: 10x RDA for women		(Persons who had vitamin use in the year prior to enrollment were ineligible.)	Distance acuity declined in the placebo group, but stable in the multivitamin group (p=0.03).
					8.3x RDA for men			The multivitamin group had better M print acuity and fewer number of scotoma in left eyes in the multivitamin group (p=0.07), which occurs after the 12th month.
					Zinc: 0.83xRDA			NON-SIGNIFICANT:
					Selenium: 0.71xRDA			No significant difference between randomized groups in refraction, metamorphopsia and LOCS II readings on nuclear color, nuclear opalescence, and posterior subcapsular opacities.
					Vit B2: ≈18xRDA			Unanticipated cortical cataractogenic effects for right eyes in the multivitamin group.
								COMMENT:
								Instruments used to measure cataract transparence were not the same over the study period and the examiners were not well instructed.

SU.VI.MAX = SUppléments en VItamines et Minéraux AntioXydants; REACT = Roche European American Cataract Trial; AREDS = Age-Related Eye Disease Study; ARMD = Age-Related Macular Degeneration; MONMD = Multicenter ophthalmic and nutritional age-related macular degeneration study

The Linxian trial was conducted in a Chinese population that was nutritionally inadequate whereas SU.VI.MAX was conducted in an apparently healthy French population. The Linxian trial and the REACT study excluded any vitamin use without specifying how recent the use was. The MONMD study excluded persons with supplement use during the year prior to enrollment. In contrast, AREDS provided Centrum^® to 66 percent of the study participants, in addition to study supplements, and SU.VI.MAX allowed use of supplements other than those under study. The Linxian trial and the SU.VI.MAX study used doses of 1–2 times RDAs. In contrast, MONMD used vitamins C and B2 at doses that were more than 10 times the RDAs; AREDS used high doses of vitamin E and zinc (10 times the RDA), and a moderate dose of vitamin C (6 times the RDA); REACT used a high dose of vitamin E. All trials employed a parallel-arm design except for the Linxian trial that used a fractional factorial design. A total of 47,289 individuals were included in this review section (Appendixes F, Evidence Tables 1a–1c; Table 2).

Study quality

Table 3

Assessment of the quality of randomized controlled (more...)

Table 3

Assessment of the quality of randomized controlled trials on the efficacy of multivitamin/mineral supplements and single nutrients in the prevention of chronic diseases and conditions

Author, year	Representativenessa		Bias and Confoundingb		Adherence and follow-upc		Statistical Analysisd		Conflict of Intereste
Multivitamin Studies, Cancer Prevention
Blot, 199364	Medium		Medium		Low		Low		Low
Wang, 199468	Medium		Medium		Medium		Medium		Low
Meyer, 200570	High		Medium		Low		High		Low
Hercberg, 200469	High		Medium		Medium		High		High
		Medium		Medium		Medium		Medium		Low
Multivitamin Studies, Cardiovascular disease prevention
Mark, 199866	Low		Low		Low		Medium		Low
Hercberg, 200469	High		Medium		Medium		High		High
		Medium		Medium		Low		High		Medium
Multivitamin Studies, Eye Disease Prevention
Sperduto, 199365	Medium		Medium		High		Medium		Low
Chylack, 200272	High		High		High		High		Low
AREDS, 2001a73	High		High		Medium		High		High
AREDS, 2001b75	High		High		High		High		High
Richer, 199674	Medium		Low		Medium		Low		Low
		High		Medium		Medium		Medium		Low
Vitamin A/ Beta-carotene Studies, Cancer Prevention
ATBC, 199497	High		Medium		Medium		High		Low
Albanes, 199698	Medium		Medium		Low		High		Low
Rautalahti, 199999	High		Medium		Medium		High		Low
Varis, 199890	High		Medium		Medium		High		Low
Omenn, 1996105	Medium		Medium		Low		High		Medium
Omenn, 199693	Medium		Medium		Medium		High		Low
Green, 199984	Medium		Medium		Low		High		Medium
Greenberg, 199685	Medium		Medium		Medium		High		High
Cook, 2000104	Medium		Medium		Medium		Medium		Medium
Frieling, 200086	Medium		Medium		Low		Medium		Medium
Hennekens, 199695	Medium		Medium		Low		Medium		Low
Lee, 199996	High		Medium		Medium		High		Medium
Blot, 199364	High		Medium		Medium		Medium		Low
		Medium		Medium		Medium		Medium		Low
Vitamin A/ Beta-carotene Studies, Cardiovascular Disease Prevention
Rapola, 1996106	High		Medium		Medium		High		Low
Leppalla, 2000107	High		Medium		Medium		High		Low
Omenn, 1996105	Medium		Medium		Low		High		Medium
Goodman, 200494	Medium		Medium		Medium		Medium		Medium
Greenberg, 199685	Medium		Medium		Medium		High		High
Liu, 1999108	Medium		Medium		Low		High		Medium
Hennekens, 199695	Medium		Medium		Low		Medium		Low
Lee, 199996	High		Medium		Medium		High		Medium
Mark, 199866	Low		Low		Low		Medium		Low
		63		60		57		76		46
Vitamin A/ Beta-carotene Studies, Eye Disease Prevention
Teikari, 1997109	High		Medium		Medium		Medium		Low
Sperduto, 199365	Medium		Medium		High		Medium		Low
		High		Medium		Medium		Medium		Low
Vitamin E Studies, Cancer Prevention
Varis, 199890	High		Medium		Medium		High		Low
Albanes, 199698	Low		Medium		Low		High		Low
Albanes, 2000102	High		Medium		Medium		High		Low
ATBC, 199497	High		Medium		Medium		High		Low
Rautalahti, 199999	High		Medium		Medium		High		Low
Heinonen, 1998101	High		Medium		Medium		High		Medium
Lee, 200587	High		Medium		Medium		High		High
		Medium		Medium		Medium		Medium		Low
Vitamin E Studies, Cardiovascular Disease Prevention
Rapola, 1996106	High		Medium		Medium		High		Low
Leppalla, 2000107
Lee, 200587	High		Medium		Medium		High		High
Lee, 199996	High		Medium		Medium		High		Medium
De Gaetano, 2001112	Medium		Medium		Medium		High		High
Sacco, 2003181	Medium		Medium		Low		High		High
		Medium		Low		Medium		High		Medium
Vitamin E Studies, Eye Disease Prevention
McNeil, 2004113	High		Medium		Medium		High		Medium
Teikari, 1997109	High		Medium		Medium		Medium		Low
		High		Medium		Medium		Medium		Low
Other Nutrients, Cancer Prevention
Clark, 1996133	Medium		Medium		Medium		High		Medium
Clark, 1998134	Medium		Medium		Low		Medium		Low
Reid, 2002135	Medium		Low		Low		Medium		Medium
Duffield-Lillico, 2002136	Medium		Low		Low		Medium		Low
Duffield-Lillico, 2002137	Medium		Low		Low		Medium		Low
Blot, 199364	High		Medium		Medium		Medium		Low
Yu, 1991139	Low		Low		Low		Low		Low
		Medium		Low		Low		Medium		Low
Other Nutrients, Cardiovascular Disease Prevention
Clark, 1996133	Medium		Medium		Medium		High		Medium
Mark, 199866	Low		High		Low		Medium		Low
Other Nutrients, Eye Disease Prevention
Sperduto, 199365	Medium		Medium		High		Medium		Low
		Medium		Medium		High		Medium		Low

For each study, we assigned a rating of high, medium or low quality for each domain of study quality based on whether the score for that domain was designated High (80–100%), Medium (50–79%), or Low (0–49%) quality.

a

Representativeness: Score was based on a total maximum score of 8 points. This included the authors' description of setting (2 points), details on inclusion and exclusion criteria (2 points), information on excluded or non-participating individuals (2 points), and description of key participant characteristics (2 points).

b

Bias and Confounding: Score was based on a total maximum score of 28 points. This included the authors' description of patient assignment (2 points), details on concealment (2 points), description of differences in patient characteristics between groups (2 points), reporting on prior supplement use (2 points), description of the differences between groups in the prior use of supplements (2 points), description of medication use during the study (2 points), details on blinding (2 points) and the success of blinding (2 points), confirmation of medical diagnoses by medical chart (2 points), independent interpretation of clinical outcomes (2 points), overall blinding (2 points), randomization of arms (2 points), detail of description of study supplements (2 points), and overall assessment of the adherence to study supplements (2 points).

c

Adherence and Follow-up: Score was based on a total maximum score of 12 points. This included the authors' description of flow of participants through each stage (2 points); patient adherence to study supplement use (2 points); description or identification of unintended cross-over between randomized groups (2 points); reporting (2 points) and description of withdrawals from the study (2 points), identifying if the study stopped earlier than planned (2 points).

d

Statistical Analysis: Score was based on a total maximum score of 12 points. This included the authors' description of statistical tests (2 points), how unintended cross-over (2 points) and loss-to-follow-up (2 points) was handled, reporting of primary endpoints (2 points), adjustment for confounders (2 points), reporting of statistical power (2 points).

e

Conflict of Interest: Score was based on a total maximum score of 2 points. This included the authors' description identifying the sources of funding (2 points).

Inclusion/exclusion criteria were clearly defined in most trials. Quality of these trials was good in terms of randomization, double masking, ascertainment of trial endpoints, adherence, and use of intention-to treat approach in statistical analyses. However, there was a lack of descriptions as to whether concealment of allocation sequence was done, and whether observers independently evaluated trial outcomes. There was a paucity of data on prior supplement use, concomitant supplement use, and medication use that may have had effects on the efficacy of study supplements. None of the trials reported success of blinding and the extent of unintended crossover. Only the AREDS and REACT studies provided information on numbers and reasons for withdrawals and percents of loss-to-follow-up (Table 3).

Cancer

The Linxian trial examined incidence of and mortality for all cancer, esophageal cancer, stomach cancer (cardia and noncardia), esophageal/gastric cardia, and other cancers.⁶⁴ After 5.25 years of follow up, no significant risk reduction by supplement use was observed for these endpoints. The only exceptions were the reductions in gastric cancer incidence (relative risk (RR) 0.84, 95% confidence interval (CI) (0.71–1.00)), cancer mortality (RR 0.87, 95% CI 0.75–1.00), especially stomach cancer mortality (RR 0.79, 95% CI 0.64–0.99) in the groups receiving β-carotene, vitamin E and selenium compared to the groups receiving other vitamin/mineral combinations,⁶⁴ and a lower non-cardia stomach cancer mortality in those receiving retinol and zinc (RR 0.59, 95% CI 0.37–0.93).⁶⁴ Reduction in cancer mortality was greater in women than in men and among those of age less than 55 years in this trial (RR 0.79, 95% CI 0.64–0.98) vs. RR 0.93, 95% CI 0.77–1.12), and (RR 0.71, 95% CI 0.55–0.92) vs. RR 0.94, 95% CI 0.80–1.11), respectively).⁶⁷ In the substudy where participants underwent endoscopy examination, there was no significant effect of β-carotene, vitamin E and selenium supplement use on worse overall diagnoses of esophageal and gastric cancer or combined cancer and dysplasia prevalence, although the odds ratios were in the protective direction ⁶⁸ (Appendixes F, Evidence Tables 1b–1e).

Figure 3. Relative risk (RR) of total cancer, gastric (more...)

   Figure 3. Relative risk (RR) of total cancer, gastric cancer and esophageal cancer incidence in relation to multivitamin/mineral supplement use

Figure 4. Relative risk (RR) of total cancer, gastric (more...)

   Figure 4. Relative risk (RR) of total cancer, gastric cancer and esophageal cancer mortality in relation to multivitamin/mineral supplement use

The SU.VI.MAX study reports no benefit on overall cancer incidence by the antioxidant supplement use in women (RR 1.04, 95% CI 0.85–1.29), but a 31 percent risk reduction (RR 0.69, 95% CI 0.53–0.91) in men.⁶⁹ As a result, there was a statistically significant interactive effect of sex and randomized group on total cancer incidence (p=.02). Women were younger than men in this trial, and generally had a healthier lifestyle as evident by higher serum β-carotene and vitamin C and fewer smokers. Among men, a moderate reduction in prostate cancer risk was observed in the antioxidant supplement group (RR 0.88, 95% CI 0.60–1.29). Further stratification analysis showed differential efficacy by baseline prostate specific antigen (PSA) level with a risk reduction among men with normal baseline PSA (≤3 μg/L) (hazard ratio (HR) 0.52, 95% CI 0.29–0.92), but not among men with elevated PSA (HR 1.54, 95% CI 0.87–2.72)⁷⁰ (Appendixes F, Evidence Table 1d, Figures 3 and 4).

Cardiovascular disease

The Linxian trial reported a non-significant lower risk of stroke mortality with the greatest risk reduction (RR 0.91, 95% CI 0.76–1.07) observed in those receiving β-carotene, selenium, and α-tocopherol with or without other study nutrients,⁶⁶ particularly in those receiving the combination of β-carotene, selenium, α-tocopherol, retinol and zinc (RR 0.71, 95% CI 0.50–1.00) as compared to the counterpart. There was no sex difference in the risk reduction. Hemorrhagic and ischemic stroke was not distinguished but other sources showed that approximately two-thirds of the strokes were ischemic in this population⁷⁶ (Appendixes F, Evidence Tables 1b–1e).

Figure 5. Relative risk (RR) of cardiovascular disease (more...)

   Figure 5. Relative risk (RR) of cardiovascular disease incidence in relation to multivitamin/mineral supplement use

In the SU.VI.MAX study, no significant difference in ischemic cardiovascular disease incidence was noted between randomized groups. There was no interaction between sex and randomized groups. The cardiovascular events in women were only 22.6 percent of the events in men⁶⁹ (Appendixes F, Evidence Table 1d, Figure 5).

Total mortality

Figure 6. Relative risk (RR) of all cause mortality (more...)

   Figure 6. Relative risk (RR) of all cause mortality in relation to multivitamin/ mineral supplement use

In the Linxian trial, total mortality was lower among those who received β-carotene, selenium, and vitamin E, but not other nutrient combinations (RR 0.91, 95% CI 0.84–0.99).⁶⁶ In the AREDS study, total mortality was 6 percent higher in the group receiving antioxidants compared to the group receiving no antioxidants, but the increase was not statistically significant.^{64, 73, 75} When limited to those participants with AMD categories 2, 3, and 4, total mortality was 19 percent and 13 percent lower in the groups receiving zinc alone or zinc combined with antioxidants respectively.⁷³ A sex difference in the relative risk for total mortality was documented in the SU.VI.MAX study (RR 0.63, 95% CI 0.42–0.93 in men and RR 1.03, 95% CI 0.64–1.63 in women)⁶⁹, but no sex or age differences were noted in the Linxian trial⁶⁷ In the REACT, 9 deaths occurred in the antioxidant group, whereas 3 deaths occurred in the placebo group. Further examination on the causes of death revealed that the deaths in the antioxidant group were due to esophagitis, sudden death, aneurysm, pulmonary fibrosis, cancer and coronary thrombosis (Appendix F, Evidence Table 1e, Figure 6).

Summary

Table 4

Grading of the quality of evidence of the efficacy (more...)

Table 4

Grading of the quality of evidence of the efficacy of multivitamins/minerals in the prevention of chronic disease

	Key Question 1 Efficacy of Multivitamins/minerals
	Cancer	CVD	Cataract	AMD
Quantity of Evidence:	2 (Linxian, SU.VI.MAX)	2 (Linxian, SU.VI.MAX)	4 (REACT, Linxian, AREDS, MONMD)	2 (AREDS, MONMD)
Number of studies
Total number of patients studied	42325 (12741+29584)	42325 (12741+29584)	10354 (297+4596+ 5390+71)	3580 (3509+71)
Quality and Consistency of Evidence:	4(RCTs)	4(RCTs)	4(RCTs)	4(RCTs)
Were study designs randomized trials (high quality), non-randomized controlled trials (medium quality), or observational studies (low quality)?
Did the studies have serious (-1) or very serious (-2) limitations in quality? (Enter 0 if none)	-1	-1	0	0
Did the studies have important inconsistency? (-1)	0	0	0	0
Was there some (-1) or major (-2) uncertainty about the directness or extent to which the people, interventions and outcomes are similar to those of interest?	-2	-2	-1	-1
Were data imprecise or sparse? (-1)	-1	-1	-1	-1
Did the studies have high probability of reporting bias? (-1)	0	0	0	0
Did the studies show strong evidence of association between intervention and recruitment outcome? (“strong” if significant relative risk or odds ratio > 2 based on consistent evidence from 2 or more studies with no plausible confounders (+1); “very strong” if significant relative risk or odds ratio > 5 based on direct evidence with no major threats to validity (+2))	0	0	0	0
Did the studies have evidence of a dose-response gradient? (+1)	0	0	0	0
Did the studies have unmeasured plausible confounders that most likely reduced the magnitude of the observed association? (+1)	+1	+1	0	0
Overall grade of evidence (high, medium, low, very low)	Very low	Very low	Low	Low

CVD = Cardiovascular disease; AMD = Age-related macular degeneration.

There is a paucity of data on the efficacy of multivitamin/mineral supplement use in the prevention of chronic disease in the general United States population. Limited data from the Linxian trial suggest 13 percent to 21 percent reductions in gastric cancer incidence, gastric cancer mortality, and cancer mortality by use of β-carotene, vitamin E and selenium supplements of doses 1 to 2 times RDAs. Results of total cancer incidence in the SU.VI.MAX trial in France were sex-dependent with a 31percent lower risk in men who received vitamin C, vitamin E, β-carotene, selenium, and zinc at doses near RDAs, but no risk reduction in women who appeared to have had higher fruit/vegetable intake. The antioxidants used in SU.VI.MAX did not confer benefit in preventing ischemic cardiovascular disease, whereas use of β-carotene, selenium, α-tocopherol, retinol, and zinc supplements in the Linxian trial had a moderate reduction (30%) in stroke mortality. Generalizability of these findings for the United States population is uncertain in view of the French paradox and the general nutritional inadequacy of the Linxian population. Multivitamin/mineral supplement use for 3 to 6 years had no significant benefits in preventing cataract. Zinc (of dose 10 times thhe RDA) alone or in combination with antioxidants had beneficial effects on AMD only in those with intermediate AMD in one or both eyes, or those with advanced AMD in one eye. Overall, the quality of individual articles was “medium” (Table 3). Taking into consideration the quantity, quality, and consistency of evidence, we concluded the strength of evidence on the efficacy of multivitamin/mineral supplementation was rated as “very low” for primary prevention of cancer and cardiovascular disease, and “low” for cataract and age-related macular degeneration (Table 4).

Key Question 2

What is Known About the Safety of Use of Multivitamin/mineral Supplements (As Defined In Key Question 1) in the General Population of Adults and Children, Based Primarily on Data From Randomized Controlled Trials and Observational Studies?

Key Question 3

What is the Efficacy Determined in Randomized Controlled Trials of Supplementation with Single Nutrients or Functionally Related Nutrient Pairs, Each at a Dose Less than the UL Determined by the Food and Nutrition Board, in the General Adult Population for Prevention Against the Development of One or More Chronic Diseases or Conditions

Our literature search identified data from randomized controlled trials that assessed the efficacy of β-carotene, vitamin A combined with β-carotene or zinc, vitamin E, folic acid with or without vitamin B12 or vitamin B6, selenium, and vitamin D with or without calcium in the primary prevention of cardiovascular disease, cancer, cataract, age-related macular degeneration, cognitive function, bone mineral density, falls or fractures. Using our search strategies, we did not identify data on the efficacy of vitamin C, iron, magnesium, vitamin B2, niacin, or calcium/magnesium supplement use in the primary prevention of chronic disease.

β-Carotene

Introduction

β-carotene is a major dietary carotenoid and the most abundant carotene found in nature. In the 1980s, several large clinical trials had been launched to determine the role of β-carotene in chronic disease prevention. The following section summarizes the evidence.

Results of the literature search

We identified 22 articles from randomized controlled trials that assessed the efficacy of β-carotene in the prevention of cancer, cardiovascular disease, diabetes mellitus, or age-related maculopathy. The 22 articles were published from 6 trials, the Alpha-tocopherol β-carotene Cancer Prevention Study (ATBC), the Βeta-Carotene and Retinol Efficacy Trial (CARET), the Nambour Skin Cancer Prevention Trial (NSCP), the Skin Cancer Prevention Study (SCP), the Physician's Health Study (PHS), and the Women's Health Study (WHS).⁸²–⁸⁷

Design of randomized controlled trials

The ATBC was a 2 by 2 factorial trial of synthetic all-rac-α-tocopherol acetate (50% powder, 50 mg per day) and synthetic β-carotene (10% water-soluble beadlets, 20 mg per day) supplementation in 29,133 Finnish smokers aged 50 to 69 years.⁸⁸ Users of vitamin E, vitamin A, and/or β-carotene in excess of predefined doses were excluded. The follow up period was 1985 to 1993. Post-intervention follow up of cancer incidence and cause-specific mortality was performed from 1993 to 1999 for cancer incidence and cause-specific mortality and up to 2001 for total mortality.⁸⁹ Gastrointestinal endoscopy was performed on 1,344 men with gastritis after a median supplementation time of 5.1 years⁹⁰ (Appendix F, Evidence Tables 3a–3c).

The CARET study consisted of two pilot studies conducted in 1985 to 1988 followed by a large trial conducted from 1988 to 1991 in the United States. The first pilot study, the Asbestos Workers Pilot Study for CARET, involved 816 men with a history of asbestos exposure. ⁹¹ The second pilot study, the Smokers Pilot Study, involved 1029 men and women with a history of cigarette smoking.⁹² The full CARET study was conducted in 18,314 high-risk men and women who had a history of asbestos exposure or smoking. Participants were randomly assigned to receive either β-carotene 50 mg and retinyl palmitate 25,000 IU per day or placebo. Prior β-carotene supplement users were excluded.⁹³ The follow up period was 1985 to 1995. Post-trial follow up of cancer incidence and mortality was performed until the end of 2001⁹⁴ (Appendix F, Evidence Tables 3a–3c).

The NSCP trial was a 2 by 2-factorial trial of β-carotene 30 mg per day and daily sunscreen among 1,621 adult Australians of age 20 to 69 years.⁸⁴ No exclusion or prior supplement use was reported. The follow up period was 1992 to 1996 (Appendix F, Evidence Tables 3a–3c).

The SCP was a trial with a parallel-arm design conducted in 1,729 adults of age 85 years or less who had at least one biopsy-proven basal cell or squamous cell skin cancer at baseline. Participants were randomized to receive placebo or β-carotene (50 mg per day) during the trial.⁸⁵ No exclusion or prior supplement use was reported. The follow up period was 1983 to 1993 (Appendix F, Evidence Tables 3a–3c).

The PHS was a 2 by 2 factorial trial of β-carotene (50 mg every other day) and aspirin conducted among 22,071 apparently healthy male physicians, aged 40–84 years, in the United States. Vitamin A supplement users were ineligible for trial enrollment. The follow-up period was 1982 to 1995 ⁹⁵ (Appendix F, Evidence Tables 3a–3c).

The WHS was a 2 by 2 by 2 factorial trial conducted in 39,876 female health professionals in the United States aged 45 years or older to determine whether alternate daily use of aspirin (100 mg), β-carotene (50 mg), and vitamin E (600 IU) can prevent cancer and cardiovascular disease.⁸⁷ β-carotene supplementation was terminated after a median treatment duration of 2.1 years (range 0 to 2.7 years), primarily because of the null findings from the PHS.⁹⁵ Users of vitamin A, β-carotene, or vitamin E were ineligible for trial enrollment. Nearly 40 percent of the trial participants reported to have multivitamin supplement use at baseline. The follow up period of this trial was 1992 to 2004 (Appendix F, Evidence Tables 3a–3c).

Similarity and heterogeneity in study design among trials

Except for the ATBC and NSCP that were conducted in Finland and Australia, respectively, the 4 other trials included in this review were conducted in the United States. Except for the SCP and NSCP, prior users of β-carotene and/or vitamin A supplements were excluded. The range of follow up was 4 to 10 years. The range of daily doses was 20 mg to 50 mg. The ATBC, PHS, WHS, and NSCP used a factorial design with α-tocopherol, aspirin, aspirin with/without vitamin E, and sunscreen, respectively, as the other intervention, whereas SCP and CARET adopted a parallel-arm study design. A total of 112,564 individuals were included in this review section. They were heterogeneous populations that ranged from high-risk people with a history of asbestos exposure and cigarette smoking (ATBC, CARET) to male physicians (PHS), female health professionals (WHS), and adults in a high sun exposure area in Australia (Appendix F, Evidence Tables 3a–3c).

Study quality

The general strengths of the randomized clinical trials were large sample size, double masking and randomization, high adherence to treatment, and ascertainment of clinical outcomes. Adherence was not reported in the CARET study, although β-carotene treatment was shown to raise the median serum β-carotene levels to 12 times the baseline levels.⁹³ The success of blinding the study was not reported in the NCSP,⁸⁴ WHS,⁹⁶ and SCP.⁸⁵ The study population was incompletely described in the SCP.⁸⁵ Most of these studies did not report on participants' prior use of supplements (Table 3).

Results

Table 5

Summary of randomized controlled trials on beta-carotene (more...)

Table 5

Summary of randomized controlled trials on beta-carotene and chronic disease

Study name/Design	Study site/ Year	Sample size	Study population (Age, sex, special characteristics)	Active supplements	Supplementation period	Self-selected supplement use	Statistically significant and statistically non-significant findings (list of diseases)
PHS86,95,104,108	USA/ 1982-1995	22071 95,104	Age range: 40–84	β-carotene 50 mg on alternate day	12.9 years 104 (mean)	Vitamin A supplement users were ineligible for trial enrollment.	STATISTICALLY SIGNIFICANT:
2 by 2 factorial trial of β-carotene and aspirin			100% men		12 years95 (mean)	23% used multivitamin supplements at baseline.	Bladder cancer
			US male physicians			6.4% of the placebo group reported taking β-carotene or vitamin A supplements during the trial.	(RR 1.5, 95% CI 1.0ndash;2.2)
						22% of theβ-carotene group stopped taking the study supplements before the end of the trial.	Thyroid cancer
							(RR 9.5, 95% CI 2.2–40.7)
							STATISTICALLY NON-SGINIFICANT:
							prostate cancer, colon cancer, rectal cancer, lung cancer, lymphoma, leukemia, melanoma, brain cancer, stomach cancer, pancreatic cancer, all cancer mortality, all cancer incidence, myocardial infarction, CVD death, all major CVD events
		21884 86			12 years (mean)		STATISTICALLY SIGNIFICANT:
							None
							STATISTICALLY NON-SIGNIFICANT:
							Non-melanoma skin cancer, basal cell carcinoma, squamous cell carcinoma
		21468 108			12 years (mean)		STATISTICALLY SIGNIFICANT:
							None
							STATISTICALLY NON-SIGNIFICANT:
							Type 2 Diabetes mellitus
WHS 87	USA	39876	Mean age: 54.6	β-carotene 50 mg on alternate day	2.1 years	Users of individual supplements of vitamin A, vitamin E, or β-carotene more than once per week were ineligible for trial enrollment.	STATISTICALLY SIGNIFICANT:
2 by 2 by 2 factorial trial of β-carotene, vitamin E and aspirin	Supplementation 1993-1996		100% women		β-carotene supplementation was terminated earlier than planned.	At the end of termination of the β-carotene component, 87% of the active group reported taking at least two thirds of the study capsules, and 9.9% of the placebo group reported taking β-carotene or vitamin A supplements outside the trial.	None
All data are from 2 post-trial follow-up studies	Follow-up 1993-1996		Female health care professionals		40% used multivitamin supplements outside the trial		STATISTICALLY NON-SIGNIFICANT:
							All cancers other than non-melanoma skin cancer, death from cancer, CVD incidence, total mortality, CVD mortality, myocardial infarction, stroke, all major CVD events
NSCP 84	Australia	809	Mean age: 48.8	β-carotene 30 mg per day	4.5 years	No reported	STATISTICALLY SIGNIFICANT:
2 by 2 factorial trial of sun screen and β-carotene	1992-1996		56.3% women				None
							STATISTICALLY NON-SIGNIFICANT:
							Basal-cell carcinoma, squamous-cell carcinoma
ATBC 90,98,101–103,106,107,109,99,100,110,	Finland	29133 99	Mean age: 57.7	β-carotene 20 mg per day	6.1 years	Users of vitamin A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20 mg, or 6 mg, respectively) were ineligible	STATISTICALLY SIGNIFICANT:
2 by 2 factorial trial of α-tocopherol and β-carotene	1984-1993		Age range: 50–69				None
			100% men				STATISTICALLY NON-SIGNIFICANT:
			Smokers (5 or more cigarettes per day)				Pancreatic cancer incidence, pancreatic cancer mortality
		1344 90	Mean age: 58.8		5.1 years (median)		STATISTICALLY SIGNIFICANT:
			100% men		Serum pepsinogen measured in 1989-91 and 1992-93		None
			Low serum pepsinogen;				STATISTICALLY NON-SIGNIFICANT:
			Smokers (5 or more cigarettes per day)				Gastric dysplasia, carcinoma, carcinoid
		1828 109	Mean age:		6.6–6.7 years		STATISTICALLY SIGNIFICANT:
			64.5–65.1 years		Ophthalmology exam performed in Nov 1992-March 1993		None
			100% men				STATISTICALLY NON-SIGNIFICANT:
			Smokers (5 or more cigarettes per day)				Nuclear cataract, cortical cataract, posterior subcapsular cataract, cataract severit
		941 110	Age 65 or older		Ophthalmology exam performed in Dec 1992-March 1993		STATISTICALLY SIGNIFICANT:
			100% men				None
			Smokers (5 or more cigarettes per day)				STATISTICALLY NON-SIGNIFICANT:
							Age-related maculopathy
		29133 98	Age range: 50–69, 100% men; Smokers (5 or more cigarettes per day)	β-carotene 20 mg per day	6.1 years	Users of vitamin A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20 mg, or 6 mg, respectively) were ineligible	STATISTICALLY SIGNIFICANT:
			Stratified by baseline data				Lung cancer
							(RR 1.16, 95% CI 1.02–1.33) for the total group,
							(RR 1.39, 95% CI 1.03–1.88) in those aged 65–69;
							(RR 1.25, 95% CI 1.07–1.46) in those smoker 20+ cigarettes/day;
							(RR 1.23, 95% CI 1.04–1.47) in those who always inhale cigarette smoke;
							(RR 1.17, 95% CI 1.03–1.34) in those exposed to asbestos;
							(RR 1.40, 95% CI 1.10–1.78) in those with dietary intake <8.1 mg/d;
							(RR 1.35, 95% CI 1.01–1.81) in those drank ethanol >11 g/d;
							RR (1.33, 95% CI 1.01–1.73) in those with baseline serum α-tocopherol 11.6–13.1 mg/L
							STATISTICALLY NON-SIGNIFICANT:
							Lung cancer in the counterparts of the subgroups described in the left column.
							Lung cancer in the subgroups defined by baseline dietary β-carotene, vitamin C, or retinol, and by serum β-carotene or retinol.
		22269 106	Median age: 56.9, 100% men	β-carotene 20 mg per day	4.7 years (median)	Users of vitamin A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20 mg, or 6 mg, respectively) were ineligible	STATISTICALLY SIGNIFICANT:
			Smokers (5 or more cigarettes per day)				None
			With no history of angina				STATISTICALLY NON-SIGNIFICANT:
							Incidence of angina pectoris
		29133 97	Mean age: 57.2		6.1 years (median)		STATISTICALLY SIGNIFICANT:
			100% men				Lung cancer incidence (RR 1.18, 95% CI 1.03–1.36);
			Smokers (5 or more cigarettes per day)				lung cancer mortality (RR 1.08, 95% CI 1.01–1.16)
		28519 107	Mean age: 57.7		6 years (median)		STATISTICALLY SIGNIFICANT:
			100% men				Intracerebral hemorrhage (RR 1.62, 95% CI 1.10–2.36)
			Smokers (5 or more cigarettes per day)				STATISTICALLY NON-SIGNIFICANT:
			With no history of stroke				Incidence of all strokes, sub-arachnoid hemorrhage, and cerebral infarction.
							Mortality of subarachoid hemorrhagic stroke, intracerebral hemorrhagic stroke, cerebral infarction, all strokes
		29133102	Mean age: 57.1	β-carotene 20 mg per day	6 years (mean)	Users of vitamin A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20 mg, or 6 mg, respectively) were ineligible	STATISTICALLY SIGNIFICANT:
			100% men				None
			Smokers (5 or more cigarettes per day)				STATISTICALLY NON-SIGNIFICANT:
							Colorectal cancer
		29133101					STATISTICALLY SIGNIFICANT:
							None
							STATISTICALLY NON-SIGNIFICANT:
							Prostate cancer incidence, prostate cancer mortality
		15618 100	Mean age: 57.0		6.3 years (mean)		STATISTICALLY SIGNIFICANT:
			100% men				None
			Smokers (5 or more cigarettes per day)				STATISTICALLY NON-SIGNIFICANT:
							Colorectal adenoma
		Post-trial follow up	Age range: 50–69, 100% men	No study supplement use during post-trial follow up	6 years for cancer incidence and cause-specific mortality		STATISTICALLY SIGNIFICANT:
		29133103	Smokers (5 or more cigarettes per day)		8 years for total mortality		Colorectal cancer 3 to 6 years after trial (RR 1.88, 95% CI 1.28–2.76)
							Total mortality (RR 1.07, 95% CI 1.02–1.12)
							STATISTICALLY NON-SIGNIFICANT:
							Lung cancer, prostate cancer, total mortality, urothelial cancer, stomach cancer, kidney cancer, pancreatic cancer, other cancers, coronary heart disease mortality, hemorrhagic stroke mortality, non-hemorrhagic stroke mortality
SCP85	United States 1983-1993	1720	Mean age: 63.2	β-carotene 50 mg /day	Median supplementation: 4.3 yrs	No exclusion was made on supplement use	STATISTICALLY SIGNIFICANT:
Parallel- arm design			31% women		Follow up: 8.2 years		None
							STATISTICALLY NON-SIGNIFICANT:
							All deaths, cardiovascular deaths, cancer deaths
CARET 93,105,183	Seattle, WA; Portland, OR; San Francisco, CA; Baltimore, MD; New Haven CT; Irvine, CA.	18314 105	Mean age:58	Retinyl palmitate 25000 IU + beta-carotene 30 mg	4 years (mean)	Participants agreed to have Vitamin A intake<5500 IU/day, and to not use beta-carotene supplements	STATISTICALLY SIGNIFICANT:
Parallel-arm design	Pilot study 1983-1988		34.3% women	Retinol in pilot phase (1985-1988) then retinyl palmitate (1988-1996)			Lung cancer (RR 1.36, 95% CI 1.07–1.73),
	Main study 1985-1996		smokers or asbestos workers				Lung cancer mortality (RR 1.59, 95% CI 1.13–2.23) from weighted analysis
							STATISTICALLY NON-SIGNIFICANT:
							Leukemia (p=0.06), mesothelioma, breast cancer, colorectal cancer, head/neck cancer, lymphoma, prostate cancer, bladder cancer
		1831493					STATISTICALLY SIGNIFICANT:
							Lung Cancer (RR 1.29, 95% CI 1.04–1.57),
							Total mortality (RR 1.17, 95% CI 1.03–1.33),
							Lung cancer death (RR 1.46, 95% CI 1.07–2.00)
							STATISTICALLY NON-SIGNIFICANT:
							Mesothelioma, cardiovascular death, prostate cancer
		17140 184	Mean age: 62, 35% women	None	Post-trial follow up (6 years)	Participants were asked to stopped taking the study supplements in 1996	STATISTICALLY SIGNIFICANT:
		year 1996-2001					Lung cancer mortality (RR 1.20, 95% CI 1.01–1.43)
							Lung cancer, all cause mortality, cardiovascular mortality,
							Lung cancer (RR 1.12, 95% CI 0.97–1.31) total mortality (RR 1.08, 95% CI 0.99–1.17)

PHS (Physicians Health Study); WHS (Women's Health Study); NS (Not Specified); ATBC (Alpha-Tocopherol, Beta Carotene Cancer Prevention Trial); CARET (Beta Carotene and Retinol Efficacy Trial).

Cancer. In the ATBC study, compared to those who did not receive β-carotene, participants receiving β-carotene had a higher lung cancer incidence and lung cancer mortality (RR 1.18, 95% CI 1.03–1.36; RR 1.08, 95% CI 1.01–1.16, respectively),^{97, 98} but no increased risk for gastric cancer,⁹⁰ pancreatic cancer,⁹⁹ colorectal adenomas,¹⁰⁰ prostate cancer ¹⁰¹ or colorectal cancer ¹⁰² In the 6-year post-trial follow up, the relative risk of lung cancer was 1.06 (95% CI 0.94–1.20) for β-carotene recipients versus non-recipients. The supplementation had a late effect on colorectal cancer (RR 1.88; 95% CI 1.28–2.76) 4 years after the end of supplementation, but no late effect on other cancer outcomes.¹⁰³ (Appendix F, Evidence Tables 3b–3e, Table 5).

In the PHS, β-carotene supplementation increased the risk of thyroid cancer (RR 9.5, 95% CI 2.2–40.7), and bladder cancer (RR 1.5, 95% CI 1.0–2.2), but had no effect on other malignant neoplasms^{95, 104} or non-melanoma skin cancer⁸⁶ (Appendix F, Evidence Table 3d, Table 5).

In the CARET study, the combination of β-carotene and vitamin A supplementation increased the incidence of lung cancer (RR 1.28, 95% CI 1.04–1.57)^{93, 105} and the effects persisted 6 years after the trial terminated, especially among women.⁹⁴ β-carotene supplementation had no effects on cancers such as leukemia, mesothelioma, bladder cancer, breast cancer, prostate cancer, colorectal cancer, head and neck cancer, or lymphoma¹⁰⁵ (Appendix F, Evidence Table 3d, Table 5).

In the SCP, β-carotene supplementation had no effect on cancer deaths⁸⁵ (Appendix F, Evidence Table 3d, Table 5).

In the WHS, β-carotene supplementation had no impact on the incidence of cancer⁹⁶ (Appendix F, Evidence Table 3d, Table 5).

In the NSCP trial, β-carotene supplementation had no impact upon the incidence of basal cell carcinoma or squamous cell carcinoma after 4 years of follow up⁸⁴ (Appendix F, Evidence Table 3d, Table 5).

Cardiovascular disease. The ATBC study participants who received β-carotene had a non-significant higher incidence of angina and stroke mortality during the trial,^{106, 107} and had higher mortality for a wide spectrum of cardiovascular disease during the post-trial follow up¹⁰³ (Appendix F, Evidence Table 3d, Table 5).

Participants receiving β-carotene and vitamin A in CARET had a non-significant increased risk of cardiovascular death after a mean follow up of 4 years (RR 1.26, 95% CI 0.99–1.61),⁹³ but the risk was lower (RR 1.02) 6 years after supplementation was terminated.⁹⁴

Participants in the WHS study had a non-significant higher risk for stroke (RR 1.42, 95% CI 0.96–2.10), but lower risk for myocardial infarction (RR 0.84, 95% CI 0.56–1.27)⁹⁶ (Appendix F, Evidence Table 3d, Table 5).

In the PHS, β-carotene supplementation had no effects on incidence of type 2 diabetes mellitus,¹⁰⁸ incidence of myocardial infarction, stroke and all important cardiovascular events, or cardiovascular mortality⁹⁵ (Appendix F, Evidence Table 3d, Table 5).

Cataract and age-related macular degeneration. In the ATBC trial, β-carotene supplementation had no effect on age-related cataract or age-related maculopathy^{109, 110} (Appendix F, Evidence Table 3d, Table 5).

Total mortality. β-carotene supplementation was associated with an 8 percent, 7 percent, and 5 percent increased risk of total mortality in the ATBC, WHS and SCP studies, respectively.^{85, 96, 97} Only the increase in the ATBC trial reached statistical significance (p=0.02). In the post-trial follow up on total mortality (8 years of follow up) of the ATBC trial, the relative risk of total mortality in the groups receiving β-carotene compared to the corresponding placebo groups was 1.07 (95% CI 1.02–1.12)¹⁰³ (Appendix F, Evidence Table 3e, Table 5).

Summary

Table 6

Grading of the quality of evidence of the efficacy (more...)

Table 6

Grading of the quality of evidence of the efficacy of single nutrients in the prevention of chronic disease

	Key Question 3 Efficacy of single nutrients and related pairs
	Vitamin E (alone)				Selenium	Beta-carotene				Calcium		Vitamin D		Vitamin D + calcium
	CVD	Cancer	Cataract	Total mortality	Cancer	Cancer	CVD	Cataract	Total mortality	BMD	Fracture	BMD	Fracture	BMD	Fracture
Quality and Consistency of Evidence:	High	High	High	High	High	High		High		4	4	4	4	4	4
Were study designs randomized trials (high quality), non-randomized controlled trials (medium quality), or observational studies (low quality)?
Did the studies have serious (-1) or very serious (-2) limitations in quality? (Enter 0 if none)	-1	-1	0	-1	0	0		-1		-2	-1	-1	-1	0	0
Did the studies have important inconsistency? (-1)	0	-1	0	0	0	-1		0		-1	-1	-1	-1	0	0
Was there some (-1) or major (-2) uncertainty about the directness or extent to which the people, interventions and outcomes are similar to those of interest?	-1	-1	0	-1	-2	0		-2		0	0	0	0	0	0
Were data imprecise or sparse? (-1)	0	0	-1	0	-1	0		-1		0	-1	0	0	0	0
Did the studies have high probability of reporting bias? (-1)	0	0	0	0	0	0		0		0	0	0	0	0	0
Did the studies show strong evidence of association between intervention and recruitment outcome? (“strong” if significant relative risk or odds ratio > 2 based on consistent evidence from 2 or more studies with no plausible confounders (+1); “very strong” if significant relative risk or odds ratio > 5 based on direct evidence with no major threats to validity (+2))	0	0	0	0	2	0		0		+1	0	0	0	0	0
Did the studies have evidence of a dose-response gradient? (+1)	0	0	0	0	0	0		0		0	0	0	0	0	0
Did the studies have unmeasured plausible confounders that most likely reduced the magnitude of the observed association? (+1)	0	0	0	0	0	0		0		0	0	0	0	1	0
Overall grade of evidence (high, medium, low, very low)	Low	Very low	Moderate	Low	Low	Moderate		Very low		Low	Very Low	Low	Low	High	High

CVD = Cardiovascular disease; BMD = bone mineral density

In summary, β-carotene was associated with increased risk of lung cancer incidence and mortality in persons who were heavy smokers or who were regularly exposed to asbestos. β-carotene supplementation did not reduce risk of other chronic disease outcomes, including cardiovascular disease, diabetes mellitus, cataract, and maculopathy. Taking into consideration the quantity, quality, and consistency of evidence, we concluded that the overall strength of evidence regarding the effects of β-carotene on the incidence of cancer and cardiovascular disease was “moderate” and on the prevalence of cataract or age-related maculopathy was “very low” (Table 6).

Vitamin E

Introduction

Vitamin E is the second most commonly used dietary supplement in the United States.¹ The following section reviews the evidence on the efficacy of vitamin E supplementation in the prevention of chronic disease.

Results of literature search

Our literature search identified 16 articles (including articles containing post-trial data) that provided evidence on the efficacy of vitamin E supplements in the prevention of chronic disease. These articles were generated from 4 randomized controlled trials, the ATBC trial, the WHS, the Primary Prevention Project (PPP), and the Vitamin E, Cataract, and Age-Related Maculopathy Trial (VECAT). The predominant source of evidence (from 12 articles, including articles containing post-trial data) on this topic stems from the ATBC trial.

Design of randomized controlled trials

The designs of the ATBC trial and the WHS were described in a previous section of the Results chapter, Design of Randomized Controlled Trials, on β-carotene (Appendix F, Evidence Tables 3f–3h).

The PPP was a randomized controlled, open-labeled, 2 by 2 factorial trial designed to investigate the efficacy of vitamin E (synthetic, 300 IU per day) and aspirin (100 mg per day) for cardiovascular disease prevention.¹¹² Participants were 4,495 men and women age 50 years or older with at least one of the major well-accepted risk factors for cardiovascular disease. Long-term vitamin E users were ineligible. At the end of the trial, the percent of participants lost to follow up was 13.6 percent in the vitamin E group. (Appendix F, Evidence Tables 3f–3h).

The VECAT was designed to evaluate whether daily vitamin E supplements reduced the risk of age-related cataracts in 1,193 Australians who were 55 to 80 years old upon entry into the study and who had early or no cataract. Trial participants were randomized to receive 500 IU per day of natural vitamin E or placebo for 4 years. Approximately 27 percent of the trial participants had prior supplement use. The percent of participants lost to follow up was 25 percent, and among those who were retained in the trial, 12 percent ceased taking study supplements¹¹³ (Appendix F, Evidence Tables 3f–3h).

Similarity and heterogeneity among trials

The participants in these trials had distinct characteristics, being female health professionals in the United States (WHS), male smokers in Finland (ATBC), or Italians who might have followed a Mediterranean diet (PPP). A total of 74,697 individuals were included in these trials with 87 percent being ATBC or WHS participants. Accordingly, approximately 27 percent of these trial participants were assigned to also take aspirin and 20 percent were assigned to also take β-carotene supplements. Vitamin E supplements used in these studies included synthetic form, natural source, and natural vitamin E at doses ranging from 50 IU per day in synthetic form to 600 IU per day of natural source (Appendix F, Evidence Tables 3f–3h).

Study quality

Inclusion/exclusion criteria were clearly defined in most trials. The quality of these trials was good with respect to randomization, double masking, ascertainment of trial endpoints, adherence, and use of an intention-to treat approach in statistical analyses (see Table 3, Assessment of Quality of Studies). There was a lack of descriptions as to whether concealment of allocation sequence was performed and whether there was an unintended crossover. The WHS and PPP trials collected data on lifestyle factors and medication use. None of the trials reported success of blinding and the extent of unintended crossover. Most trials provided no information on numbers and reasons for withdrawals and percent lost to follow up.

Results.

Cancer. In the ATBC trial, synthetic α-tocopherol of 50 IU per day had no benefit on the incidence of lung cancer and gastric neoplasm,^{90, 98} lung cancer mortality, or pancreatic cancer mortality,^{97, 99} but increased colorectal adenoma incidence (RR 1.66, 95% CI 1.19–2.32)¹⁰⁰. Questions have been raised whether the finding on colorectal adenoma was due to increased rectal bleeding by α-tocopherol supplementation, leading to the increased diagnosis of polyps. In contrast to these findings, men who received α-tocopherol supplements had a non-significant protective effect on colorectal cancer development (RR 0.78, 95% CI 0.55–1.09)¹⁰² and had a 32 percent and 41 percent reduction in the incidence of, and the mortality from prostate cancer respectively.¹⁰¹ The reduction was evident for clinical prostate cancer but not for latent cancer. In the post-trial follow up, the protective effect of α-tocopherol against prostate cancer was attenuated (RR 0.88, 95% CI 0.76–1.03). The moderate protective effects of α-tocopherol on colorectal cancer during the trial was no longer evident in the 6-year post-trial follow up, and α-tocopherol had no late effects on other cancers.¹⁰³

Table 7

Summary of randomized controlled trials on vitamin (more...)

Table 7

Summary of randomized controlled trials on vitamin E and chronic disease

Study name/Design	Study site/ Year	Sample size	Study population (Age, sex, special characteristics)	Active Supplements	Supplementation Period	Self-selected supplement use	Statistically significant and statistically non-significant findings (list of diseases)
WHS87	USA 1992-2004	39876	Mean age (SD): 54.6 (7.0), 100% women	α-tocopherol (natural source, 600 IU on alternate day)	10.1 years	Users of individual supplements of vitamin A, vitamin E, or β-carotene more than once per week were ineligible for trial enrollment	STATISTICALLY SIGNIFICANT:
2 by 2 by 2 factorial trial of β-carotene, vitamin E and aspirin						40% used multivitamin supplements outside the trial	Cardiovascular death (RR 0.76, 95% CI 0.59–0.98)
							STATISTICALLY NON-SIGNIFICANT:
							Major cardiovascular event, incidence of myocardial infarction, incidence of stroke, ischemic stroke incidence, hemorrhagic stroke incidence, total cancer, breast cancer, lung cancer, colon cancer, cancer mortality, total mortality
ATBC90,97,98,101–103106,107,109,99,100,110,	Finland 1984-1993	2913399	Mean age: 57.7 Age range: 50–69 100% men Smokers (5 or more cigarettes per day)	α-tocopheryl acetate 50 mg per day	6.1 years	Users of vitamin A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20 mg, or 6 mg, respectively) were ineligible	STATISTICALLY SIGNIFICANT:
2 by 2 factorial trial of α-tocopherol and β-carotene							None
							STATISTICALLY NON-SIGNIFICANT:
							Pancreatic cancer incidence, pancreatic cancer mortality
		134490	Mean age: 58.8 100% men Low serum pepsinogen; Smokers (5 or more cigarettes per day)		5.1 years (median)		STATISTICALLY SIGNIFICANT:
					Serum pepsinogen measured in 1989-91 and 1992-93		None
							STATISTICALLY NON-SIGNIFICANT:
							Gastric dysplasia, carcinoma, carcinoid
		1828109	Mean age: 64.5–65.1 years 100% men Smokers (5 or more cigarettes per day)	α-tocopheryl acetate 50 mg per day	6.6–6.7 years	Users of vitamin A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20mg, or 6 mg, respectively) were ineligible	STATISTICALLY SIGNIFICANT:
					Ophthalmology exam performed in Nov 1992-March 1993		None
							STATISTICALLY NON-SIGNIFICANT:
							Nuclear cataract, cortical cataract, posterior subcapsular cataract, cataract severity
		941110	Age 65 or older 100% men Smokers (5 or more cigarettes per day)		Ophthalmology exam performed in Dec 1992-March 1993		STATISTICALLY SIGNIFICANT:
							None
							STATISTICALLY NON-SIGNIFICANT:
							Age-related maculopathy
		2913398	Age range: 50–69, 100% men; Smokers (5 or more cigarettes per day)		6.1 years		STATISTICALLY SIGNIFICANT:
			Stratified by baseline data				None
							STATISTICALLY NON-SIGNIFICANT:
							Lung cancer
							Overall and in the subgroups defined by age, cigarettes smoking, years of cigarette smoking, cigarette smoke inhalation, asbestos exposure, dietary intake of vitamin E, β-carotene, vitamin C, retinol, alcohol as ethanol, and serum levels of α-tocopherol, β-carotene, and retinol
		22269106	Median age: 56.9, 100% men Smokers (5 or more cigarettes per day)	α-tocopheryl acetate 50 mg per day	4.7 years (median)	Users of vitamin A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20mg, or 6 mg, respectively) were ineligible	STATISTICALLY SIGNIFICANT:
			With no history of angina				Angina (RR 0.91, 95% CI 0.83–0.99 for α-tocopherol to no α-tocopherol)
							STATISTICALLY NON-SIGNIFICANT:
							Angina ( RR 0.97 and 0.96 in the α-tocopherol group and α-tocopherol+β-carotene group, respectively, compared to placebo)
		2913397	Mean age: 57.2 100% men Smokers (5 or more cigarettes per day)		6.1 years (median)		STATISTICALLY SIGNIFICANT:
							None
							STATISTICALLY NON-SIGNIFICANT:
							Lung cancer, lung cancer mortality, total mortality
		28519107	Mean age: 57.7 100% men Smokers (5 or more cigarettes per day)		6 years (median)		STATISTICALLY SIGNIFICANT:
			With no history of stroke				Fatal subarachnoid hemorrhagic stroke (RR 2.81, 95% CI 1.37–5.79)
							Cerebral infarction (RR 0.86, 95% CI 0.75–0.99)
							STATISTICALLY NON-SIGNIFICANT:
							Incidence of all strokes, sub-arachnoid hemorrhage (RR 1.50, 95% CI 0.97–2.32), intracerebral hemorrhagic stroke, mortality of intracerebral hemorrhagic stroke, cerebral infarction, all strokes
		29133102	Mean age: 57.1, 100% men Smokers (5 or more cigarettes per day)	α-tocopheryl acetate 50 mg per day	6 years (mean)	Users of vitamin A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20mg, or 6 mg, respectively) were ineligible	STATISTICALLY SIGNIFICANT:
							None
							STATISTICALLY NON-SIGNIFICANT:
							Colorectal cancer (RR 0.78, 95% CI 0.55–1.09)
		29133101					STATISTICALLY SIGNIFICANT:
							Prostate cancer incidence (RR 0.68, 95% CI 0.53–0.88)
							Prostate cancer mortality (RR 0.59, 95% CI 0.35–0.99)
							STATISTICALLY NON-SIGNIFICANT:
							None
		15538100	Mean age: 57.0 100% men Smokers (5 or more cigarettes per day)		6.3 years (mean)		STATISTICALLY SIGNIFICANT:
			No colorectal cancer diagnosis (15 cases had a history of polyps)				Colorectal adenoma (RR 1.66, 95% CI 1.19–2.32)
							STATISTICALLY NON-SIGNIFICANT:
							None
		Post-trial follow up	Age range: 50–69 100% men Smokers (5 or more cigarettes per day)	No study supplement use during post-trial follow up	6 years for cancer incidence and cause-specific mortality		STATISTICALLY SIGNIFICANT:
		29133103			8 years for total mortality		Hemorrhagic stroke mortality (RR 1.40, 95% CI 1.00–1.96)
							STATISTICALLY NON-SIGNIFICANT:
							Lung cancer, prostate cancer, colorectalc cancer, total mortality, urothelial cancer, stomach, kidney cancer, pancreatic cancer, other cancers, coronary heart disease mortality, non-hemorrhagic stroke mortality, total mortality
PPP112,181	Italy, 1994-1998	1031182	Mean age (SD): 64.2 (7.6)	all-racα-tocopherol 300 IU per day	3.4 years (median)	Prior long-term use of vitamin E was an exclusion criterion	STATISTICALLY SIGNIFICANT:
2 by 2 factorial trial of all-racα-tocopheryl acetate and aspirin			42% women				Peripheral artery disease (RR 0.37, 95% CI 0.14–0.96) in persons with no type 2 diabetes at baseline
Premature termination of the trial			Stratified by type 2 diabetes among those with at least one risk factor of cardiovascular disease at baseline				STATISTICALLY NON-SIGNIFICANT:
							Combined CV deaths, nonfatal MI and stroke, total CV events, CV deaths, non CV deaths, all MI, all stroke, angina pectoris, transient ischemic attack, revascularization procedure, all deaths in persons with or without diabetes; Peripheral artery disease in persons with diabetes
		4495112	Mean age (SD): 64.4 (7.6)	all-racα-tocopherol 300 IU per day	3.7 years (median)	Prior long-term use of vitamin E was an exclusion criterion	STATISTICALLY SIGNIFICANT:
			57% women				Peripheral artery disease (RR =0.54, CI = 0.30–0.99)
			With at least one risk factor for cardiovascular disease; 23% disbetics				STATISTICALLY NON-SIGNIFICANT:
							Main combined endpoint, total CV events or diseases, CV Deaths, non-CV deaths, all MI, non-fatal MI, all stroke, non-fatal stroke, transient ischemic attack, peripheral artery disease, revascularization procedures, angina pectoris, all deaths
VECAT113	Melbourne, Australia, 1995-2000	1193	Mean age: 65.7, 56% women	RRR-α-tocopherol 500 IU per day	4 years planned	24%	STATISTICALLY SIGNIFICANT:
							None
							STATISTICALLY NON-SIGNIFICANT:
							Cortical cataract, nuclear cataract, posterior subcapsular cataract, any cataract

WHS (Women's Health Study); VECAT (Vitamin E, Cataract and Age-Related Maculopathy Trial); ATBC (Alpha-Tocopherol, Beta Carotene Cancer Prevention Trial); CARET (Beta Carotene and Retinol Efficacy Trial); PPP (Primary Prevention Project); SD (Standard Dilatation).

In the WHS study, vitamin E of 600 IU on alternate days did not affect the risk of developing total invasive cancer, breast cancer, lung cancer, and colon cancer, or the risk of cancer death⁸⁷ (Appendix F, Evidence Table 3i, Table 7).

Cardiovascular disease. In the ATBC trial, all-rac-α-tocopheryl acetate of 50 IU per day had a borderline effect in reducing the incidence of angina (RR 0.91 comparing alpha-tocopherol with or without beta-carotene to no alpha-tocopherol with or without beta-carotene; RR 0.97 comparing alpha-tocopherol alone to placebo), decreased the risk of cerebral infarction (RR 0.86, 95% CI 0.75–0.99), and increased the risk of subarachnoid hemorrhage (RR 1.50, 95% CI 0.97–2.32) and fatal subarachnoid hemorrhage (RR 1.81, 95% CI 0.49–1.32).¹⁰⁶ A similar increased risk in hemorrhagic stroke persisted during the post-trial follow up.¹⁰³

In the PPP, ¹⁰⁷ the evidence was inconclusive due to small numbers of events and premature stopping of the trial; there was a non-significant increased risk for main cardiovascular endpoints (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) (RR 1.07, 95% CI 0.74–1.56), but a lower risk for total cardiovascular events or diseases (RR 0.94, 95% CI 0.77–1.16)¹¹² (Appendix F, Evidence Table 3i, Table 7).

In the WHS, use of vitamin E, 600 IU every other day had no effects on fatal and non-fatal myocardial infarction and fatal and non-fatal stroke, but reduced total cardiovascular death (RR 0.76, 95% CI 0.59–0.98).^{87, 96} There was no effect of vitamin E supplementation on hemorrhagic stroke (RR 0.92, 95% CI 0.61–1.38)⁸⁷ (Appendix F, Evidence Table 3i, Table 7).

Serum lipid levels. Shekelle etal. conducted a systematic review of the effects of vitamin E on the prevention and treatment of cardiovascular disease.¹¹⁴ The review, published in April 2004, was part of a larger evidence report on the effects of vitamin C, vitamin E, and coenzyme Q10 on cardiovascular outcomes.¹¹⁵ The review included an examination of the effects of vitamin E on lipid levels. The search strategy was comprehensive and retrieved English and non-English studies from multiple electronic databases. Additional studies were obtained by hand-searching reference lists from key articles and by consulting experts in the field. Multiple synonyms for vitamin E and for clinical trials were used in the initial search, but only randomized trials in humans using clinical or important surrogate outcomes were included in the report. Two independent evaluators using a standardized form extracted study data, and quality was assessed using the Jadad scale. Both primary and secondary prevention trials were evaluated. Meta-analyses were performed whenever groups of studies were judged to be sufficiently similar (Appendix F, Evidence Table 3i, Table 7).

The Shekelle review included 84 eligible trials of the effect of vitamin E on cardiovascular outcomes. However, only four of the trials were primary prevention studies, and these were deemed to be too heterogeneous (with respect to the type of intervention) to permit meta-analysis to be performed. The individual results of these 4 studies (ATBC,¹¹⁶ PPP,¹¹⁷ SCP,¹¹⁸ and Linxian¹¹⁹) were presented by the authors in narrative form. With respect to lipid lowering, the authors stated that “the 2 large primary prevention trials (ATBC and Linxian) reported clinically insignificant (but statistically significant) changes in (lipid) outcomes,” and that “there is no evidence that vitamin E alone or in combination has a clinically or statistically significant favorable or unfavorable effect on lipids.” In their meta-analyses of all primary and secondary prevention trials on the lipid effects of vitamin E compared to placebo, they found effect sizes that were not significant for total cholesterol (effect size -0.07, 95% CI -0.31 to 0.08), low-density cholesterol (effect size -0.07, 95% CI -0.24 to 0.10), or high-density lipoprotein (effect size 0.01, 95% CI -0.21 to 0.22).¹¹⁶ A negative effect size would indicate a favorable effect of treatment (Appendix F, Evidence Table 3i, Table 7).

Cataract and age-related macular degeneration. The evidence concerning vitamin E supplements and cataract is compatible with no effect. In the VECAT trial,¹¹³ the relative risk of cataract in the vitamin E group versus the placebo group was 1.0 for any cataract (95% CI 0.8–1.4). The relative risk for specific types of cataract were 0.9 for cortical cataract (95% CI 0.5–1.6), 1.1 for nuclear cataract (95% CI 0.8–1.5), and 0.5 for posterior subcapsular cataract (95% CI 0.2–1.1)¹¹³ (Appendix F, Evidence Table 3i, Table 7).

In the ATBC trial, lens opacity was measured at the end of the trial in a random sample of 1,828 participants.¹⁰⁹ The results showed that participants randomized to the α-tocopherol group were not different from the non-α-tocopherol group with respect to the risk of having nuclear cataract (OR 0.8, 95% CI 0.4–1.4), cortical cataract (OR 0.9, 95% CI 0.6–1.4), or posterior subcapsular cataract (OR 0.9, 95% CI 0.4–1.8)¹⁰⁹(Appendix F, Evidence Table 3i, Table 7).

The same approach was used in the ATBC trial to assess the association between α-tocopherol and the end-of-trial prevalence of age-related maculopathy.¹¹⁰ The prevalence of age-related maculopathy was higher among those assigned to receive α-tocopherol supplements than in the placebo group (32% versus 25%), showing no evidence of a beneficial affect of α-tocopherol¹¹⁰(Appendix F, Evidence Table 3i, Table 7).

Total mortality. The relative risk for total mortality in the vitamin E supplement users compared to non-users was 1.04 (95% CI 0.93–1.16), 1.02 (95% CI 0.95–1.09), and 1.07 (95% 0.61–1.90) in the WHS, the ATBC, and the PPP, respectively. In the post-intervention follow up on mortality (8 years of follow up) of the ATBC trial, the relative risk of total mortality in α-tocopherol users compared to non-users was 1.01 (95% CI 0.96–1.05).¹⁰³ Investigators in the WHS reported that “the main causes of death, apart from cardiovascular and cancer deaths, were pulmonary diseases (32 vitamin E, 22 placebo) and violent deaths, excluding suicide (9 vs. 6). None of these causes of deaths was significantly related to vitamin E.” ⁸⁷ The relative risk of cardiovascular death and cancer death in the WHS was 0.76 (95% CI 0.59–9.98) and 1.12 (95% CI 0.95–1.32), respectively.⁸⁷ The VECAT documented 31 deaths (20 in vitamin E; 11 in placebo), and the authors reported “no consistent or unusual patterns were identified among the specific causes of death recorded”¹¹³ (Appendix F, Evidence Table 3j, Table 7).

Summary

Vitamin E supplements have been studied for efficacy in the primary prevention of cancer, cardiovascular disease, cataract, and age-related macular degeneration. There was a lack of effects of vitamin E supplement use in the prevention of these diseases, except for a 32 percent reduction in prostate cancer incidence, a 41 percent reduction in the prostate cancer mortality, and a 22 percent reduction in colorectal cancer in the ATBC trial. The findings on hemorrhagic stroke were conflicting between the ATBC trial and WHS trial in that the former found a higher risk with use of low-dose α-tocopherol supplements but the latter found a lower risk with use of a high dose. Taking into consideration the quantity, quality, and consistency of evidence on the efficacy of vitamin E in preventing chronic disease, we concluded that the overall strength of evidence is “very low” for cancer, “low” for the relationship to cardiovascular disease, and “moderate” for cataract (Table 6).

Key Question 4

What is Known about the Safety of Use of the Following Single Nutrients in the General Population of Adults and Children, Based Primarily on Data From Randomized Controlled Trials and Observational Studies?

Summary of the Key Findings

Results from this systematic review indicate a relative paucity of data that specifically address the efficacy of multivitamin/mineral supplement use in the prevention of chronic disease in the general population of the United States. The data were on the efficacy of designed combinations of vitamins and minerals; none of the trials used the one-a-day multivitamins (of approximately 100% of the RDAs) prevailing on the market. The Linxian trial suggests that supplementation with combined β-carotene, vitamin E and selenium supplements at doses 1 to 2 times the RDA for 5 years had 13 percent to 21 percent reductions in gastric cancer incidence, gastric cancer mortality, and total cancer mortality in a nutritionally deprived Chinese population. The reduction in cancer mortality was stronger in women than in men, and in persons of age 55 or younger. There were no significant effects on total cancer incidence and cerebrovascular mortality. The SU.VI.MAX study in a French population documented a 31 percent reduction in overall cancer risk by use of 5 antioxidants (vitamin C, vitamin E, β-carotene, selenium, and zinc) for 8 years in men but not in women, and a 12 percent reduction in prostate cancer risk, particularly a 48 percent risk reduction in those with normal prostate specific antigen levels at baseline. There was no significant effect of the combined antioxidants on ischemic cardiovascular disease incidence. In this trial, men had lower serum levels of vitamin C and β-carotene than women at baseline. Multivitamin/mineral supplement use for 3 to 6 years had no significant benefits in preventing cataract in 3 trials in the United States (with one trial also in United Kindom) and the Linxian trial. High-dose zinc combined with antioxidants had beneficial effects on age-related macular degeneration only in those with intermediate age-related macular degeneration in one or both eyes, or those with advanced age-related macular degeneration in one eye.

Overall, total mortality data pointed to either no increased risk or lower risk in the groups with multivitamin/mineral supplement use. Total mortality was 9 percent lower among those who received β-carotene, selenium, and vitamin E in the Linxian trial; there was no sex- or age-difference in the relative risks. In the AREDS study, total mortality was 6 percent higher in the group receiving antioxidants compared to the group receiving no antioxidants, but the increase was not statistically significant. Among the participants at high risk for age-related macular degeneration, total mortality was 13 percent to 20 percent lower in the groups receiving zinc alone or zinc combined with antioxidants.^{64, 75} In the SU.VI.MAX study, a sex-difference was documented for the relative risk of total mortality among those receiving antioxidants and zinc compared to those receiving placebo. In the REACT, total mortality rate was not calculated. Nine deaths occurred in the antioxidant group, whereas 3 deaths occurred in the placebo group. The deaths in the antioxidant group were caused by esophagitis, sudden death, aneurysm, pulmonary fibrosis, cancer, and coronary thrombosis.

Daily supplementation with β-carotene of 20 mg, 30 mg or 50 mg was not protective against malignancies, cardiovascular disease outcomes, diabetes mellitus, cataract or age-related maculopathy. Supplementation with β-carotene with or without vitamin A increased the incidence of lung cancer in persons with asbestos exposure or in cigarette smokers, and was associated with increased mortality in some trials. To date, there has been no randomized controlled trial that assessed the efficacy of vitamin A alone in preventing chronic disease. Studies in selected populations (nutritionally inadequate, asbestos exposure, or smokers) showed no benefit of combinations of vitamin A and zinc or vitamin A and β-carotene for the prevention of stroke mortality, esophageal or gastric cancer incidence, or cardiovascular or all-cause mortality.

Vitamin E supplements (synthetic α-tocopherol 50 mg or 300 IU per day, or natural source, 600 IU per day) have been studied for primary prevention of cancer, cardiovascular disease, cataract, and age-related eye disease. The evidence predominantly comes from the ATBC and WHS studies.^{68, 87, 90, 96, 98}–^{100, 107} There was a lack of effects of vitamin E in the prevention of these diseases, except for a 32 percent reduction in prostate cancer incidence, a 41 percent reduction in the prostate cancer mortality, and a 22 percent reduction in colorectal cancer in heavy smokers in the ATBC, and decreased cardiovascular deaths (primarily sudden death) in the WHS participants, particularly in those aged 65 years or older. The findings on hemorrhagic stroke were conflicting between the ATBC trial and the WHS; the former found a higher risk with use of low-dose α-tocopherol supplements but the latter found a lower risk with use at a high dose.

Two previous systematic reviews reported that supplementation with folic acid at daily doses of 0.75 mg or 30 mg, alone or in combination with vitamin B12 and/or vitamin B6 for 5–12 weeks, had no significant effects on cognitive function in 5 small randomized controlled trials. Combined vitamin B2 and niacin supplement use for 5 years had no significant effects on cerebrovascular mortality, total mortality, total cancer incidence, and esophageal or gastric dysplasia/cancer incidence and esophageal or gastric cancer mortality in a poorly nourished population in China.

In a study in persons with a history of non-melanoma skin cancer, supplementation with selenium of 200 mcg per day had no effect on cardiovascular outcomes, but had protective effects on total mortality and incidence of lung, colorectal, and prostate cancers. Another study in China found a significantly reduced risk for liver cancer in those who used selenium supplements of 200 mcg/day for two years.

Due to the substantial amount of efficacy data on calcium/vitamin D and osteoporosis, we reviewed systematic review articles supplemented with data from recent randomized controlled trials and data from randomized controlled trials meeting our inclusion criteria that were not included in previous systematic reviews. The previous reviews reported that supplementation with calcium has short-term (particularly within one year) benefit on retaining bone mineral density in postmenopausal women, and a possible effect in preventing vertebral fractures. The reviews also indicated that combined vitamin D₃ (700–800 IU/day) and calcium (1000 mg/day) may reduce the risk of hip and other non-vertebral fractures in populations with low levels of vitamin D and/or calcium. Recent published data from the WHI trial were consistent with these systematic reviews in showing a 1.06 percent higher hip bone density (p<.02) and a 12 percent non-significant lower risk for hip fracture in postmenopausal women after receiving calcium carbonate (500 mg twice a day) and vitamin D₃ (200 IU twice a day) for an average of 7 years as compared to women receiving a placebo. In this trial, participants were allowed to have self-selected use of multivitamin supplement as well as calcium and vitamin D supplements up to 1000 mg and 600 IU per day, respectively, and thus had a baseline average daily intake of 1150 mg calcium and 365 IU vitamin D. Hence, the WHI participants had higher intake of calcium than the general population (761 mg per day). The WHI trial found no benefit of calcium and vitamin D supplementation in preventing colorectal cancer incidence.

For evidence on the safety of multivitamin/mineral supplements when used for the purpose of preventing chronic disease, we identified 10 studies using multivitamin/mineral preparations and 24 studies using single nutrients for primary prevention of chronic disease. Doses were usually 2 to 10 times the RDA. Overall, we found no consistent pattern of increased adverse effects in the active group compared with the placebo group, with the exception of changes in skin color, which was common in studies in which beta-carotene was part of the multivitamin preparation.

Supplementation with β-carotene with or without vitamin A also increased the incidence of lung cancer in persons with asbestos exposure or in heavy smokers, and was associated with increased mortality. Vitamin A supplementation may moderately increase serum triglyceride levels. Calcium supplementation increased the risk of kidney stones. Vitamin E supplementation was associated with an increased incidence of epistaxis but was not associated with an increased risk of more serious bleeding events, such as hemorrhagic stroke. Iron supplementation was found to reduce weight gain in iron-sufficient, non-anemic children in a small randomized controlled trial. But more recent trials have not fully clarified this issue, because they targeted deficient populations and/or included other micronutrients in the intervention formulation.

Efficacy of Multivitamin/mineral Supplements

Between the Linxian trial and the SU.VI.MAX trial, the types of vitamin/mineral supplements overlapped and the doses were similar. The efficacy was somewhat different, but had similar implications.^{64, 68}–^{70, 111, 161, 162} While the multivitamin/mineral supplements used in the Linxian trial reduced cancer mortality by 21 percent in women and by 7 percent in men, the efficacy of the multivitamin/mineral supplementation in the SU.VI.MAX in reducing cancer incidence was only evident in men. This sex-dependent efficacy may be accounted for by the different nutritional status of the study populations, i.e., generally poor nutritional status in the Linxian population and the suboptimal antioxidant status in men compared with women in the SU.VI.MAX.⁶⁹ These findings also corroborated observational studies that suggest benefits of fruits and vegetables on cancer prevention. However, they did not suggest that supplementation with multivitamins and minerals can replace a balanced, healthful diet to achieve an optimal health state because these studies were not designed to address that question. In view of the inadequate nutritional intake in the Linxian population and the “French paradox,” the generalizability of the findings from the SU.VI.MAX and Linxian trials to the United States population is uncertain.

For cataract prevention, AREDS was the largest trial with findings internally consistent in showing no benefits of multivitamin/mineral supplement use. While the REACT found a deceleration in cataract progression in the United States study site, similar benefits were not seen in the United Kingdom study site. For the prevention of age-related macular degeneration, the AREDS study found benefits of high-dose (10 times RDA) zinc alone or in combination with antioxidants in persons with intermediate age-related macular degeneration in one or both eyes, or persons with advanced age-related macular degeneration in one eye. The MONMD study was conducted in persons with advanced dry age-related macular degeneration. The study suffered from missing data and unclear data analysis and presentation, but the authors concluded that the antioxidant supplements used in the study stabilized but did not improve dry age-related macular degeneration. It appears that benefits of multivitamin/mineral supplements in the prevention/management of age-related macular degeneration were limited to persons with moderate or advanced age-related macular degeneration. However, such inference was based on findings from two trials (n=3,580) with one that was very small (n=71).

With multivitamin/mineral supplements in wide use by the general public in the United States, particularly middle-aged or older individuals, it would be difficult now to recruit trial participants for the conduct of large-scale randomized placebo-controlled trials to determine the efficacy of multivitamin supplementation in chronic disease prevention. In the AREDS, 55 percent of study participants had used some vitamins/minerals before enrollment, and consequently, the study investigators provided a free brand name multivitamin to 66 percent of the study participants. 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 that 40 percent of the WHS participants had multivitamin/mineral supplement use in addition to study supplements, and when limited to non-multivitamin supplement users, the relative risk of major cardiovascular disease was 0.88 (95% CI 0.75–1.03), in contrast to a relative risk of 1.02 (95% CI 0.84–1.25) among multivitamin supplement users.⁸⁷ We have found that very few studies reported participants' self-selected supplement use, and most studies allowed use of supplements that were not under investigation. This limitation was rarely addressed in the literature.

Efficacy of β-carotene

Much research interest has been devoted to elucidating how β-carotene may increase lung cancer risk in high-risk individuals. “Antioxidants” have been assumed to exert in vivo anti-oxidative effects, based on in vitro observations. In fact, the oxidative propensity of a purported “antioxidant” depends at least on the concentrations, the redox potential of the molecule, and the biological environment the molecule is in (e.g., the oxygen tension and the existence of other oxidants/antioxidants). For example, carotenoids may inhibit or enhance apoptosis depending on their concentration, concerted action of other oxidants/antioxidants, cell type, and redox status.¹⁶³ At low oxygen tension, β-carotene may act as an antioxidant, while at high oxygen tension, it may behave as a pro-oxidant,¹⁶⁴ although a pro-oxidant effect was not corroborated by an in vitro experiment on human bronchial epithelial cells.¹⁶⁵ While β-carotene has a pivotal role in preventing vitamin A deficiency, the general lack of benefits from β-carotene supplementation and its potential harms in increasing lung cancer risk among high-risk individuals argue against supplementation with β-carotene alone for chronic disease prevention in the general population.

Efficacy of Vitamin E

In addition to β-carotene, vitamin E is the most extensively studied single nutrient as a chemopreventive agent. Several systematic review articles on vitamin E were identified in our literature search.^{114, 166}–¹⁶⁹ However, in the majority of the previous reviews, primary prevention trials were not separated from secondary prevention trials,^{166, 114, 168} and when aggregate efficacy was calculated, the efficacy of a single nutrient in one intervention arm was not separated from the efficacy of multiple nutrients in one intervention arm.^{166, 114, 168} A systematic review can give misleading results for the efficacy of a single nutrient by including data from trials of multiple nutrients in an intervention arm (which is a multivitamin/mineral intervention). This argument is based on the rationale that several nutrients share common mechanisms of action, that nutrient-nutrient interaction may exist, and that the efficacy of an individual nutrient cannot be determined in a trial that includes multiple nutrients in an intervention arm. This argument is also substantiated by a systematic review in which the aggregate effect of vitamin E alone on cardiovascular death, fatal myocardial infarction, non-fatal myocardial infarction was consistently in the protective direction (RR 0.96, 0.97, and 0.72, respectively), but the RR was 1.03, 1.02, and 0.99 respectively when efficacy was calculated for vitamin E in combination with other nutrient(s).¹¹⁴

The general lack of benefits of vitamin E in the primary and secondary prevention of cancer, cardiovascular disease, cataract, and age-related macular degeneration was unexpected in view of the substantial evidence from experiments, animal studies and epidemiologic studies that showed great promise of vitamin E. Natural vitamin E has eight forms, α-, β-, γ-, and δ-tocopherols and α-, β-, γ-, δ-tocotrienols. Supplements of RRR-α-tocopherol, that is not naturally occurring, but derived from methylating γ-tocopherol in vegetable oil, are often commercially labeled as “natural source” vitamin E (as used in the WHS⁸⁷).⁹⁶ It has been shown that high intake of α-tocopherol may enhance the metabolism of other forms of vitamin E.¹⁷⁰–¹⁷¹ Because γ-tocopherol is the predominant (70%) vitamin E in the typical American diet,¹⁷² and because γ-tocopherol and its metabolite may have biological effects,^{173, 174} it has been hypothesized that reductions in circulating γ-tocopherol levels by α-tocopherol supplementation may compromise the efficacy of α-tocopherol, if any.¹⁷⁵ In the present review, we found that many trials that used vitamin E did not report the chemical forms. Presumably, all trials used some esters of α-tocopherol because α-tocopherol was the center of research attention in the past, and γ-tocopherol or mixed tocopherols were only available on the market in recent years.

Based on data from the PPP and WHS, neither synthetic α-tocopherol of 300 IU per day for a short term, 3.6 years, nor natural source α-tocopherol of 600 IU every other day for a long-term, 10 years, had beneficial effects in the primary prevention of cardiovascular outcomes.^{87, 112} One intriguing finding from the WHS was the significantly lower risk of cardiovascular death (primarily sudden death), which might have been due to chance alone.⁸⁷

Prompted by the findings from the ATBC trial and the NCP trial on the reduced risk for prostate cancer,^{101, 133} the National Cancer Institute has launched the Selenium and Vitamin E Cancer Prevention Trial (SELECT) to test for the efficacy of daily use of α-tocopherol supplements in the primary prevention of prostate cancer in 32,400 men. The SELECT trial uses synthetic α-tocopherol of a high dose, 400 IU, and will be closed out in 2013.¹⁷⁶

Vitamin/mineral Supplement Use and Total Mortality

The implications of the impact of vitamin/mineral supplement use on total mortality are uncertain. Total mortality is relevant to the context of chronic disease prevention because it may provide a clue to potential harms and can be considered as a reference outcome in risk/benefit analysis. However, because two of the causality criteria cannot be applied to death outcome (i.e., response to re-challenge and response to discontinuation of use), the risk for death should be considered based on plausible biological mechanisms and the evidence on the effects of the nutrients on specific disorders. With this rationale along with the consideration on the great heterogeneity in the study design (i.e., factorial design vs. parallel-arm design), doses of supplements, duration of supplement use, and characteristics of study participants, we did not attempt to calculate an aggregate estimate for total mortality for the trials that reported such data. Instead, we examined the causes of death that might have accounted for the difference in total mortality between randomized groups.

The 9 percent reduced risk of total mortality by multivitamins/minerals in the Linxian trial was likely to be driven by the reduction in stomach cancer mortality. Similarly, reduced total mortality in men in the SU.VI.MAX may reflect the 31 percent reduction in cancer incidence.

The higher total mortality by β-carotene supplementation during the conduct of ATBC trial was primarily due to lung cancer and cardiovascular disease, whereas the higher total mortality in the first 4 years of post-trial follow up was primarily due to a wide spectrum of cardiovascular diseases.¹⁰³ How β-carotene increased the risk of cardiovascular mortality remains unclear.

A contentious issue regarding vitamin E supplementation is its impact on total mortality. The issue was set off by a recent meta-analysis from which an excess of 39 deaths per 10,000 persons was reported (95% CI 3 to 74 per 10,000) for trials using vitamin E at doses greater than or equal to 400 IU per day.¹⁶⁸ In contrast, mortality was reduced (risk difference was -16 per 10,000 (-40 to 10 per 10,000) for trials using lower doses (less than 400 IU per day).¹⁶⁸ This meta-analysis had the shortcoming in combining 9 primary prevention trials and 10 secondary prevention trials, and combining data from 9 trials using vitamin E alone and data from 10 trials using vitamin E combined with other nutrients, including β-carotene which has been linked with an increased risk for total mortality. Furthermore, most trials that used high doses were secondary prevention trials in persons with various types of diseases and medication use.

In the present review on vitamin E supplement use for primary prevention, the ATBC and the WHS participants comprised 87 percent of the study populations. In the ATBC trial, a 2 percent increased risk of total mortality was observed at the end of the supplementation period, but a 4 percent risk “reduction” was observed in the next 3 years, followed by a 5 percent increase for the next 3 years and 0 percent for the next 2 years.¹⁰³ The overall relative risk of total mortality during the 8 years of post-trial follow up was 1.01 (95% CI 0.96 to 1.05) and there was no difference in the relative risk of mortality throughout the post-trial follow up period.¹⁰³ These findings suggest no late effects of α-tocopherol supplementation on risk of death in heavy smokers. In the WHS,⁸⁷ the authors reported that “the main causes of death, apart from cardiovascular and cancer deaths, were pulmonary diseases (32 vitamin E, 22 placebo) and violent deaths, excluding suicide (9 vs. 6). None of these causes of deaths was significantly related to vitamin E.” The relative risk of cardiovascular death and cancer death in the WHS was 0.76 (95% CI 0.59–9.98) and 1.12 (95% CI 0.95–1.32), respectively.⁸⁷ The VECAT documented 31 deaths (20 in vitamin E; 11 in placebo), and the authors reported that “no consistent or unusual patterns were identified among the specific causes of death recorded.”¹¹³ In view of these data along with consideration of biological plausibility, we find no convincing evidence to suggest vitamin E supplement use increases risk of death per se.

Timing and Duration of Supplement Use

Timing and duration of supplement use is an important determinant of the efficacy. However, these issues have rarely been addressed in the literature and little is known about the optimal time to start and stop supplementation. For the reasons of feasibility and resource constraints, most randomized controlled trials have had a follow up period of approximately 5 years, and some followed for only 2 years, while a chronic disease may take 10 to 20 years to develop.

In the ATBC and CARET studies, lung cancer risk was increased by β-carotene alone or by combined β-carotene and retinol over 5 to 10 years of supplementation among heavy smokers and persons regularly exposed to asbestos, suggesting that the supplementation regimens might have accelerated the progression of carcinogenesis in these high-risk groups.

The CARET study reported a late effect of β-carotene supplementation on lung cancer.⁹⁴ The ATBC trial observed a late effect on colorectal cancer, but not lung cancer.¹⁰³ These post-trial follow up data may provide some clues to how likely the link between β-carotene supplementation and increased lung cancer incidence was causal, and how the effects may vary with carcinogenesis processes, but the data may also be simply due to chance alone or be subject to confounding by trial participants' changes in supplement use after the closeout of the trial.

An intriguing finding from the WHS study was that a significantly lower risk of major cardiovascular events was limited to women aged 65 or older who received vitamin E supplements for 10 years (RR 0.74).⁸⁷ This finding is not congruent with the oxidative hypothesis stating that oxidative damage occurs early in the atherosclerosis process,¹⁷⁷ nor with the data that showed that early atherosclerotic lesions occurred in adolescents.^{178, 179} In the Linxian trial with 5 years of follow up, benefits of α-tocopherol, selenium and β-carotene on cancer mortality, cardiovascular mortality and total mortality were more evident in those aged less than 55 years.⁶⁷ The SU.VI.MAX trial found a protective effect of antioxidants on prostate cancer incidence among men who had normal prostate specific antigen levels, but not in men who had elevated prostate specific antigen levels after 8 years of follow up.⁷⁰ The benefit on prostate cancer by β-carotene supplement use in the ATBC trial was limited to clinical prostate cancer but not for latent cancer.¹⁰¹ If cancer development takes more than 10 years to develop, these data would seem to have provided paradoxical information on whether antioxidant supplements should be used earlier or later in the life span, let alone whether different chemopreventive agents may act differently along the carcinogenesis process. Additional data from subgroup analyses from trial enrollment to diagnosis with adjustment for potential confounding variables such as age in other completed or on-going trials are needed before a clear picture can be seen.

Doses of Vitamin/mineral Supplements

The RDA is the average daily dietary intake level sufficient to meet the nutrient requirement of nearly all (97 to 98 percent) apparently healthy individuals in a particular age and gender group. There is a wide range of doses of vitamins and minerals formulated into over-the-counter supplements. The “one-a-day” type of multivitamins/mineral supplements may contain nutrients of 100% to 300% of the RDAs for adults. The doses of B vitamins in other multivitamin preparations are high; usually 1667% of the RDAs, and up to 6000% of the RDAs. For vitamin E, commonly used doses in individual vitamin E or multivitamin supplements are 100, 200, 400, and 800 IU which, if of natural form, correspond to 333%, 667%, 1332% and 2640% of the RDA for vitamin E. For vitamin C, commonly used doses in individual vitamin C supplements or multivitamin supplements are 250 mg, 500 mg, and 1000 mg, which correspond to approximately 417%, 833%, and 1667% of the RDA for vitamin C.

In this review, only two trials of multivitamin/minerals supplements reported data on cancer and cardiovascular outcomes and the benefits on these outcomes were implicated in those who had inadequate nutrient intake. The active supplements (combined vitamin E, selenium, and β-carotene; combined vitamin E, selenium, β-carotene, vitamin C and zinc) in these two trials were of doses around 100%-200% of the RDAs. Hence, the efficacy of lower or higher doses of the nutrients was not known. With respect to prevention of age-related macular degeneration, the AREDS study used a high dose of vitamin E (400 IU) and zinc (2 times the UL), and the benefit on preventing the progression to advanced age-related macular degeneration appeared to have come primarily from the groups receiving zinc. In this study, of nearly 100 comparisons, a few adverse effects occurred more often in participants receiving zinc as compared to participants receiving no zinc, including more difficulties in swallowing the pill (17.8% vs. 15.3%), more hospitalizations due to genitourinary problems (7.5% vs. 4.9%), more “adverse circulatory experiences” (0.9% vs. 0.3%) and more anemic individuals (13.2% vs. 10.2%).

In the WHI study, participants were allowed to have self-selected use of multivitamin supplements, as well as calcium and vitamin D supplements up to 1000 mg and 600 IU per day, respectively. Hence, the WHI participants had a baseline average daily intake of 1150 mg calcium and 365 IU vitamin D. If women randomized to the calcium supplementation group also used their own calcium supplements and multivitamin supplements that contained calcium, a daily total intake could have approached the UL, 2500 mg, and led to a higher risk for adverse effects such as kidney stone formation.

Safety Consideration

As noted previously, the potential adverse effects of multivitamin or single-nutrient supplements have not been systematically studied in well-controlled trials. Because of the uncertainties regarding design (exposure, doses, etc.) and the ethical constraints, such studies may never be carried out. Our assessment of the safety of supplements, therefore, must rely on the safety monitoring during randomized controlled trials and on case reports and other observational data.

Since the ULs were defined based on limited data or extrapolations, and generally were based on one single indicator of adverse effects, it is not surprising that several trials reported no adverse effects after consumption of doses above the UL. These studies may have used indicators other than those used to define the UL for that nutrient, or may have had only slight increases in an adverse effect that was not significantly different from the placebo group. A few adverse effects, because they appear with certain consistency in different trials, may be interpreted as common responses in the general population. For example, yellowing of the skin with sustained consumption of β-carotene at daily doses of 8 mg or higher has been described in most studies using this nutrient. Similarly, increases in serum triglycerides with vitamin A supplementation have been reported in several studies. Minor bleeding, particularly epistaxis, also appears to be a relatively common effect of vitamin E supplementation. But as noted above, there is no evidence that this vitamin results in an increased risk of more serious bleeding events, such as hemorrhagic stroke.

A general conclusion, with the caveats mentioned regarding the limited data available, is that consumption of multivitamin supplements for prolonged periods (1 to 8 years) appears to be safe. We found no reports of major, life-threatening adverse effects, and no evidence of increased mortality in groups consuming multivitamin supplements. A similar general conclusion can be reached for single-nutrient supplements. However, the late effects of β-carotene on cardiovascular death in heavy smokers deserve further investigation for the underlying mechanisms. In addition, some studies confirmed the adverse effects used to define the UL, as for example, gastrointestinal symptoms and/or diarrhea with vitamin C. While the UL for this nutrient was set at 2 g per day, some studies have reported these symptoms with doses of 750 mg per day. It is recognized that the ULs represent a probability of an adverse event in the general population, and that that probability (and therefore the UL threshold) may vary across subgroups and in different circumstances.

Limitations

An enormous volume of literature exists on the effects of multivitamin/mineral supplements when seeking to include the literature on all of the single nutrients that are often included in multivitamin supplements. To find the most relevant literature on our questions, we had to design a search strategy that sacrificed some degree of sensitivity in order to have reasonable specificity. Thus, it is possible that the search strategy missed some studies that have potentially relevant data. We tried to minimize this problem by performing hand searching of the references in key articles and reviews, and by asking our peer reviewers to identify any important studies that were missing in the draft report. Clinical experts may question the efficiency of our systematic approach to searching the massive volume of literature on multivitamin/mineral supplements, but we were concerned about the risk of bias in selecting articles for inclusion in the review if we had relied only on experts for identifying eligible studies.

In addition, for our review of evidence on the efficacy of multivitamin/mineral supplements in preventing chronic disease, we focused on randomized controlled trials as the strongest source of evidence. We also focused on primary prevention studies because they are the ones most relevant to use of multivitamins in the general population of healthy adults. Although we focused on randomized controlled trials only for efficacy data, we included observational studies in our consideration of the safety of multivitamins/mineral supplements.

Many of the studies had important methodologic limitations. One particularly important limitation is that study groups often were permitted to use vitamin/mineral supplements other than the assigned study interventions. Such leeway would have attenuated the observed efficacy of study supplements. In addition, most studies did not provide information on trial participants' characteristics, such as medication use, that may have modified the effects of the nutrients of interest.

There is marked heterogeneity of the literature on our key questions, with differences in study design (e.g., some of the trials used a factorial design), targeted study population (with different cultural/lifestyle and genetic backgrounds), chemical forms and doses of supplements, and specific outcome measures. This degree of heterogeneity makes it difficult to synthesize results across studies, and generally makes it inappropriate to perform quantitative synthesis (i.e., meta-analysis). The differences in study populations are particularly problematic because few studies have examined the efficacy of multivitamin/mineral supplements in the general United States population, making it difficult to determine whether the results of studies in other countries such as China and France can be applied to the United States population.

There has been inconsistent reporting on the potential adverse effects of the nutrients of interest. A significant proportion of data in the literature concerning adverse events came from case reports that are subject to serious methodological limitations. As a result, the overall strength of the evidence on adverse effects is weak. In addition, the implications of data from case reports are uncertain. In a previous systematic review of case reports of adverse effects of drugs, it was found that 83 percent of suspected adverse reactions were not further evaluated in confirmatory studies, and adverse effect alerts were not systematically incorporated into published drug reference information.¹⁴⁰

Conclusions

Limited evidence accumulated to date suggests potential benefits of multivitamin/mineral supplements in the primary prevention of cancer in individuals with poor nutritional status or suboptimal antioxidant intake. However, the heterogeneity in the study populations upon which this evidence is based limits generalization to the United States population. The evidence also indicates that multivitamin/mineral supplement use does not have significant effects in the primary prevention of cardiovascular disease and cataract, but may confer benefits to slow the progression of age-related macular degeneration among persons at high risk for developing advanced stages of the disease.

We also conclude that regular supplementation with a single nutrient or a mixture of nutrients for years has no significant benefits in the primary prevention of cancer, cardiovascular disease, cataract, age-related macular degeneration or cognitive decline. A few exceptions, that were reported in a single or a few trials, included a decreased incidence of prostate cancer with use of synthetic α-tocopherol (50 mg per day) in smokers, a decreased progression of age-related macular degeneration with high doses of zinc alone or zinc in combination with antioxidants in persons at high risk for developing advanced stages of the disease, and a decreased incidence of cancer with use of selenium (200 mcg per day). Supplementation with calcium has short-term (particularly within one year) benefit on retaining bone mineral density in postmenopausal women, and a possible effect in preventing vertebral fractures. Combined vitamin D₃ (700–800 IU/day) and calcium (1000 mg/day) may reduce the risk of hip and other non-vertebral fractures in individuals with low levels of intake. Supplementation with β-carotene increased lung cancer risk in persons with asbestos exposure or cigarette smoking.

The overall quality and quantity of the literature on the safety of multivitamin/mineral supplements is limited. Available data suggest multivitamin/mineral supplement use for 1 to 8 years is safe. Among the adverse effects reported in randomized controlled trials, a prominent one is yellowing of the skin among β-carotene supplementation. Vitamin A supplementation may moderately increase serum triglyceride levels. Calcium supplementation may increase the risk of kidney stones. Vitamin E supplementation was associated with an increased incidence of epistaxis but was not associated with an increased risk of more serious bleeding events.

Future Research

In vitro studies and animal models have helped us to understand the function of nutrients under a controlled environment. However, these types of studies often have over-simplified the sophistication of the human body. There is a gap in our knowledge of how specific nutrients work in vivo to prevent disease. Future research should be directed toward filling the gap by developing valid in vivo biomarkers and applying them in the settings of randomized controlled trials to examine how nutrients influence the body's physiological function and pathological processes, and how nutrients work in concert to do so. Identifying an optimal dose in dose-response studies is critical to guide the design of future large-scale randomized controlled trials when the conduct of the trials is considered worthwhile.

Nutritional research has adopted a reductionist approach that emphasizes the role of individual nutrients in physiologic function or disease process. In view of the complex pathological processes of chronic diseases, the idea of using a single nutrient or a few nutrients to modify disease risk carries considerable optimism. The design and conduct of several large-scale randomized controlled trials on antioxidants was derived from epidemiological data that showed a lower risk of chronic disease (predominantly cancer and cardiovascular disease) in those who had higher circulating levels or dietary intake of some micronutrients. Because of residual confounding and measurement errors in dietary assessment, dietary data from observational studies can be better examined by patterns of food consumption with a multivariate approach, rather than by ranking of specific nutrient intake with a univariate approach.

We have found that many studies did not report study participants' self-selected supplement use before and during the trial participation, and allowed self-selected supplement use during the trial. Similarly, there was a lack of information on other variables that might have modified the effects of study supplements. Collective study findings also may not apply to every individual. Additional research should be done, particularly in existing randomized controlled trials, to examine how efficacy may vary by age, time since trial enrollment to diagnosis, self-selected supplement use, dietary patterns, disease history, medication use, and/or genetic polymorphisms.

With many food products being fortified with several nutrients, Americans' dietary intake of certain nutrients may well be above the RDAs. Hence, it is important to study the level of intake among consumers and assess how nutrient fortification may influence the public's health. An adverse event reporting system needs to be in place to facilitate this type of research.

For policy making, research should be conducted to estimate the cost-effectiveness and the risk/benefit profile of multivitamin/mineral supplement use or more generally, dietary supplement use, in the general population. Such research should also consider subpopulations for which these parameters may differ.

Implications

The results of this systematic review have important implications for clinical practice and public health policy. When people ask about the need for multivitamin/mineral supplements, clinical practitioners should be aware that while multivitamin/mineral supplements are unlikely to have serious adverse effects, it remains unclear whether multivitamin/mineral supplementation is efficacious in preventing cancer, cardiovascular disease, or other major chronic diseases and conditions in the general United States adult population. Clinical practitioners may need to take into consideration other factors, such as nutritional status, when making recommendations about the need for multivitamin/mineral supplements. Forpublic health policy makers, our conclusion isthat evidence is insufficient to universally recommend or discourage routine use of multivitamin/mineral supplementsby adults in the general United States populationfor primary prevention of chronic disease

Technical Experts and Peer Reviewers

• Lindsay Allen, RD, PhD

• USDA - Agricultural Research Center

• Western Human Nutrition Research Center and Program in International Nutrition

• 1 Shields Avenue, SurgeE IV

• Davis, CA

• Bruce Ames, PhD

• Children's Hospital Oakland Research Institute (CHORI)

• 5700 Martin Luther King Jr. Way

• Oakland, CA

• John Beard, PhD

• Department of Nutritional Sciences,

• Penn State University

• S-128A Henderson South Bldg.

• University Park,PA

• John W. Erdman, Jr.

• Professor

• University of Illinois

• Division of Nutritional Sciences

• Urbana, IL

• Gary Goodman, MD, MS

• Fred Hutchinson Cancer Research Center

• Seattle, WA

• Alice Lichtenstein, DSc

• Senior Scientist

• Director of the Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging

• Professor of Family Medicine and Community Health

• Tufts University School of Medicine

• Boston, MA

• Joel A. Simon, MD, MPH

• General Internal Medicine Section (111A1)

• San Francisco Veterans Affairs Medical Center and University of California

• 4150 Clement Street

• San Francisco, CA

• Emily White, PhD

• Cancer Prevention Research Program

• Fred Hutchinson Cancer Research Center

• Seattle, WA

Internal Technical Experts

• Leon Gordis, MD, DPH

• Professor

• Bloomberg School of Public Health

• Department of Epidemiology

• Baltimore, MD

• Alfred Sommer, MD

• Bloomberg School of Public Health

• Dean- Finance & Admin

• Baltimore, MD

MEDLINE Strategy

Cochrane Library (Reviews and CENTRAL) Strategy

EMBASE Strategy

References