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Fortmann SP, Burda BU, Senger CA, et al. Vitamin, Mineral, and Multivitamin Supplements for the Primary Prevention of Cardiovascular Disease and Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Nov. (Evidence Syntheses, No. 108.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Vitamin, Mineral, and Multivitamin Supplements for the Primary Prevention of Cardiovascular Disease and Cancer

Vitamin, Mineral, and Multivitamin Supplements for the Primary Prevention of Cardiovascular Disease and Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force [Internet].

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Scope and Purpose

We conducted this systematic review to help the Agency for Healthcare Research and Quality (AHRQ) update its recommendation on the use of multivitamins for the prevention of cardiovascular disease (CVD) and cancer in the general population. The U.S. Preventive Services Task Force (USPSTF) will use this review to update its 2003 recommendations on routine vitamin supplementation to prevent chronic diseases.1 This review addresses the benefits and harms of single, paired, and multiple vitamins and/or minerals as primary prevention for CVD and cancer in the general population without nutritional deficiencies or existing chronic diseases.


Vitamins and Minerals

Vitamins (e.g., vitamin A, B, C, D, and E) are organic compounds that are essential to maintaining health. Minerals, on the other hand, are inorganic substances that humans need to maintain their health (e.g., calcium, iron, zinc).2 Multivitamin and/or multimineral supplements contain three or more vitamins and/or minerals without herbs, hormones, or drugs. The U.S. Food and Nutrition Board of the Institute of Medicine has also determined that each of these components is present at a dose less than the tolerable upper intake level.2-8 We refer to multivitamin/multimineral supplements as multivitamins because this is how they are marketed and sold. We do not consider other essential nutrients, such as essential fatty acids, to be vitamins or minerals.

Between 1941 and 1994, the Recommended Dietary Allowances (RDAs) of the United States and the Dietary Standards/Recommended Nutrient Intakes (RNIs) of Canada dictated the nutrition polices of their respective countries. By the 1990s, however, concerns about the accuracy of the RDAs and RNIs in both countries arose as nutritional research advanced and measurement of nutrients improved. In 1997, the Food and Nutrition Board published a broader set of dietary reference values called Dietary Reference Intakes (DRIs). DRIs expanded upon and replaced RDAs and RNIs with four categories of intakes intended to help individuals optimize their health, prevent disease, and avoid consuming too much of a specific nutrient (Table 1).2

Table 1. Dietary Reference Intake Definitions.

Table 1

Dietary Reference Intake Definitions.

Most commercially available supplements generally contain vitamins and/or minerals at doses that are close to the recommended dietary allowance, but are still below the tolerable upper intake levels set by the U.S. Food and Nutrition Board (Appendix A Table 1).

Regulation of Dietary Supplements in the United States

In October 1994, the U.S. Government passed the Dietary Supplement Health and Education Act (DSHEA). This act amended the Federal Food, Drug, and Cosmetic Act and significantly changed the regulation of dietary supplements in the United States. This act also created a new regulatory framework for establishing the safety and labeling of dietary supplements. Before this act, dietary supplements were subject to the same regulatory requirements as other foods. Under DSHEA, however, the manufacturers or distributors of dietary supplements became responsible for determining the safety of their dietary supplements. Additionally, this act does not compel manufacturers to provide the U.S. Food and Drug Administration (FDA) with the evidence they rely on to substantiate safety or effectiveness before or after they market their products. Likewise, the FDA does not need to approve dietary supplements before marketing. Manufacturers are required, however, to show evidence that any representations or claims about the dietary supplement are not false or misleading. After a supplement reaches market, the FDA is responsible for regulating and taking action against any unsafe dietary supplement. As such, the manufacturer, packer, or distributor is required to submit to the FDA all serious adverse event reports associated with use of the dietary supplement in the United States. Despite this responsibility, however, there is no formal postmarketing surveillance of supplements. As a result, consumers and health care providers are responsible for reporting serious adverse events to the manufacturer or FDA.

Use of Vitamin and Mineral Supplements in the United States

Vitamin and mineral supplements are the most commonly used dietary supplements in the United States9 and are available in numerous forms (e.g., individual vitamins, minerals, and multivitamin combinations). According to the National Health and Nutrition Examination Survey III, nearly half of the U.S. population (44% of men, 53% of women) reported using a dietary supplement. Multivitamin supplements are the most common (Table 2),10 and supplement use has also increased over time.11 In 2010, vitamins accounted for 34 percent of the $28.1 billion in annual sales of dietary supplement in the United States and minerals accounted for 8 percent.12

Table 2. Vitamin and Mineral Supplement Use in the United States, NHANES 2003–2006.

Table 2

Vitamin and Mineral Supplement Use in the United States, NHANES 2003–2006.

Individuals primarily use vitamin and mineral supplements to promote health and/or to prevent and mitigate disease. The National Family Opinion for the Natural Marketing Institute surveyed a representative sample of U.S. heads of households (n=2,002) regarding their motivations for using supplements.13 This survey found that over 65 percent of respondents reported they used vitamin or mineral supplements to improve health and wellness. In addition, nearly 50 percent of respondents felt that dietary supplements helped prevent and treat cancer and heart disease. In a series of surveys of health care providers (Healthcare Professionals [HCP] Impact Study), 57 to 96 percent of respondents said they personally used dietary supplements at least occasionally, primarily for health and wellbeing.14-16

Current Clinical Practice in the United States

In the HCP Impact Study, 72 percent of physicians (n=900), 89 percent of nurses (n=277), and 97 percent of registered dietitians (n=300) surveyed recommended dietary supplements to patients for their overall health and wellness.14,16 Among 300 cardiologists responding to the same 2008 survey, 55 percent of those who recommended using dietary supplements reported heart health as the primary reason for the recommendation to their patients.15 Several professional organizations and Federal agencies have made recommendations about using multivitamin supplements to prevent chronic disease (Table 3). These groups concluded that there is insufficient evidence to make a recommendation for the use of dietary supplements in the prevention of chronic disease in the general population. They advise patients to obtain essential nutrients through diet.

Table 3. Recommendations of Other Organizations.

Table 3

Recommendations of Other Organizations.

Prevalence and Burden of CVD and Cancer in the United States

Incidence and Mortality

Over 1.2 million people experience a first or recurrent coronary event and nearly 800,000 have a stroke each year in the United States (Table 4).17 CVD is increasingly affecting the elderly (age 65 years and older) and affects more men than women.17 Additionally, the prevalence of coronary heart disease is greatest among American Indians/Native Americans (11.6%), followed by blacks (6.5%), Hispanics (6.1%), and whites (5.8%).18 Asians and Pacific Islanders have the lowest prevalence (3.9%).18

Table 4. Framingham Heart Study Average Annual Incidence Rates of Cardiovascular Disease in the United States, 1980–2003.

Table 4

Framingham Heart Study Average Annual Incidence Rates of Cardiovascular Disease in the United States, 1980–2003.

Heart disease is the leading cause of death in the United States across both sexes and all races and ethnicities (Table 5).19 In 2009, CVD (i.e., coronary heart disease, hypertensive heart disease, heart failure, and stroke) accounted for about one in every three deaths in the United States (age-adjusted mortality rate, 243.9 per 100,000).17 Over one third (34%) of CVD deaths occurred in people younger than age 75 years.17 Coronary heart disease (myocardial infarction [MI], angina, and sudden death) accounted for about half of CVD deaths; stroke accounted for 16 percent of CVD deaths.17 In 2009, men were more likely to die from CVD than women (age-adjusted mortality rate, 287.2 per 100,000 men vs. 196.1 per 100,000 women).17 These mortality rates were higher among blacks in both sexes than whites. American Indian/Alaskan Natives and Asian/Pacific Islanders had lower rates among both sexes.

Table 5. Centers for Disease Control and Prevention Age-Adjusted Mortality Rates of Cardiovascular Disease in the United States Based on I00-I99 Codes, 2009.

Table 5

Centers for Disease Control and Prevention Age-Adjusted Mortality Rates of Cardiovascular Disease in the United States Based on I00-I99 Codes, 2009.

In 2012, over 1.6 million individuals were diagnosed with cancer in the United States.20 The annual age-adjusted incidence rate for any cancer was 465.2 per 100,000 individuals, with men about 1.3 times more likely to be diagnosed with cancer than women. The median age at diagnosis was 66 years. Table 6 gives the incidence of the major types of cancer stratified by sex and race/ethnicity, derived from the National Cancer Institute Surveillance Epidemiology and End Results Program. Among men, cancer rates are highest in black males. These rates are primarily driven by high prostate cancer incidence rates. Black men also have the highest incidence of lung cancer compared with other sex-race/ethnicity groups. Cancer rates are lowest in Asian/Pacific Islander women (a grouping that likely hides considerable heterogeneity). Among women, whites have the highest overall incidence of cancer, mainly due to relatively high rates of breast cancer. Cancer rates are also high in black women. Black women have a breast cancer incidence only slightly lower than that of white women, and black women have the highest rates of colorectal cancer among women.20

Table 6. SEER Incidence Rates of Cancer in the United States, 2005–2009.

Table 6

SEER Incidence Rates of Cancer in the United States, 2005–2009.

In 2009, cancer was the second leading cause of death in the United States, and 570,000 cancer deaths were expected in 2012.19,20 The overall age-adjusted mortality rate for any cancer was 178.7 per 100,000 individuals, with a median age at death of 72 years. These rates differed by sex, and men were more likely to die from cancer than women (219.4 vs. 151.1 per 100,000). Prostate cancer in men and breast cancer in women are the main contributors to cancer mortality. Colorectal cancer and lung cancer are also contributors in both sexes (Table 7). Black men and women have the highest total cancer mortality and the highest mortality rates for all the major cancer sites.20 Prostate cancer mortality in black men is more than twice that in other race/ethnic groups.20

Table 7. SEER Mortality Rates of Cancer in the United States, 2005–2009.

Table 7

SEER Mortality Rates of Cancer in the United States, 2005–2009.

Traditional Risk Factors and Common Pathologic Mechanisms for CVD and Cancer

The risk factors for CVD are quite well-established and include age, sex, blood pressure, smoking status, and blood cholesterol level. The effects of age and sex are interrelated. This is evidenced by the fact that women generally develop CVD when they are about 10 years older than men. Randomized, controlled trials (RCTs) have definitively established the causal relationship between elevated blood pressure and cholesterol levels and CVD. There are many other factors that affect CVD risk, including genetic variation. The major risk factors of elevated blood pressure, abnormal lipid levels, and smoking, plus other lifestyle factors (diabetes; obesity; consumption of fruits, vegetables, sodium, and alcohol; psychosocial factors; and regular physical activity) account for about 90 percent of the variance in CVD rates worldwide.21 Cancer risk is considerably more complex because of the varied nature of cancers and because both environmental factors and genetics are critically involved. Despite the differences in their clinical manifestations, CVD and cancer share several risk and etiologic factors. Cigarette smoking, poor nutrition, physical inactivity, and obesity are associated with both CVD and many cancers (particularly breast and colorectal). Inflammation and oxidative stress, both prime targets of vitamin and mineral supplements, appear to account for at least part of this overlap. Cigarette smoke contains many oxidative compounds, while dietary fruits and vegetables contain high amounts of antioxidant compounds, and regular physical activity is associated with lower levels of inflammatory markers.22 Inflammation and high oxidative potential produce arterial wall damage and exacerbate the impact of hypertension and dyslipidemia.23 The most atherogenic forms of low-density lipoprotein (LDL) are highly susceptible to oxidation, and only oxidized LDL particles stimulate atherosclerosis.24 Oxidative damage to DNA causes formation of multiple aberrations, including DNA adducts, methylation, single strand breaks, and genomic instability, that likely lead to mutagenesis and oncogenesis.25

Another possible common pathway for CVD and cancer etiology is methionine metabolism. Methionine is a sulfur-containing amino acid derived from dietary sources (particularly animal protein) and intracellular turnover of proteins. Methionine metabolism results in the generation of S-adenosylmethionine, an important methyl donor to RNA, DNA, proteins, and other compounds. Methylation may interfere with tumor suppressor genes and produce chromosomal aberrations that contribute to oncogenesis.26,27 The methionine cycle also includes homocysteine, a cytotoxic compound that is an independent risk factor for CVD.28 Interestingly, the conversion of homocysteine to methionine is the major route for eliminating the former compound from cardiovascular cells and is dependent on B vitamins, including, but not limited to, B12 and folate.

Role of Vitamins and Minerals in the Prevention of CVD and Cancer

The principal rationale for advocating multivitamin supplementation in both CVD and cancer prevention is the overlap of risk factors, particularly inflammation, oxidative stress, and methionine metabolism. This is important given that several dietary supplements are known to have antioxidant and anti-inflammatory effects or influence methionine metabolism. This has served as the rationale for proposing dietary supplements as an effective means to prevent both CVD and cancer.

Oxidative damage by free radicals and other reactive species is ubiquitous and there are numerous, interacting biochemical mechanisms by which vitamins and/or minerals might protect against these effects, thus reducing both CVD and cancer risk. Fat-soluble antioxidant vitamins such as vitamin E circulate principally in lipoproteins, especially LDLs. As noted above, oxidized LDL is highly atherogenic and vitamin E protects against this oxidation. To maintain vitamin E in its antioxidant or reduced state, however, circulating, water-soluble antioxidants such as vitamin C are required. Natural, enzymatic antioxidants (e.g., superoxide dismutase, glutathione peroxidase) catalyze the reactions that suppress free radicals and peroxide and contain copper, zinc, and manganese as integral parts of their structure, providing a rationale for supplementing with minerals.

Several B vitamins (folate, B6, and B12) are important in homocysteine metabolism. This is important given that about half of the homocysteine generated in a typical diet is metabolized through transsulfuration, which does not generate methionine and is dependent on B6. The other half of this homocysteine is remethylated to methionine through reactions that require folate and B12 as cofactors. As methyl donors, these vitamins are also essential for normal nucleotide and DNA synthesis and repair. High doses of these vitamins could have negative consequences, however, as hypermethylation may contribute to oncogenesis. In addition, numerous clinical trials conducted over the past decade have failed to show benefit of high-dose folic acid supplementation despite favorable effects on serum homocysteine levels.29 Some observers posit that these overall negative results could be hiding important subgroup differences,30 including baseline levels of B vitamins and renal function. These issues illustrate the complexities created by the interrelationships of genetics, diet, and supplementation.

Vitamin E (gamma-tocopherol), zinc, and vitamin A are thought to inhibit inflammation, another presumed protective mechanism provided by vitamins and minerals. In addition, other effects of vitamins may be relevant to other chronic diseases, such as enhanced immunity (vitamins A, C, and E and zinc and calcium) or stimulation of collagen synthesis (vitamin C). The implications of these effects for CVD and cancer, however, remain uncertain. Other effects, such as regulation of cell differentiation, proliferation, and apoptosis may be related to these diseases. Research has also suggested that vitamins A, C, and D and alpha-tocopherol inhibit angiogenesis, which might help prevent cancer. This effect, however, would likely exacerbate vascular disease.31-36

Normal human exposure to vitamins and minerals is through diet (any intake of food), which includes a vast array of known and unknown micronutrients that interact in complex ways with each other and with macronutrients, such as fiber and fatty acids. This is complicated further by the fact that individuals may absorb and metabolize food in ways that influence the effects of these nutrients. As such, even the most complex multivitamin cannot hope to mimic the content of a healthful diet that includes a wide variety of unprocessed foods. Additionally, the components of single vitamin or multivitamin supplements may vary substantially from what is found in whole foods, which could alter biological impact. Vitamin E, for example, exists in eight chemical forms in food, with gamma-tocopherol being the most abundant form in the U.S. diet (Appendix A Table 1). However, vitamin E supplements generally contain alpha-tocopherol, which is also abundant in the diet but can act as a pro-oxidant under some circumstances. Whether or not this pro-oxidant effect of alpha-tocopherol is important in vivo or affects the stability or potency of other nutrients in a combined pill is unknown, but it illustrates the complexity of vitamin supplementation. The importance of a supplement's chemical form and potential vitamin-vitamin interaction can be exponentially expanded when we consider its potential interactions with other nutrients, supplements, and medications.

For these reasons, the use of vitamin and mineral supplements cannot be recommended based solely on mechanistic studies. Similarly, multiple biases and confounding by unmeasured covariates can affect the results of cohort (longitudinal) studies. These limitations diminish the ability of cohort studies to establish a causal link. As such, RCTs are essential to proving benefit and detecting harm. Unfortunately, the number of trials available for multiple and single vitamins is quite small considering the widespread use of these agents. This is partly due to the special regulatory environment for supplements and the lack of incentive for manufacturers to conduct randomized trials.

Previous USPSTF Recommendation

In 2003, the USPSTF concluded that the current evidence was insufficient to assess the balance of benefits and harms of the use of supplements of vitamins A, C, or E; multivitamins with folic acid; or antioxidant combinations for the prevention of cancer or CVD in asymptomatic adults (I statement). This review found poor-quality evidence to determine if vitamins reduce the risk for CVD or cancer, and available RCTs were inadequate or conflicting. Based on this review, the USPSTF recommended against the use of beta-carotene supplements, either alone or in combination, for the prevention of cancer or CVD in asymptomatic adults (D recommendation). This recommendation was based on good-quality evidence that beta-carotene had no benefit in the prevention of CVD and cancer and actually might cause harm in some adult populations (i.e., an increased risk of lung cancer in heavy smokers).1


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