Vitamins and Dietary Supplements: Controversy and Confusion

Liron D. Sinvani, MD¹ • Christian N. Nouryan, MA² • Renee Pekmezaris, PhD^2-5 • Gisele P. Wolf-Klein, MD^1,5,6

Affiliations:

¹Department of Medicine-Geriatrics, North Shore-LIJ Health System, Great Neck, NY
²Department of Population Health and Health Services Research, North Shore-LIJ Health System, Great Neck, NY
³Department of Patient Oriented Research, Feinstein Institute for Medical Research, Manhasset, NY
⁴Department of Population Health, Hofstra North Shore-LIJ School of Medicine, Hofstra University, Hempstead, NY
⁵Division of Geriatrics, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
⁶Department of Medicine, Hofstra North Shore-LIJ School of Medicine, Hofstra University, Hempstead, NY
____________________________________________________________________________________________________________________________________

Abstract: Millions of Americans routinely consume dietary supplements, making it into a billion-dollar industry. However, despite their vast popularity among persons of all ages, there are conflicting data as to whether using these supplements is effective in the prevention of chronic illness or promotes overall health. In many studies, use of supplements has been associated with severe adverse outcomes and increased all-cause mortality. Conflicting evidence can be very confusing to physicians as well as patients. This article synthesizes the current body of literature to identify the most significant evidence that supports and refutes the use of vitamins and dietary supplements. In geriatric patients, physicians should be aware of the potential negative outcomes before recommending supplements to their patients until more conclusive studies are conducted in this unique patient population.

Key words: Vitamins, dietary supplements, complementary and alternative medicine, preventive medicine.
__________________________________________________________________________________________________________________________________

More than 100 million Americans routinely consume dietary supplements.¹ The vitamin industry boasts annual sales of nearly $30 billion in the United States, with steady growth seen over the past 5 years, which is impressive considering this growth occurred during a worldwide recession.² This phenomenon is not restricted to the United States alone, as similar trends are seen across Japan and Europe, with the global supplement market valued at $68 billion.³

Despite the extreme popularity of supplements and their important role in medical history, new and emerging research has created controversy regarding whether these supplements may cause more harm than benefit. In this article, we review the conflicting evidence regarding the use of vitamins and dietary supplements to prevent chronic disease and promote overall health and wellness. The history of supplements is briefly discussed to place our evolving understanding of their role in healthy diets into the larger context of modern medicine. Assuming that the use of supplements by the general population will continue to grow, clinical take-home points are dispersed throughout this article so that physicians can properly advise patients who inquire about their value and safety.

A Brief History of Vitamins and Supplements 

The earliest use of dietary supplements is documented in the Kahun Gynecological Papyrus (1800 BC).⁴ The text contains diagnoses and treatments for women’s health issues, including gynecological disease and fertility. Rough translations of the ancient text allude to eating raw liver to treat blindness, aching eyes, and neck pain.⁴ In 1753, British naval surgeon James Lind published Treatise of the Scurvy, which reported the results of one of the first systematic clinical trials ever conducted; his work identified that citrus fruit (ie, vitamin C) could cure scurvy.⁵ In the 1880s, Japanese naval medical officer Takaki Kanehiro observed that beriberi, a disease causing inflammation of the nerves and heart failure, more commonly occurred in poor sailors (prisoners, low ranked sailors), who had limited diets (ie, rice) as compared with the naval officers, whose diets included various types of meat and vegetables.⁶ Kanehiro concluded that beriberi was more likely a nutritional deficiency (later identified as vitamin B₁ deficiency), and not an infectious disease, as his contemporary medical officers believed.

In the early 1900s, scientists began to isolate individual vitamins. In 1912, Polish-born chemist Casimir (Kazimierz) Funk presented his scientific approach to isolating the substances responsible for curing several diseases, including beriberi and scurvy, and coined the term vitamine deficiencies (vita meaning life in Latin; amine meaning nitrogen-containing organic compound).^7,8  His work culminated in 1914 with the publication of The Vitamines.⁷ By 1941, the 13 essential vitamins needed for normal cell function and growth were isolated and named.⁸

According to Harper,⁹ the first official dietary recommendation came from the British Parliament with the passage of the Merchant Seaman’s Act of 1835. It was not until World War I that the United States government issued its own set of dietary recommendations, which established standards for daily calories and protein intake (70-80 g daily and 3000 calories for men and armed forces personnel, with scaled-down values for women and children).^9,10 The Food and Nutrition Board was established in 1940, having originated from a committee set up by the US National Academy for Sciences during World War II.⁹ The Food and Nutrition Board was responsible for establishing the first set of Recommended Dietary Allowance (RDA) guidelines.^9,11 The RDA was updated periodically until 1994, when a new paradigm was developed by the Institute of Medicine (IOM): Dietary Reference Intakes (DRI).¹¹ Whereas RDAs were the average daily intake meeting the requirements of 97.5% of the general population, DRIs focus on the average required nutritional needs of the population according to age group and sex.¹¹ The IOM continues to update DRIs with new scientific research. A comprehensive set of DRI resources is available at the US Department of Agriculture (USDA) Website.

Today, advertising for dietary supplementation targets every segment of the population, from infants to older adults, with a supplement to suit nearly every need. Preventing chronic conditions and maintaining high functioning and independence are chief concerns for the aging baby boomers, who represent a major driver of growth in the vitamin and supplement industry. Moreover, physicians and nurses have become just as likely as the average consumer to use dietary supplements, several recent surveys have found.^12,13 In a 2009 survey of 900 physicians and nearly 300 nurses, 72% of physicians and 89% of nurses reported using dietary supplements.¹² Moreover, 79% of physicians and 82% of nurses said they have recommended dietary supplements to their patients. In 2011, a survey of 900 physicians found high usage of occasional dietary supplements among cardiologists (57%), dermatologists (75%), and orthopedists (73%).¹³ These physicians frequently recommended use of dietary supplements to their patients for reasons related to their specialty, and noted orthopedists as the most frequent group to recommend supplements (91%).

The Vitamin Conundrum

One of the biggest barriers to fully understanding the safety and efficacy of supplements is the lack of standardized terminology in clinical studies. Because the US Food and Drug Administration (FDA) does not strictly regulate vitamins and dietary supplements, there are no standard or regulatory definitions to differentiate between vitamins, multivitamins, mineral supplements, and dietary supplements (ie, what nutrients each contains or in what amounts). Manufacturers have applied these terms without consistency to products that have varied compositions and characteristics.¹⁴ For example, one product may be labeled as a dietary supplement even if it contains the same type and amount of vitamins and minerals as a different products labeled as a multivitamin. For the purpose of this literature review, we will use the terms that the investigators of each study have used.

At least in industrialized countries today, decades of nutrition research have certainly made life-threatening vitamin deficiencies far less common than in the past. In the United States, standardized practices of food fortification and affordable, well-balanced meals have reduced the incidence of nutritional deficiencies.¹⁵ With these advancements in nutrition, one may question the need for supplementation. Federal guidelines, such as the 2010 Dietary Guidelines for Americans issued by the USDA and the US Department of Health and Human Services, advise meeting nutrient requirements primarily through consuming foods, with limited vitamin and dietary use.¹⁶ The guidelines support the use of supplements in pregnant and breastfeeding women (eg, iron), women of child-bearing age (eg, folic acid), and individuals aged 50 years and older (eg, vitamin B₁₂). The guidelines give the following statement regarding supplement use¹⁵:

Sufficient evidence is not available to support a recommendation for or against the use of multivitamin/mineral supplements in the primary prevention of chronic disease for the healthy American population. Supplements containing combinations of certain nutrients may be beneficial in reducing the risks of some chronic diseases when used by special populations. For example, calcium and vitamin D supplements may be useful in postmenopausal women who have low levels of these nutrients in their diets, to reduce their risk of osteoporosis. In contrast, high levels of certain nutrient supplements may be harmful, if a nutrient’s Tolerable Upper Intake Level is exceeded. Supplement use may be discussed with a health care provider to establish need and correct dosage.

Unlike production and distribution of medication, the supplement industry is not subject to strict regulation by the FDA. Dietary supplements are classified under the “food” umbrella per the Dietary Supplement Health and Education Act (DSHEA) of 1994.¹⁷ The DSHEA states that ingredients sold in the United States prior to 1994 may be marketed without evidence of efficacy or safety. For newer ingredients (ie, introduced after 1994), the DSHEA requires that manufacturers provide the FDA with evidence supporting a “reasonable expectation of safety.”¹⁷ As a consequence of this act, from 1994 to 2012, the number of supplements on the market increased from 4000 to 55,000, but only 170 new supplements were reported to the FDA.¹ In 2011, the FDA issued a Draft Guidance letter proposing new regulations for dietary supplements. The purpose, as the FDA reported, is to assist the supplement industry with assessing whether a premarket safety notification for dietary supplements containing a new dietary ingredient is necessary, and if so, how to prepare these notifications.¹⁸ Although the guidelines are not yet established as legally enforceable responsibilities, they came under fire by many individuals in the supplement industry, who criticize the guidelines for being too stringent. Opponents have argued that requiring scientific evidence of safety undermines the stipulations of the DSHEA. The full extent of these proposed regulations is yet to be determined.¹

However, lack of regulation may pose public health consequences. Recent studies have demonstrated that commonly used vitamins and minerals such as antioxidants, including vitamin A and vitamin E, calcium, vitamin D, folic acid, and omega-3 fatty acids, are associated with increased mortality and other adverse outcomes.^19-23 At the same time, studies continue to suggest benefits of vitamins and dietary supplements for a variety of medical conditions, including cancer.^24,25 While the medical profession often views vitamins and supplements as simply producing “expensive urine,”²⁶ the real question is: are vitamins and dietary supplements beneficial or harmful? These contradictory findings can be very confusing to both physicians and patients. What follows is a brief overview of the evidence that supports and refutes the use of antioxidants, B vitamins, and omega-3 fatty acids.

The Iowa Women's Health Study 
The Iowa Women’s Health Study (IWHS) was designed to explore the dietary habits and health outcomes of more than 40,000 postmenopausal women (aged 55-69 years at baseline; mean age, 61.6 years).²⁷ Specifically, the primary aims of the IWHS were to determine if the distribution of body fat predicts incidence of chronic diseases, with primary end points being total mortality and incident cancers of the breast, endometrium, and ovaries; and to determine what degree diet and other lifestyle factors influence risk of chronic disease.²⁸ Data regarding participants’ lifestyles and use of dietary supplements were collected over 18 years via surveys conducted in 1986, 1989, 1992, 1997, and 2004. Forty percent of the sample (N=15,600) had died by 2006. The study demonstrated that 85% of respondents between the ages of 55 and 69 took at least one dietary supplement per day, with almost 30% taking four or more.²⁹ Overall use increased from 66% in 1984 to 85% in 2004. The most commonly used vitamins and supplements in 2004 were multivitamins (62.5%), calcium (60.5%), vitamin E (31.9%), vitamin C (28.9%), and vitamin D (11.9%).²⁹

More than 300 papers have been published based on analyses of IWHS data.²⁸ A 2011 study Mursu and colleagues²⁹ is considered a landmark longitudinal study because it concluded that several commonly used dietary supplements, especially supplemental iron, are associated with increased mortality risk in older women. Specifically, increased mortality was associated with the use of multivitamins (absolute risk increase of 2.4%), iron (3.9%), folic acid (5.9%), vitamin B₆ (4.1%), magnesium (3.6%), zinc (3%), and copper (18%). Although causality was not proven in this study, these results remain unsettling.

Multivitamins are the most commonly used dietary supplement, with more 60% of women in the IWHS reporting their use.²⁹ Yet, the 2010 Dietary Guidelines for Americans did not find evidence to recommend the use of multivitamins in the prevention of chronic disease.^16,30,31 The Iowa study has found an association between standard multivitamin use and increased mortality risk; additionally, there is data suggesting whether supplements increase cancer risk. From 1986 to 2009, more than 10,000 incident cancers occurred in the cohort participants.²⁸  However, the results of a randomized controlled trial published in 2012 demonstrated daily multivitamin use significantly reduced the incidence of total cancer (hazard ratio, .92).^24,29 These contradicting findings are puzzling.

One of the most striking findings of the IWHS was the strong, dose-dependent association between iron and mortality risk. Data from the National Health and Nutrition Examination Survey (NHANES) suggest that men and postmenopausal women consume the recommended 8 mg per day of iron. One 300 mg tablet of iron sulfate contains 50 to 60 mg of elemental iron. Misuse of iron supplementation may pose a risk for toxicity in people who are not iron deficient.³² Iron overload has been associated with heart disease.^33,34 On the contrary, appropriate iron stores are associated with lower rates of heart disease.³⁵ 

Continued on next page

Risks and Benefits of Antioxidants 
In addition to the Iowa study, several other publications, such as the Nurse’s Health Study, the SELECT (Selenium and Vitamin E Cancer Prevention) trial, and multiple meta-analyses,have gathered evidence over the past decade supporting concern regarding potentially harmful side effects of antioxidant supplementation.^36-39 Antioxidants, such as vitamin A, vitamin E, vitamin C, and selenium, have been thought to prevent or delay chronic diseases, such as cancer, cardiovascular disease, and dementia. Whereas diets rich in antioxidants are associated with lower risks, supplementation with antioxidants is not recommended by agencies such as the National Institutes of Health (NIH), due to insufficient evidence of benefit.^40-42

In the United States, there are some food products, such as milk, yogurt, and cereals, that are fortified with vitamin A. Data from NHANES (1999-2000) show that the average American consumes about 3300 IU per day, a value above the RDI for vitamin A (between 2000-3000 IU per day depending on age).⁴³ Some foods that are rich in vitamin A and provide more than the necessary daily value include sweet potatoes (one has 561% of the recommended daily value) cantaloupe, pumpkin pie, carrots, spinach, and liver.³² Of note, a typical multivitamin provides between 2500 and 10,000 IU vitamin A, which is substantially more than the current RDI.

Over the past few decades, studies have raised concern regarding vitamin A supplementation, even in limited amounts. In 1996, a randomized-controlled trial concluded that supplementation with vitamin A and its derivatives was associated with adverse events, including cancer and increased mortality.⁴⁴ The Nurses’ Health Study in 2002 demonstrated an association between vitamin A supplementation and osteopenia with fractures.³⁶ More recently, a 2012 Cochrane review article, which contained 67 trials with more than 230,000 total participants, found that treatment with vitamin A, vitamin E, and beta-carotene (at median doses of 1650 μg, 400 mg, and 15.5 mg, respectively) was associated with an increase in mortality.¹⁹

With regard to vitamin E, the Food and Nutrition Board set the RDI between 6 IU and 28.4 IU per day, depending on age. Vitamin E supplementation has been used to prevent and treat coronary heart disease, cancer, cognitive decline, and eye disorders. However, the Institute of Medicine has determined that there is insufficient evidence for routine use of vitamin E.⁴² According to the NHANES database, 11.3% of adults take at least 400 IU of vitamin E daily. Most vitamin E supplements contain at least 100 IU, with some providing more than 400 IU—values well above the recommended intakes.

Vitamin E has been commonly used by older men to prevent prostate cancer. In 2011, the SELECT trial examined associations between vitamin E, selenium supplementation, and prostate cancer.³⁷ This multinational randomized controlled trial followed 35,000 men for a median of 7 years and had four arms: vitamin E (400 IU/day) alone, selenium (200 μg/day) alone, both vitamin E and selenium, and a placebo. The three intervention groups were associated with an increased risk of prostate cancer over the placebo, while vitamin E alone was significantly associated with an increased risk of prostate cancer by 17% after 7 years.³⁷

On the other hand, a recent Italian study suggests that patients who underwent a polypectomy may benefit from an antioxidant cocktail.²⁵ In this double-blind trial, 411 patients were randomized to receive a combination of selenium 200 μg, zinc 30 mg, vitamin A 2 mg, vitamin C 180 mg, and vitamin E 30 mg, or a placebo. The study revealed a statistically significant 39% risk reduction of adenoma recurrence after a 4-year median follow-up (range 1-15 years).²⁵

Similarly, although a diet rich in antioxidants has demonstrated protective properties against dementia, the data on the benefits of antioxidant supplements are mixed.⁴¹ New research questions supplement use in Alzheimer’s disease.⁴⁵ In a double-blind, placebo-controlled clinical trial, the antioxidant combination of vitamin E 800 IU daily, vitamin C 500 mg daily, and alpha-lipoic acid (ALA) 900 mg daily demonstrated a small reduction in cerebrospinal fluid markers that may represent a decrease in oxidative stress.⁴⁵ However, the supplemental combination of vitamin E, vitamin C, and ALA was associated with significant cognitive decline as characterized by lower scores on the Mini-Mental State Examination.

Vitamin C has been used for the prevention and treatment of cancer, cardiovascular disease, age-related macular degeneration and cataracts, and the common cold. Although vitamin C supplementation has low potential for toxicity, several studies have shown association with health risks.^29,46 In the IWHS, vitamin C supplementation was associated with an increased risk of cardiovascular mortality, and mega-doses of vitamin C in the setting of iron overload have been associated with arrhythmias.^29,46

The B Vitamins 
Folate, a water-soluble B vitamin, is found in supplements and fortified foods. It is a general consensus that women who are pregnant should take folate to decrease the risk of birth defects. Vitamin B₁₂ is recommended for vegetarians, who may experience deficiencies, as a result of not eating fish, meat, or dairy products—the chief providers of B₁₂.^47,48 However, folate has been studied inconclusively for the prevention of many diseases, such as cancer, cardiovascular disease, hypertension, and hearing loss.^15,49 Folic acid supplementation in individuals who are not deficient has been associated with increased malignancy. A recent review of 10 randomized controlled trials of folic acid supplementation showed a borderline significant association with frequency of overall cancer. Six of those trials looked at specific cancers and found a positive association with prostate cancer.²⁰

Omega-3 Fatty Acids 
Considerable interest in omega-3 fatty acids developed in the late 1970s, as scientists noticed low incidence of mortality, cardiovascular disease, asthma, and inflammatory disease in Eskimos (natives of Greenland), whose diets consist mainly of fatty fish.⁵⁰ Today, the American Medical Association recommends eating fish at least twice per week to maintain healthy levels of these essential nutrients required by the human body.⁵¹ Omega-3 fatty acids are used widely for the prevention and treatment of coronary artery disease, high cholesterol, dementia, depression, asthma, and inflammatory diseases. Supplements are readily available in many forms, including prescription medications, often labeled as “medical foods,” such as omega-3-acid ethyl ester or eicosapentaenoic acid (EPA) and over-the-counter formulations, such as docosahexaenoic acid (DHA). While the benefit of a diet rich in omega-3 fatty acids is clear, the use of supplements has been more controversial.

Two separate 2012 meta-analyses of placebo-controlled trials with 68,680 participants and 20,485 participants, respectively, found that evidence for the consumption of omega-3 fatty acids (average daily dose EPA 1.51 g or .77 g, DHA .60 g daily; and average daily dose of EPA or DHA 1.7 g daily, [range, 0.4-4.8 g daily], respectively) is insufficient for primary and secondary cardiovascular prevention with regard to cardiac death and all-cause mortality.^52,53 In addition, a 2012 double-blind randomized control trial of 12,526 subjects found that daily supplementation of omega-3 fatty acids 1 g did not reduce the rate of cardiovascular events, even in high-risk patients.⁵⁴

A 2012 study of 2501 individuals aged 45 to 80 years showed a potential association between omega-3 supplementation and adverse outcomes.²¹ After 5 years, 7% of the subjects developed cancer and 2% died. Among women, there were 21 cases of cancer in the intervention group and eight cases in the control group. Supplementation of omega-3 was significantly and strongly associated with an increased risk of cancer and cancer mortality in women (hazard ratio=3.02 and 5.49, respectively).²¹ The authors found no significant association between cancer outcomes and B vitamins.

Conclusion 

The vitamin and dietary supplement industry is a loosely regulated multibillion-dollar business. The widespread use of supplements raises medical, social, and ethical concerns, given the unclear benefits and the associations with health risks. In the absence of convincing guidelines, healthcare professionals need to keep abreast of current research to appropriately counsel their patients regarding the potential benefits and the possible adverse effects of vitamin and supplement use. A balanced diet, rich in natural nutrients, and, when appropriate, supplemented in a safe manner, is the best approach to preventive care.

References

1. Cohen PA. Assessing supplement safety–the FDA’s controversial proposal. N Engl J Med. 2012;366(5):389-391.

2. Vitamin and Supplement Manufacturing in the US: Market Research Report. IBIS World. www.ibisworld.com/industry/default.aspx?indid=490. Accessed November 27, 2012.

3. Vitamin and Supplement Industry: Market Research Reports, Statistics and Analysis. Report Linker. www.reportlinker.com/ci02037/Vitamin-and-Supplement.html. Accessed November 27, 2012.

4. Griffith FL. The Petrie Papyri: Hieratic Papyri from Kahun and Gurob. London, England: Bernard Quaritch; 1898:6. www.etana.org/sites/default/files/coretexts/15145.pdf. Accessed November 27, 2012.

5. Bartholomew M. James Lind’s Treatise of the Scurvy. Postgrad Med J. 2002;78(925):695-696.

6. Itokawa Y. Kanehiro Takaki (1849-1920) - a biographical sketch. J Nutr. 1976;106(5):581-588.

7. Griminger P. Casimir Funk - a biographical sketch. J Nutr. 1972;102(9):1105-1113.

8. Rosenfeld L. Vitamine -- vitamin. The early years of discovery. Clin Chem. 1997;43(4):680-685.

9. Harper AE. Contributions of women scientists in the US to the development of recommended dietary allowances. J Nutr. 2003;133(11):3698-3702.

10. Stiebeling HK. Food budgets for nutrition and production programs. Washington, DC: US Department of Agriculture; 1933:183.

11. A Report of the Subcommittees on Interpretation and Uses of Dietary Reference Intakes and Upper Reference Levels of Nutrients, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board. Dietary Reference Intakes: Applications in Dietary Assessment. Washington, DC: The National Academies Press; 2000:29.

12. Dickinson A, Boyon N, Shao A. Physicians and nurses use and recommend dietary supplements: report of a survey. Nutr J. 2009;8:29.

13. Dickinson, A, Shao A, Boyon N, Franco JC. Use of dietary supplements by cardiologists, dermatologists and orthopedists: report of a survey. Nutr J. 2011;10:20.

14. National Institutes of Health Office of Dietary Supplements. Multivitamin/mineral supplements. http://ods.od.nih.gov/factsheets/MVMS-HealthProfessional/. Updated January 13, 2013. Accessed March 8, 2013.

15. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B₆, Folate, Vitamin B₁₂, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academies Press; 1998.

16. US Department of Agriculture, US Department of Health and Human Services. Dietary Guidelines for Americans 2010. 7^th ed. Washington, DC: US Government Printing Office; 2010.  www.cnpp.usda.gov/Publications/DietaryGuidelines/2010/PolicyDoc/PolicyDoc.pdf. Accessed November 27, 2012.

17. Dietary Supplement Health and Education Act of 1994. Public Law No. 103-417. Office of Dietary Supplements. http://ods.od.nih.gov/about/dshea_wording.aspx. Published October 25, 1994. Accessed November 27, 2012.

18. US Food and Drug Administration. Draft guidance for industry: dietary supplements: new dietary ingredient notifications and related issues. Published July 2011. Accessed March 8, 2013.

19. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2012;3:CD007176.

20. Wien TN, Pike E, Wisløff T, Staff A, Smeland S, Klemp M. Cancer risk with folic acid supplements: a systematic review and meta-analysis. BMJ Open. 2012;2(1):e000653.

21. Andreeva VA, Touvier M, Kesse-Guyot E, Julia C, Galan P, Hercberg S. B vitamin and/or ω-3 fatty acid supplementation and cancer: ancillary findings from the supplementation with folate, vitamins B6 and B12, and/or omega-3 fatty acids (SU.FOL.OM3) randomized trial. Arch Intern Med. 2012;172(7):540-547.

22. Amer M, Qayyum R. Relation between serum 25-hydroxyvitamin D and C-reactive protein in asymptomatic adults (from the continuous National Health and Nutrition Examination Survey 2001 to 2006). Am J Cardiol. 2012;109(2):226-230.

23. Bolland M, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040.

24. Gaziano JM, Sesso HD, Christen WG, et al. Multivitamins in the prevention of cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2012;308(18):1871-1880.

25. Bonelli L, Puntoni M, Gatteschi B, et al. Antioxidant supplement and long-term reduction of recurrent adenomas of the large bowel. A double-blind randomized trial. J Gastroenterol. Published online ahead of print October 13, 2012.

26. Lewis M, Lewis G. Dietary Supplements: Creating Expensive Urine? Or, a Key Addition to Modern Medicine? Lewis Publications, 2007.

27. Park K, Harnack L, Jacobs DR Jr. Trends in dietary supplement use in a cohort of pstmenopausal women from Iowa. Am J Epidemiol. 2009;169(7):887-892.

28. Iowa Women’s Health Study. University of Minnesota Masonic Cancer Center Website. Updated May 18, 2012. Accessed March 8, 2013.

29. Mursu J, Robien K, Harnack LJ, Park K, Jacobs DR Jr. Dietary supplements and mortality rate in older women: the Iowa Women’s Health Study. Arch Intern Med. 2011;171(18):1625-1633.

30. Park SY, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN. Multivitamin use and the risk of mortality and cancer incidence: the multiethnic cohort study. Am J Epidemiol. 2011;173(8):906-914.

31. Li K, Kaaks R, Linseisen J, Rohrmann S. Vitamin/mineral supplementation and cancer, cardiovascular, and all-cause mortality in a German prospective cohort (EPIC-Heidelberg). Eur J Nutr. 2012;51(4):407-413.

32. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium and Zinc. Washington, DC: National Academies Press; 2001:290.

33. Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology. 2011;283(2-3):65-87.

34. Sempos CT, Looker AC, Gillum RF, Makuc DM. Body iron stores and the risk of coronary heart disease. N Engl J Med. 1994;330(16):1119-1124.

35. Sullivan JL. Iron therapy and cardiovascular disease. Kidney Int Suppl. 1999;69:S135-S137.

36. Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. JAMA. 2002; 287(1):47-54.

37. Klein EA, Thompson IM Jr, Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011;306(14):1549-1556.

38. Caraballoso M, Sacristan M, Serra C, Bonfill X. Drugs for preventing lung cancer in healthy people. Cochrane Database Syst Rev. 2003;(2):CD002141.

39. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet. 2003;361(9374):2017-2023.

40. Stanner SA, Hughes J, Kelly CN, Buttriss J. A review of the epidemiological evidence for the 'antioxidant hypothesis'. Public Health Nutr. 2004;7(3):407-422.

41. Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA. 2002;287(24):3223-3229.

42. Institute of Medicine, Food and Nutrition Board. DRI Dietary Reference Intakes: Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academies Press; 2000.

43. Food and Nutrition Board. Dietary Reference Intakes: Tolerable Upper Intake Levels, Vitamins. United States Department of Agriculture Website. Accessed March 8, 2013.

44. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):1150-1155.

45. Galasko DR, Peskind E, Clark CM, et al. Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Arch Neurol. 2012;69(7):836-841.

46. McLaran CJ, Bett JH, Nye JA, Halliday JW. Congestive cardiomyopathy and haemochromatosis—rapid progression possibly accelerated by excessive ingestion of ascorbic acid. Aust N Z J Med. 1982;12(2):187-188.

47. Supplements: A scorecard. Harvard Health Publications. https://www.health.harvard.edu/newsletters/Harvard_Mens_Health_Watch/2012/April/supplements-a-scorecard. Published April 2012. Accessed November 28, 2012.

48. Elmadfa I, Singer I. Vitamin B-12 and homocysteine status among vegetarians: a global perspective. Am J Clin Nutr. 2009;89(5):1693S-1698S.

49. Martí-Carvajal AJ, Solà I, Lathyris D, Salanti G. Homocysteine lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2009;4:CD006612.

50. Bang HO, Dyerberg J, Sinclair HM. The composition of the Eskimo food in north western Greenland. Am J Clin Nutr. 1980;33(12):2657-2661.

51. Fish 101. American Heart Association. www.heart.org/HEARTORG/GettingHealthy/NutritionCenter/Fish-101_UCM_305986_Article.jsp. Updated January 20, 2012. Accessed November 28, 2012.

52. Kwak SM, Myung SK, Lee YJ, Seo HG. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012;172(9):686-694.

53. Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA. 2012;308(10):1024-1033.

54. ORIGIN Trial Investigators, Bosch J, Gerstein HC, et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367(4):309-318.

Disclosures: The authors report no relevant financial relationships.

Address correspondence to: Renee Pekmezaris, PhD, North Shore-LIJ Health System, 175 Community Drive, 2nd Floor Suite 242G, Great Neck, NY 11021; rpekmeza@nshs.edu