Vitamins and Mortality: In Defense of Supplements

From Medscape Internal Medicine

Vitamins and Mortality: In Defense of Supplements

Ayaz Virji, MD

The article by Mursu and colleagues^[1] that was recently reported on in Medscape News (see Medscape article below) indicates that ad libitum use of multivitamins does not reduce all-cause mortality in women; to the contrary, it may slightly increase it. This arm of the Iowa Women's Health Study consisted of 38,772 elderly white women with a mean age of 61.6 years who were followed over 20 years. This well-designed, observational cohort study adjusted for diverse confounders, including body mass index (BMI), physical activity, smoking status, and educational level.

When interpreting these results, as for any other nutraceutical intervention, it would be imprudent to make broad, imprecise statements about the "ineffectiveness" of dietary supplements, although it may be tempting to do so. It is important to consider the limitations of the study to help prevent unscientific conclusions. The authors themselves conceded, "It is not advisable to make a causal statement of excess risk based on these observational data."^[1]
 
Mursu and colleagues' study, although well executed, has several methodological limitations. It used the Harvard Service Food Frequency Questionnaire, which was originally designed to assess the diets of low-income women and gather information on dietary supplements used. However, the dietary supplement portion of the questionnaire has not been independently validated. In addition, a certain subset of patients inappropriately substitutes dietary supplements for medications to manage chronic disease. This concerning, yet uncaptured, trend could potentially confound the results.

The study did not report on the specific doses, excluding calcium and iron, or source of the supplements used. Both of these factors play an important role in the net effect of supplements on patient health. Take vitamin E, for example. Recent studies show that supplemental vitamin E doses > 400 IU may increase risk for congestive heart failure and prostate cancer, although in aggregate the data are inconclusive.^[2,3]

The Nurses' Health Study found that women who consumed 100 IU of vitamin E daily had a 44% reduction in developing major coronary disease.^[4] Of note, 4 times the therapeutic dose of an angiotensin-converting enzyme inhibitor is likely to result in a similar reversal of outcome. There would be little disagreement regarding the inappropriateness of a conclusion on the safety and efficacy of an angiotensin-converting enzyme inhibitor without considering the dose or the population using it. The same consideration was not given to dietary supplements in this assessment, however. A targeted, rational strategy for supplement use, developed in partnership with a medical provider, is likely to lead to a different outcome than that reported in the current study.

As is the case for pharmaceutical agents, various isomers of the same vitamin have different clinical effects. Considering vitamin E again, alpha-tocopherol (which is more commonly found in supplements) and gamma-tocopherol (which is more commonly found in food sources) have different anti-inflammatory properties and vary in bioavailability. It is likely that a healthy ratio of these 2 substances is more important to preventing coronary artery disease than is taking one isomer in excess, which may deplete the other.^[5] In addition, unlike for pharmaceutical agents, the source of vitamin supplement plays an important role. Synthetic vitamin E (dl-alpha-tocopherol) is thought to be much less potent than its natural vitamin E (d-alpha-tocopherol) counterpart and may have a varying clinical effect.

Whether it's chromium and reduced carbohydrate cravings, carnitine and improved claudication symptoms, or green tea and greater life expectancy,^[6-8] much remains unanswered regarding the net effect of a particular supplemental nutrient or group of nutrients on overall health. Perhaps advancements in the field of nutrigenomics will help light our way on their utility. Nonetheless, when comparing apples to apples, "polynutrient" is far less toxic than polypharmacy; the latter incurs 100,000 related deaths annually. A conventional multivitamin supplement should still be generally recognized as safe.

References

1. 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;171:1625-1633. Abstract
2. 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;306:1549-1556. Abstract
3. Lonn E, Bosch J, Yusuf S, et al; HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer. JAMA. 2005;293:1338-1347. Abstract
4. Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med. 1993;328:1444-1449. Abstract
5. Jiang Q, Christen S, Shigenaga MK, Ames BN. gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr. 2001;74:714-722. Abstract
6. Martin J, Wang ZQ, Zhang XH, et al. Chromium picolinate supplementation attenuates body weight gain and increases insulin sensitivity in subjects with type 2 diabetes. Diabetes Care. 2006;29:1826-1832. Abstract
7. Brevetti G, di Lisa F, Perna S, et al. Carnitine-related alterations in patients with intermittent claudication: indication for a focused carnitine therapy. Circulation. 1996;93:1685-1689. Abstract
8. Kuriyama S, Shimazu T, Ohmori K, et al. Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study. JAMA. 2006;296:1255-1265. Abstract

From Medscape Medical News

Vitamin Supplements Associated With Increased Risk for Death

Emma Hitt, PhD

October 10, 2011 — In women aged 55 to 69 years, several widely used dietary vitamin and mineral supplements, especially supplemental iron, may be associated with increased risk for death, according to new findings from the Iowa Women's Health Study.

Although many vitamin supplements did not appear to be associated with a higher risk for total mortality, several were, including multivitamins, vitamins B₆, and folic acid, as well as minerals iron, magnesium, zinc, and copper.

Jaakko Mursu, PhD, from the Department of Health Sciences, Institute of Public Health and Clinical Nutrition at the University of Eastern Finland in Kuopio, Finland, and colleagues reported their findings in the October 10 issue of the Archives of Internal Medicine.
"Supplements are widely used, and further studies regarding their health effects are needed," Dr. Mursu and colleagues write. "Also, little is known about the long-term effects of multivitamin use and less commonly used supplements, such as iron and other minerals."
The current study sought to evaluate the link between supplement use and total mortality rate, using data from the Iowa Women's Health Study. A total of 38,772 older women were included in the analysis. Women were aged between 55 to 69 years, with an average of 61.6 years at the beginning of the study in 1986. Self-reported data on vitamin supplement use were collected in 1986, 1997, and 2004.

A total of 15,594 deaths were reported through December 31, 2008, representing about 40% of the initial participants. The use of multivitamins overall was associated with 2.4% increased absolute risk for death (hazard ratio, 1.06; 95% confidence interval, 1.02 - 1.10). Self-reported use of dietary supplements increased substantially between 1986 and 2004. In addition, supplement users had a higher educational level, were more physically active, and were more likely to use estrogen replacement therapy.

Vitamin B₆, folic acid, iron, magnesium, and zinc were associated with about a 3% to 6% increased risk for death, whereas copper was associated with an 18.0% increased risk for total mortality when compared with corresponding nonuse.

In contrast, use of calcium was inversely related to risk for death (hazard ratio, 0.91; 95% confidence interval, 0.88 - 0.94; absolute risk reduction, 3.8%).
The researchers assessed the findings for iron and calcium in more detailed analyses conducted during shorter periods (10-year, 6-year, and 4-year follow-up) and found results similar to those for the analyses conducted during the entire time.

"In agreement with our hypothesis, most of the supplements studied were not associated with a reduced total mortality rate in older women," Dr. Mursu and colleagues conclude. "In contrast, we found that several commonly used dietary vitamin and mineral supplements, including multivitamins, vitamins B₆, and folic acid, as well as minerals iron, magnesium, zinc, and copper, were associated with a higher risk of total mortality."

"Although we cannot rule out benefits of supplements, such as improved quality of life, our study raises a concern regarding their long-term safety," the authors add.
In a related editorial, Goran Bjelakovic, MD, DMSc, and Christian Gluud, MD, DMSc, from the Centre for Clinical Intervention Research, Cochrane Hepato-Biliary Group, Rigshospitalet, Copenhagen University Hospital, Denmark, note that the current study adds "to the growing evidence demonstrating that certain antioxidant supplements, such as vitamin E, vitamin A, and beta-carotene, can be harmful."

"We cannot recommend the use of vitamin and mineral supplements as a preventive measure, at least not in a well-nourished population," they add. "Those supplements do not replace or add to the benefits of eating fruits and vegetables and may cause unwanted health consequences."

This study was partially supported by the National Cancer Institute and the Academy of Finland, the Finnish Cultural Foundation, and the Fulbright program’s Research Grant for a Junior Scholar. One study author is an unpaid member of the Scientific Advisory Board of the California Walnut Commission. The other authors and editorialists have disclosed no relevant financial relationships.
 
Arch Intern Med. 2011;171:1625-1633,1633-1634.

Authors and Disclosures
Journalist
Emma Hitt, PhD

Emma Hitt is a freelance editor and writer for Medscape. Disclosure: Emma Hitt, PhD, has disclosed no relevant financial relationships. Dr. Hitt does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Dr. Hitt does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.