A Closer Look at Discouraging Results from Dietary Supplement Studies

The study that led to the aforementioned media coverage, “Dietary Supplements and Mortality Rate in Older Women,” was published on October 10, 2011 in the Archives of Internal Medicine, a bi-monthly, peer-reviewed medical journal published by the American Medical Association. The authors’ conclusions were based on data collected from the Iowa Women’s Health Study, a long-term effort to examine the relationship between chronic disease and diet and lifestyle choices. The study began in 1986 with more than 40,000 participants between 55 and 69 years old.⁹

“It’s important to keep in mind that this is an associative—not a cause-and-effect—study,” said Duffy MacKay, vice president of scientific and regulatory affairs at CRN.⁸ “The study may make for interesting scientific water cooler discussion, but [it] certainly does not warrant sweeping, overstated concerns for elderly women.”

The data showed that the use of various supplements—including multivitamins, vitamin B6, folic acid, iron, magnesium, zinc, and copper—were associated with an increased risk of death among study participants. The correlation was most pronounced for iron. "Based on existing evidence, we see little justification for the general and widespread use of dietary supplements,” the authors concluded. However, the authors acknowledged that dietary supplements should “be used with strong medically based cause, such as symptomatic nutrient deficiency.”¹

Nutrition research expert Alan R. Gaby, MD, argues that flaws in the study’s methodology should lessen the validity of the findings. “They did not report the actual death rates, only the statistically adjusted death rates of supplement users compared to non-users,” he explained. “The problem is, for every category in which they made this adjustment—caloric intake, cigarette smoking, body mass index, blood pressure, diabetes, physical activity, and intake of fruits and vegetables—the supplement users were in the healthier category.”¹⁰

According to Dr. Gaby, researchers over-adjusted the supplement users death rates because of their overall better health, skewing the results. “The authors of the study have reached an incorrect conclusion, based on the data that were collected,” he said. “When the data were adjusted only for age and caloric intake, there was no statistically significant difference in death rate between the 2 groups.”¹⁰

Although less publicized, researchers discontinued a study designed to assess the affect of omega-3 oil and antioxidant supplementation in patients with acute lung disease after finding no benefit and a potential for harm. According to the article, which was published in early October, participants receiving omega-3 supplements spent more time on ventilators and in the intensive care unit. The 60-day mortality rate for patients receiving omega-3 supplements was greater as well.³

More recently, researchers from the Cleveland Clinic published a study in JAMA that linked vitamin E use to an increased risk of prostate cancer. The authors’ conclusions were based on data from the Selenium and Vitamin E Cancer Prevention Trial (SELECT), which began in 2001. Funded primarily by the National Cancer Institute (NCI), the study found that men who took daily vitamin E supplements were 17% more likely to develop prostate cancer.⁴

Researchers conducting the SELECT study used a type of synthetic vitamin E previously found to reduce the risk of developing prostate cancer in the Alpha-Tocopherol Beta Carotene (ATBC) Study, which was designed to assess the effect of vitamin E and beta carotene on lung cancer in Finnish male smokers.¹¹ NCI noted that because the ATBC Study was not designed to assess the relationship between vitamin E and prostate cancer, its findings may, in fact, be due to chance.

“Another possible reason that men in ATBC had a reduction in prostate cancer incidence, while men on SELECT did not, is that the dose of vitamin E used in SELECT (400 IU/day) was higher than the dose used in the ATBC (50 IU/day),” NCI explained on its website. “Researchers sometimes talk about a ‘U-shaped response curve’ where very low or very high blood levels of a nutrient are harmful but more moderate levels are beneficial; while the ATBC dose may have been preventive, the SELECT dose may have been too large to have a prevention benefit.”¹¹

According to the Linus Pauling Institute—a micronutrient research center at Oregon State University—vitamin E is an umbrella term for 8 distinct antioxidants with slightly different chemical structures. “Alpha-tocopherol is the only form of vitamin E that is actively maintained in the human body,” the Institute’s website explained. “The form of alpha-tocopherol found in foods is  RRR-alpha-tocopherol (also referred to as ‘natural’ or  d-alpha-tocopherol). Synthetic alpha-tocopherol, which is labeled all-rac- or dl-alpha-tocopherol, has only one-half the biological activity of RRR-alpha-tocopherol.”¹²

Dr. Gaby described how the distinction between the various forms of vitamin E is essential to understanding its impact on the human body. “Isolated alpha-tocopherol is the form present in most vitamin E supplements, and is the form of vitamin E used in almost all clinical research. But we know that large doses of the alpha form deplete the body of the gamma form, and this upsets the natural balance of vitamin E derived from food,” he said. “Because of this, it appears that large doses of isolated alpha-tocopherol may be harmful.”

Shortly after the Cleveland Clinic study was published, CRN issued a press release questioning the authors’ conclusions. “Even taking the results of this SELECT research at face value, although ‘statistically significant’ to a statistician, one wonders if an absolute increase in the risk of prostate cancer of 1.6 cases per 1,000 person-years is really a ‘significantly increased risk of prostate cancer’ as noted in the article,” said MacKay.¹³

According to Neil Levin, nutrition editor at NOW Foods in Bloomingdale, Illinois: “There are dietary sources, synergies, and dependencies for antioxidants that affect their serum levels and potential toxicity more than measuring supplemental levels. Isolated dosing of single nutrients is more of a drug model that often does not do justice to the way that antioxidants work in vivo,” he said. “In other words, a lack of data on dietary intakes, and the influences of other nutrients, makes supplementation alone a poor predictor of either serum levels or how the nutrient operates in any individual's body. Other non-causal relationships, such as why people may take supplements to compensate for perceived health deficits, are other often ignored variables” (e-mail, October 31, 2011).

CRN recommends that concerned individuals talk to their doctors about which supplements are right for them. Despite the media attention, MacKay says that drastic action is not required based on the results of these studies. “Your best chance for living a long and healthy life is to engage in healthy lifestyle practices, and many in the scientific community maintain that rational, reasonable use of vitamins and other supplements is part of that equation,” said MacKay. “Talk to your doctor, or other healthcare practitioner, if you have concerns—but read between the lines of individual studies and don’t make your decisions—either for or against supplements—based solely on hype.”⁸

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