Study Finds No Benefit for Dietary Supplements
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Posted on April 16th, 2019 by Dr. Francis Collins
More than half of U.S. adults take dietary supplements . I don't, but some of my family members do. But does popping all of these vitamins, minerals, and other substances really lead to a longer, healthier life? A new nationwide study suggests it doesn't.
Based on an analysis of survey data gathered from more than 27,000 people over a six-year period, the NIH-funded study found that individuals who reported taking dietary supplements had about the same risk of dying as those who got their nutrients through food. What's more, the mortality benefits associated with adequate intake of vitamin A, vitamin K, magnesium, zinc, and copper were limited to food consumption.
The study, published in the Annals of Internal Medicine, also uncovered some evidence suggesting that certain supplements might even be harmful to health when taken in excess . For instance, people who took more than 1,000 milligrams of supplemental calcium per day were more likely to die of cancer than those who didn't.
The researchers, led by Fang Fang Zhang, Tufts University, Boston, were intrigued that so many people take dietary supplements, despite questions about their health benefits. While the overall evidence had suggested no benefits or harms, results of a limited number of studies had suggested that high doses of certain supplements could be harmful in some cases.
To take a broader look, Zhang's team took advantage of survey data from tens of thousands of U.S. adults, age 20 or older, who had participated in six annual cycles of the National Health and Nutrition Examination Survey (NHANES) between 1999-2000 and 2009-2010. NHANES participants were asked whether they'd used any dietary supplements in the previous 30 days. Those who answered yes were then asked to provide further details on the specific product(s) and how long and often they'd taken them.
Just over half of participants reported use of dietary supplements in the previous 30 days. Nearly 40 percent reported use of multivitamins containing three or more vitamins.
Nutrient intake from foods was also assessed. Each year, the study's participants were asked to recall what they'd eaten over the last 24 hours. The researchers then used that information to calculate participants' nutrient intake from food. Those calculations indicated that more than half of the study's participants had inadequate intake of vitamins D, E, and K, as well as choline and potassium.
Over the course of the study, more than 3,600 of the study's participants died. Those deaths included 945 attributed to cardiovascular disease and 805 attributed to cancer. The next step was to look for any association between the nutrient intake and the mortality data.
The researchers found the use of dietary supplements had no influence on mortality. People with adequate intake of vitamin A, vitamin K, magnesium, zinc, and copper were less likely to die. However, that relationship only held for nutrient intake from food consumption.
People who reported taking more than 1,000 milligrams of calcium per day were more likely to die of cancer. There was also evidence that people who took supplemental vitamin D at a dose exceeding 10 micrograms (400 IU) per day without a vitamin D deficiency were more likely to die from cancer.
It's worth noting that the researchers did initially see an association between the use of dietary supplements and a lower risk of death due to all causes. However, those associations vanished when they accounted for other potentially confounding factors.
For example, study participants who reported taking dietary supplements generally had a higher level of education and income. They also tended to enjoy a healthier lifestyle. They ate more nutritious food, were less likely to smoke or drink alcohol, and exercised more. So, it appears that people who take dietary supplements are likely to live a longer and healthier life for reasons that are unrelated to their supplement use.
While the study has some limitations, including the difficulty in distinguishing association from causation, and a reliance on self-reported data, its findings suggest that the regular use of dietary supplements should not be recommended for the general U.S. population. Of course, this doesn't rule out the possibility that certain subgroups of people, including perhaps those following certain special diets or with known nutritional deficiencies, may benefit.
These findings serve up a reminder that dietary supplements are no substitute for other evidence-based approaches to health maintenance and eating nutritious food. Right now, the best way to live a long and healthy life is to follow the good advice offered by the rigorous and highly objective reviews provided by the U.S. Preventive Services Task Force . Those tend to align with what I hope your parents offered: eat a balanced diet, including plenty of fruits, veggies, and healthy sources of calcium and protein. Don't smoke. Use alcohol in moderation. Avoid recreational drugs. Get plenty of exercise.
 Trends in Dietary Supplement Use Among US Adults From 1999-2012. Kantor ED, Rehm CD, Du M, White E, Giovannucci EL. JAMA. 2016 Oct 11;316(14):1464-1474.
 Association among dietary supplement use, nutrient intake, and mortality among U.S. adults.. Chen F, Du M, Blumberg JB, Ho Chui KK, Ruan M, Rogers G, Shan Z, Zeng L, Zhang. Ann Intern Med. 2019 Apr 9. [Epub ahead of print].
 Vitamin Supplementation to Prevent Cancer and CVD: Preventive Medication .. U.S. Preventive Services Task Force, February 2014.
Association Among Dietary Supplement Use, Nutrient Intake, and Mortality Among U.S. Adults: A Cohort Study
The health benefits and risks of dietary supplement use are controversial.
To evaluate the association among dietary supplement use, levels of nutrient intake from foods and supplements, and mortality among U.S. adults.
Prospective cohort study.
NHANES (National Health and Nutrition Examination Survey) data from 1999 to 2010, linked to National Death Index mortality data.
30 899 U.S. adults aged 20 years or older who answered questions on dietary supplement use.
Dietary supplement use in the previous 30 days and nutrient intake from foods and supplements. Outcomes included mortality from all causes, cardiovascular disease (CVD), and cancer.
During a median follow-up of 6.1 years, 3613 deaths occurred, including 945 CVD deaths and 805 cancer deaths. Ever-use of dietary supplements was not associated with mortality outcomes. Adequate intake (at or above the Estimated Average Requirement or the Adequate Intake level) of vitamin A, vitamin K, magnesium, zinc, and copper was associated with reduced all-cause or CVD mortality, but the associations were restricted to nutrient intake from foods. Excess intake of calcium was associated with increased risk for cancer death (above vs. at or below the Tolerable Upper Intake Level: multivariable-adjusted rate ratio, 1.62 [95% CI, 1.07 to 2.45]; multivariable-adjusted rate difference, 1.7 [CI, -0.1 to 3.5] deaths per 1000 person-years), and the association seemed to be related to calcium intake from supplements (≥1000 mg/d vs. no use: multivariable-adjusted rate ratio, 1.53 [CI, 1.04 to 2.25]; multivariable-adjusted rate difference, 1.5 [CI, -0.1 to 3.1] deaths per 1000 person-years) rather than foods.
Results from observational data may be affected by residual confounding. Reporting of dietary supplement use is subject to recall bias.
Use of dietary supplements is not associated with mortality benefits among U.S. adults.
Primary Funding Source:
National Institutes of Health.
A recent study found that more than half of U.S. adults reported use of dietary supplements in the previous 30 days (1). Whether dietary supplement use is associated with health benefits or risks is controversial. The overall evidence suggests no benefits or harms, but a few randomized controlled trials have reported adverse outcomes associated with dietary supplement use, especially at high doses (2, 3). For example, the ATBC (Alpha-Tocopherol, Beta-Carotene Cancer Prevention) study and CARET (Beta-Carotene and Retinol Efficacy Trial) found that β-carotene supplements (20 or 30 mg/d) increased risk for lung cancer among smokers (4, 5), and SELECT (Selenium and Vitamin E Cancer Prevention Trial) reported that supplemental use of vitamin E (400 IU/d) increased risk for prostate cancer among men (6).
Although randomized controlled trials usually assess dietary supplement use at a specific dose, prospective cohort studies allow for evaluation of dose dependence versus threshold effects and potential heterogeneous effects of nutrient intake from supplements versus foods (7). For example, the CPS-II (Cancer Prevention Study II) Nutrition Cohort found that higher doses of supplemental calcium (≥1000 mg/d) were associated with increased risk for all-cause death in men, but lower doses (<1000 mg/d) or calcium intake from foods were not associated with mortality outcomes (8). Therefore, both the dose of the supplement and the nutrient source (foods vs. supplements) can play critical roles in determining the benefits or risks of nutrient intake.
Using a nationally representative sample of U.S. adults, we evaluated the association between dietary supplement use and mortality from all causes, cardiovascular disease (CVD), and cancer. We further assessed whether adequate or excess nutrient intake was associated with mortality and whether the associations differed by nutrient intake from foods versus supplements.
More than half of participants (51.2%) reported use of dietary supplements in the previous 30 days, and 38.3% reported use of MVM supplements. Compared with nonusers, supplement users were older and were more likely to be female and non-Hispanic white, have higher levels of education and family income, eat a healthy diet, and be physically active. They were also less likely to be current smokers, heavy drinkers, or obese but reported a higher prevalence of comorbid conditions at baseline (Table 1).
The most commonly used vitamin supplements were vitamin C (40.3% [95% CI, 39.3% to 41.4%]), vitamin E (38.6% [CI, 37.6% to 39.6%]), and vitamin D (37.6% [CI, 36.6% to 38.6%]). The most commonly used mineral supplements were calcium (38.6% [CI, 37.6% to 39.6%]), zinc (34.5% [CI, 33.5% to 35.4%]), and magnesium (33.3% [CI, 32.3% to 34.3%]). Levels of total nutrient intake were higher among supplement users than nonusers for all 25 nutrients. When nutrient intake from supplements was not accounted for, supplement users still had higher intake levels from foods for 23 nutrients (Table 2).
More than half of participants had inadequate intake of vitamin D (67.4% [CI, 65.7% to 69.1%]), vitamin E (61.6% [CI, 60.5% to 62.8%]), choline (96.7% [CI, 96.3% to 97.2%]), vitamin K (62.2% [CI, 60.9% to 63.5%]), and potassium (99.1% [CI, 99.0% to 99.3%]). The prevalence of participants with excess intake was less than 5% for all nutrients except niacin (7.1% [CI, 6.5% to 7.6%]) (Table 2).
During a median follow-up of 6.1 years, 3613 deaths occurred, including 945 CVD deaths and 805 cancer deaths. Supplemental use of most individual nutrients was associated with lower risk for all-cause death but not CVD or cancer death. However, all of the associations were statistically insignificant after multivariable adjustment, except that lycopene supplement use was associated with lower risk for all-cause death (RR, 0.82 [CI, 0.68 to 0.98]) and cancer death (RR, 0.66 [CI, 0.46 to 0.96]) (Table 3; Appendix Table 1).
Adequate intake of vitamin K (RR, 0.79 [CI, 0.70 to 0.90]) and magnesium (RR, 0.85 [CI, 0.74 to 0.98]) was associated with lower risk for all-cause death (Table 4). Adequate intake of vitamin A (RR, 0.61 [CI, 0.43 to 0.88]), vitamin K (RR, 0.68 [CI, 0.54 to 0.86]), copper (RR, 0.29 [CI, 0.17 to 0.51]), and zinc (RR, 0.50 [CI, 0.36 to 0.71]) was associated with lower CVD mortality (Appendix Table 2). Excess intake of calcium was associated with higher cancer mortality (RR, 1.62 [CI, 1.07 to 2.45]) (Appendix Table 3).
When sources of nutrient intake were further evaluated, the lower all-cause mortality associated with adequate intake of vitamin K and magnesium was restricted to intake from foods (vitamin K from foods: RR, 0.79 [CI, 0.69 to 0.92]; RD, -2.3 [CI, -3.7 to -0.9] deaths per 1000 person-years; vitamin K from supplements: RR, 0.96 [CI, 0.79 to 1.17]; RD, -0.4 [CI, -2.4 to 1.6] deaths per 1000 person-years; magnesium from foods: RR, 0.78 [CI, 0.65 to 0.93]; RD, -2.7 [CI, -4.5 to -0.9] deaths per 1000 person-years; magnesium from supplements: RR, 1.00 [CI, 0.87 to 1.14]; RD, 0.0 [CI, -1.6 to 1.5] deaths per 1000 person-years) (Table 4). Similarly, the lower CVD mortality associated with adequate intake of vitamin A, vitamin K, zinc, and copper was restricted to intake from foods (Appendix Table 2). However, the higher cancer mortality associated with excess calcium intake was attributable to high doses from supplements rather than foods. Supplemental calcium intake of 1000 mg/d or higher was associated with increased risk for cancer death (RR, 1.53 [CI, 1.04 to 2.25]; RD, 1.5 [CI, -0.1 to 3.1] deaths per 1000 person-years) (Appendix Table 3 and Appendix Figure 1).
Similar associations were found among participants with or without comorbid conditions at baseline (Appendix Tables 4, 5, 6) and those with high versus low nutrient intake from foods at baseline (Appendix Table 7). Stratified analysis revealed that vitamin D supplement use was not associated with mortality among participants with serum 25-hydroxyvitamin D levels less than 50 nmol/L; however, among those with levels of 50 nmol/L or higher, vitamin D supplement use at more than 10 mcg/d was associated with increased risk for all-cause death (RR, 1.34 [CI, 1.00 to 1.78]; RD, 2.7 [CI, -0.2 to 5.6] deaths per 1000 person-years) and cancer death (RR, 2.11 [CI, 1.18 to 3.77]; RD, 1.6 [CI, 0.2 to 3.1] deaths per 1000 person-years) (Appendix Table 8 and Appendix Figures 2 and3).
We found that dietary supplement use was not associated with mortality benefits in a nationally representative sample of U.S. adults. The evidence suggests that adequate nutrient intake from foods was associated with reduced mortality and excess intake from supplements could be harmful.
We initially found that any supplement use, MVM supplement use, and supplemental use of individual nutrients were each associated with lower risk for all-cause death after adjustment for age, sex, and race/ethnicity. However, most of the associations became statistically insignificant after additional adjustment for education and lifestyle factors. These results suggest that supplement use itself does not have direct health benefits. The apparent association between supplement use and lower mortality may reflect confounding by higher socioeconomic status and healthy lifestyle factors that are known to reduce mortality. Our results and those of others (18, 19) suggest that supplement users have higher levels of education and income and a healthier lifestyle overall (for example, better diet, higher levels of physical activity, no smoking or alcohol intake, and healthy weight) than nonusers. In addition, we and others (20, 21) found that supplement users had higher levels of nutrient intake from foods alone than nonusers. Thus, supplement users may have already had lower prevalence of nutrient inadequacy that contributed to lower mortality.
Our null findings are consistent with those from other recent cohort studies. For example, dietary supplement use was not associated with all-cause, CVD, or cancer death among 23 943 participants in the EPIC-Heidelberg (European Prospective Investigation into Cancer and Nutrition) study (22). Long-term multivitamin use was not associated with reduced incidence of or death due to stroke among 86 142 women in the NHS (Nurses' Health Study) (23). Similarly, systematic review of cohort studies and intervention trials does not support the benefits of supplement use for primary prevention of CVD or cancer (3, 24). Although use of lycopene supplements was associated with lower risk for all-cause and cancer death in our study, prior evidence from prospective cohort studies does not support an association between lycopene-containing foods and cancer risk (25). Evidence from randomized controlled trials also does not support the chemopreventive role of lycopene supplements in prostate cancer (26, 27). Overall, the current evidence does not support mortality benefits associated with use of dietary supplements.
We found that the mortality benefits associated with adequate intake of some nutrients, such as vitamin A, vitamin K, magnesium, zinc, and copper, were restricted to intake from foods. There was also evidence that excess intake of some nutrients may have adverse effects. For example, we found higher cancer mortality with total calcium intake above the Tolerable Upper Intake Level. The potential harm of excess calcium intake has not been consistently reported (28), with some trials reporting reduced cancer risk with high intake (29–31) and others raising concerns about its safety (32–34). For example, the HPFS (Health Professionals Follow-up Study) reported that total calcium intake of 1500 mg/d or higher was associated with increased risk for advanced or fatal prostate cancer among 47 750 men in the cohort (35). In a recent systematic review of 11 cohort studies, high total calcium intake was associated with increased risk for prostate cancer (relative risk, 1.11 [CI, 1.02 to 1.20]), and the association seemed stronger among persons followed for 10 or more years (relative risk, 1.22 [CI, 1.07 to 1.38]) (36). The underlying mechanisms are unclear and may involve stimulation of calcium-sensing receptors to promote secretion of parathyroid hormone–related protein, which could subsequently inhibit cell differentiation and alter proliferation (37). We further evaluated calcium intake from foods versus supplements and found increased cancer mortality only for high doses (≥1000 mg/d) from supplements rather than foods. These data are consistent with results from 59 744 men in the CPS-II Nutrition Cohort, where lower supplemental doses (<1000 mg/d) or calcium intake from foods did not increase risk, whereas higher supplemental doses (≥1000 mg/d) were associated with increased all-cause mortality (8). The difference between calcium from supplements versus foods may be explained by the different effects on circulating calcium: High intake from foods can lead to reduced intestinal absorption and increased urinary excretion, whereas long-term supplement use does not diminish circulating calcium levels (34).
We found that vitamin D supplementation at doses above 10 mcg/d might be associated with increased all-cause and cancer death among persons without vitamin D deficiency. Whether vitamin D supplementation reduces premature death or prevents cancer is controversial. Prior meta-analysis of intervention trials suggests that vitamin D supplements may modestly reduce all-cause and cancer mortality (38), but recent trials did not support its role in preventing cancer or CVD (39–41). The most recent trial, VITAL (Vitamin D and Omega-3 Trial), did not detect an effect of vitamin D supplements at a dose of 2000 IU/d on reducing cancer or CVD incidence among 25 817 participants during a median follow-up of 5.3 years (42). Potential benefits or harms of vitamin D supplement use need to be further evaluated.
Strengths of our study include use of a nationally representative sample of U.S. adults, longitudinal study design, and collection of data using validated measures. However, several limitations must be considered. First, dietary supplement use was assessed in the previous 30 days, which may not reflect habitual use or capture changes in use after baseline assessment. Prevalence and dosage of supplement use were based on self-report and so are subject to recall bias. However, NHANES documented that the ingredient and dosage information were obtained from the bottles and nutrition fact labels at the time of the interview 80% of the time (43), which reduces misclassification error due to recall bias.
Second, self-reported dietary intake is also subject to measurement error. NHANES incorporated one or two 24-hour diet recalls per person, which does not capture long-term intake because of large day-to-day variations in food intake. To improve the estimation of usual intake, we applied the NCI method to reduce measurement error associated with dietary intake estimated using diet recalls (44–46). Measurement error cannot be ruled out, however, and is likely to be nondifferential (independent of mortality), which attenuates the associations.
Third, supplement use is highly correlated with participants' socioeconomic status and lifestyle factors, such as education, smoking, body mass index, alcohol intake, physical activity, and diet quality. Having chronic health conditions, such as cancer, CVD, hypertension, or diabetes, may also motivate initiation of dietary supplement use. To minimize the chance of residual confounding, we adjusted for all of these factors in the multivariable models. In addition, we stratified participants by presence of comorbid conditions at baseline, and the associations remained similar. However, supplement use may be associated with factors that we have not identified and adjusted for, and residual confounding may still be present.
Fourth, mortality outcomes were determined through linkage to the National Death Index via a probabilistic match (11), which may have resulted in misclassification. A prior validation study showed that the method was highly accurate, with 96.1% of the decedents and 99.4% of the living participants classified correctly (47).
Fifth, given the limited sample size, we were unable to evaluate dietary supplement use and mortality from specific CVD conditions or cancer types or mortality due to conditions other than CVD or cancer.
Finally, we evaluated multiple nutrients, which can lead to spurious findings due to multiple comparisons. Humans consume foods and nutrients that are highly correlated. The complex interactions among nutrients are likely to play a more important role in determining health outcomes than individual nutrients. Thus, our findings on individual nutrients should be considered exploratory and interpreted with caution.
In conclusion, use of dietary supplements was not associated with mortality benefits among a nationally representative sample of U.S. adults. Although adequate nutrient intake from foods could contribute to reduced risk for death, excess intake from supplements might increase mortality. The potential risks and benefits of dietary supplement use for health need to be further evaluated in future studies.