Little has been reported about daily users of multiple dietary supplements. We assembled a sample of long-term users of multiple dietary supplements for the purpose of describing their supplement usage patterns. On average, Multiple Supp users in this study consumed 17 different supplements every day. Dietary supplements consumed on a daily basis by more than 50% of Multiple Supp users included a multivitamin/mineral, B-complex, vitamin C, carotenoids, vitamin E, calcium with vitamin D, omega-3 fatty acids, flavonoids, lecithin, alfalfa, coenzyme Q10 with resveratrol, glucosamine, and a herbal immune supplement. Women also consumed gamma linolenic acid and a probiotic supplement, whereas men also consumed zinc, garlic, a soy protein supplement, and saw palmetto (Table ). By comparison, in NHANES 1999–2000, 52% of those surveyed reported taking a dietary supplement in the past 30 days; 35% reported having taken a multivitamin/mineral; 12.7% having taken vitamin E; 12.4% having taken vitamin C; 10.4% having taken calcium; and 5.2% having taken B-complex vitamins [4
]. Consistent with other reports describing dietary supplement users [4
], Multiple Supp users as a group were primarily White, better educated, more affluent, and older.
A second objective of the study was to conduct a cross-sectional comparison of the relevant biomarker and nutrient concentrations in the Multiple Supp users, with those of Single Supp users (multivitamin/mineral users) and No Supp users (non-users) in NHANES 2001–20002 and NHANES III. Nutrient concentrations in serum or RBC generally increased across the three supplement user groups. It is notable that Single Supp users had higher circulating concentrations than No Supp users for RBC folate and serum retinol, ascorbic acid, and alpha tocopherol. This fact has important implications for nutrition intervention trials, some of which have permitted participants, including those in the control group, to take a multivitamin/mineral supplement [25
]. Our findings suggest that this practice may weaken the power of trials to detect treatment effects of the study supplement.
Degree of supplement use was associated with several markers of disease risk. Elevated serum homocysteine concentrations were found in approximately 45% of No Supp users, 37% of Single Supp users, and 11% of Multiple Supp users, despite the fact that the data were obtained after the 1998 fortification of grain products with folate, and despite the low prevalence of inadequate RBC folate in any of the user groups. If moderately-elevated serum homocysteine is shown to be an important cardiovascular disease risk factor, the findings of this study suggest that intake of the relevant B vitamins above what is typically found in a multivitamin/mineral supplement, and/or the diet, may produce a more favorable homocysteine-lowering effect.
Circulating CRP concentration has been shown to be predictive of future cardiovascular disease risk in prospective studies among asymptomatic individuals and may have a direct effect on the progression of atherosclerosis [26
]. In the present study, serum CRP concentrations decreased and serum ascorbic acid increased with increasing degree of supplement use (Tables and ). This finding is consistent with recent reports that vitamin C supplementation lowers plasma CRP concentrations [27
], and that dietary intakes of vitamin C and plasma ascorbic acid concentration are inversely associated with plasma CRP [28
]. Studies are underway to confirm the impact of vitamin C supplementation on circulating CRP and other markers of immune function.
Serum ascorbic acid concentration >1.0 mg/dL has been suggested as optimal relative to reduced risk of cardiovascular disease and cancer [24
]. By this definition, over 94% of Multiple Supp had optimal concentrations, compared to approximately 47% and 22% in Single Supp and No Supp users, respectively. Suboptimal concentrations, defined as <0.4 mg/dL [23
], were not found in the Multiple Supp user group, and were found in approximately 9% and 32% of Single Supp and No Supp users, respectively.
Serum 25-hydroxyvitamin D in Multiple Supp users is of interest because of possible beneficial and adverse effects from supplemental intake of vitamin D. Improving 25-hydroxyvitamin D concentrations above the level associated with subclinical deficiency (<37.5 nmol/L) may reduce the risk of skeletal fractures [16
]. Also, parathyroid hormone concentrations become minimal when 25-hydroxyvitamin D concentrations exceed 100 nmol/L. Conversely, serum concentrations >600 nmol/L are associated with hypercalcemia [19
]. Among Multiple Supp users, no individuals had serum 25-hydroxyvitamin D concentrations <37.5 nmol/L or >600 nmol/L, and the mean (SD) was 131.4 (45.26) nmol/L with a range of 39.30 to 263.80 nmol/L. No comparative data were available from NHANES participants.
Supplement use was also associated with lower serum triglycerides and higher HDL-cholesterol concentrations. In consequence, the risk of an elevated ratio of total cholesterol to HDL-cholesterol was significantly lower in the Multiple Supp group compared to the No Supp group (Table ). Prevalent use of fish oil supplements in the Multiple Supp users may explain these findings as omega-3 fatty acids in fish oil have been shown to increase HDL-cholesterol and decrease triglyceride concentrations [29
]. Although beyond the scope of the present study, lower risk of cardiac arrhythmias may be another benefit of consumption of omega-3 fatty acids [30
Self-assessed health status has been found to be a remarkably good marker of prospective health outcomes [32
]. Compared to No Supp users, Multiple Supp users were more likely to describe their health as 'very good' or 'excellent', whereas this was not the case with Single Supp users (Table ).
Risk of elevated systolic or diastolic blood pressure was significantly lower in the Multiple Supp group compared to No Supp users, but not in Single Supp users compared to No Supp users (Table ). Dietary interventions have been shown to reduce blood pressure [33
]. However, clinical trials of individual nutrients have typically found small and inconsistent effects [33
]. Dietary folate and vitamin C, as well as plasma ascorbic acid, have been found to be inversely associated with blood pressure in observational studies [34
]. However, intervention trials with vitamin C have yielded inconsistent results [35
], while in two small trials, folic acid has been effective at lowering blood pressure [36
]. The finding of a lower risk of elevated blood pressure in the Multiple Supp group, which also had the highest concentrations of RBC folate and serum ascorbic acid, suggests that the relationship between these nutrients and blood pressure may warrant further investigation.
The lower risk of diabetes in the Multiple Supp group is consistent with evidence that oxidative stress may be a mechanism linking insulin resistance with dysfunction of pancreatic beta cells and endothelial dysfunction, eventually leading to diabetes [38
]. Although biomarkers of oxidative stress were not available in the three user groups, serum concentrations of antioxidants including ascorbic acid, carotenoids, and alpha tocopherol were all significantly higher in the Multiple Supp users compared to the other groups (Table ).
An important limitation of the study is the fact that the data are cross-sectional, and therefore the reported associations, particularly with health outcomes (i.e., blood pressure and diabetes), cannot presume causality. Also, the three user groups should not be interpreted to represent unbiased national estimates. In addition, although we adjusted for potential confounders such as age, sex, income, education, and BMI, residual confounding could possibly account for the findings. Better access to health care and variables related to higher socioeconomic status in the supplement user groups (e.g., healthier diets and lifestyles) are logical hypotheses that may account for these results. However, the No Supp and Single Supp user groups were similar with respect to education and income (Table ), so these factors may not explain the significantly better nutrient and C-reactive protein concentrations seen for Single Supp users in Table , and homocysteine and HDL risk levels (Table ). Furthermore, the lack of differences across the three user groups in biomarkers such as serum total cholesterol and LDL-cholesterol suggest that factors related to health care access and socioeconomic status do not fully explain the results.
This study is the first we are aware of to describe the usage patterns of long-term users of multiple dietary supplements, an unusual sample that cannot be captured in national representative surveys. While only 3 individuals out of over 11,000 surveyed in NHANES 2001–2002 had taken 20 or more kinds of dietary supplements in the past 30 days, in our Multiple Supp users, 87% of the sample reported having taken 20 or more kinds of supplements daily. Thus, this sample of Multiple Supp users affords a rare opportunity to understand a segment of the population that take multiple dietary supplements, and to understand the nutrient and other correlates of this practice. In addition, Multiple Supp users were long-term consumers of dietary supplements. Thus, their serum nutrient and biomarker concentrations were likely to be representative of their long-term supplementation patterns.