Vitamin Supplement Use and Diabetes Mellitus Incidence among Adults in the United States
Earl S. Ford
From the Division of Nutrition and Physical Activity, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 4770 Buford Highway, Mailstop K24, Atlanta, GA 30341 (e-mail: esf2{at}cdc.gov)(Reprint requests to Dr. Ford at this address).
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ABSTRACT
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In some studies, use of vitamin supplements has been inversely associated with the risk of several chronic diseases, but little is known about whether vitamin use affects the risk of diabetes mellitus. Using data from the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study, the author examined whether vitamin use was related to diabetes incidence in a cohort of United States adults aged 2574 years. In the analytic sample of 9,573 participants, 1,010 participants developed diabetes mellitus during about 20 years of follow-up. A smaller percentage of participants with incident diabetes (21.4%) reported using vitamins during the previous month at baseline compared with participants who remained free of this disease (33.5%) (p < 0.001). After multiple adjustment, the hazard ratios for participants using vitamin supplements were 0.76 (95% confidence interval (CI): 0.63, 0.93) for all participants, 0.70 (95% CI: 0.54, 0.92) for men, and 0.84 (95% CI: 0.64, 1.11) for women. Sex did not modify the association between vitamin use and diabetes incidence. Whether specific vitamins or other factors closely correlated with vitamin use account for this observation is unclear.
cohort studies; diabetes mellitus; incidence; vitamins
Abbreviations:
CI, confidence interval; HR, hazard ratio; NHANES, National Health and Nutrition Examination Survey; NHEFS, National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study
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INTRODUCTION
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Vitamin and mineral supplement use has increased considerably in the United States during the past 2 decades (1





8
) as evidence has emerged about the possible benefits of vitamin use on reducing the risk of developing some chronic diseases, including cardiovascular disease and cancer (9
). Adequate intake of fruits and vegetables, which are rich sources of vitamins and minerals, may lower the risk of all-cause mortality and of morbidity and mortality from cardiovascular disease and cancer (10


14
).
Little is known about whether the use of vitamin supplements could be associated with lower risks for developing diabetes mellitus. In prospective studies, vitamin C intake was inversely related to glucose intolerance (15
), whereas two Finnish studies have provided mixed findings about the association between blood concentrations of vitamin E and incidence of diabetes mellitus (15
, 16
). In addition, a few studies have also suggested that adequate fruit and vegetable consumption may lower the risk of developing diabetes (17

20
). Because so little is known about a possible protective effect of vitamin use on the risk of diabetes mellitus, I examined the association between diabetes incidence and vitamin use in a national sample of US adults.
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MATERIALS AND METHODS
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Participants aged 2574 years in the first National Health and Nutrition Examination Survey (NHANES I), conducted from 19711975, were followed through 1992 or 1993 (n = 14,407). The original sample was selected by using a complex sampling design to ensure that results would be representative of the noninstitutionalized civilian population. Details of the NHANES I and the NHANES I Epidemiologic Follow-up Study (NHEFS) have been published elsewhere (21



26
).
Four attempts were made to contact participants or their surrogates in person, and during later follow-ups, by telephone, in 19821984, 1986 (participants aged
55 years only), 1987, and 19921993. Permission to obtain hospital records was requested. Deaths were identified through searches of the National Death Index, the Health Care Financing Administration enrollee files, and other tracing mechanisms. A participant was considered deceased only if a death certificate had been received or a proxy interview had been completed to verify the death. Death certificates have been obtained for 97 percent of deceased participants through 1993.
Participants were considered to have diabetes if: 1) they confirmed that they had ever been told by a doctor that they had diabetes during any of the four follow-up contacts, 2) a hospitalization record contained the International Classification of Diseases, Ninth Revision, Clinical Modification code 250 on any one of 10 diagnoses listed on the hospital discharge sheet, or 3) the death certificate included code 250. Participants with diabetes identified from their self-report were asked to report the year of onset. I designated the midpoint of that year as the date of onset. For participants who did not report a year of onset, I assigned the midpoint between the last date of known contact and the date of the most recent interview. The date of onset was chosen as the date on which the condition was first reported or recorded on institutional records or death certificates.
Participants who reported at baseline that they had ever been told that they had diabetes were considered as prevalent cases, as were participants who, during later follow-up contacts, reported a date of onset that occurred in their year of baseline interview or earlier. They were excluded from analysis.
Several questions about vitamin use were asked of participants at baseline. Before their phlebotomy, participants were asked, "Have you taken vitamins within the last 30 days?" (yes/no). In addition, as part of the dietary interview, participants were asked, "Are you taking vitamins or minerals?" Answers included no; yes, regularly; and yes, irregularly. Participants who answered yes were then asked to report in more detail what they were using. These categories included unknown or prescriptions; multiple vitamins, multiple vitamins with additional supplements; multiple vitamins and minerals, multiple vitamins and minerals with additional supplements; iron only; multiple vitamins with iron; iron with additional supplementsGeritol (GlaxoSmithKline, Research Triangle Park, North Carolina); vitamin E, vitamin E with additional supplements, vitamin A, vitamin A with additional supplements, vitamin D, vitamin D with additional supplements; vitamin C, vitamin C with additional supplements; calcium, calcium with additional supplements; dolomiteminerals with calcium and magnesium; vitamin B complex, vitamin B complex with additional supplements; and miscellaneous (cod liver oil; brewer's yeast, kelp lectchiein, yeast tablets, alfalfa tablets, liver tablets, potassium, folruma 24, iodine, bone meal, bone marrow, protein pills, amino acid pills, fluoride, and energol-wheat germ concentrate). In addition, during the first follow-up interview (19821984), participants were asked, "Are you now taking multivitamin pills including therapeutic and geriatric multivitamins and Geritol?" (yes/no).
Baseline covariates included age, race or ethnicity (non-White, White), education (years), cigarette smoking (never, former, current), systolic blood pressure, use of antihypertensive medication (yes/no), serum cholesterol concentration (mg/dl), body mass index (kg/m2), recreational exercise (much, moderate, little, or no exercise), nonrecreational exercise (very active, moderately active, quite inactive), alcohol consumption (0, 12,
3 drinks per day), fruit and vegetable intake (servings per day), percent of calories consumed as fat, and total energy intake. For smoking, I used a variable constructed in part from responses obtained during the baseline interview and in part from the first follow-up interview (27
, 28
). Two questions were used to create the categories of smoking: "Have you smoked at least 100 cigarettes during your entire life?" and "Do you smoke cigarettes now?" Cholesterol was measured by using a modification of the Abell-Kendall method. Fruit and vegetable intake and percent of calories consumed as fat were determined from a single 24-hour dietary recall questionnaire administered to 11,348 participants.
Two-sample comparisons of categorical and continuous variables were made using t tests. With the use of direct standardization, baseline characteristics and age-adjusted incidence rates were standardized to the age distribution from the 1980 census. Person-time was calculated for each participant from the time of entry into the study until one of the following conditions occurred: 1) the participant developed diabetes, 2) the participant died or left the study, or 3) follow-up was completed in 1993. The independent association between vitamin use at baseline and diabetes mellitus incidence was examined by using proportional hazard models. To account for the complex sampling design, I used the software SUDAAN (29
) in all analyses except for evaluation of proportionality assumptions, which were done in SAS (30
).
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RESULTS
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Of 14,407 participants in the NHEFS, 11,348 answered the dietary questionnaires. After deletion of persons who contributed no follow-up time, 10,925 participants remained. I excluded participants with a race or ethnicity other than White or African American (n = 172). Additional exclusions for incomplete information to establish diabetes incidence, diabetes prevalence, pregnancy, and missing data for covariates reduced the analytic sample to 9,573 participants, of whom 1,010 developed diabetes during the course of the study.
Participants who developed diabetes were older than those who remained free of the disease (table 1). After adjustment for age, participants who developed diabetes were less likely to be White, had fewer years of education, had a higher systolic pressure, had a higher serum cholesterol concentration, were heavier, were more likely to be sedentary, and consumed fewer fruits and vegetables compared with participants who remained free of diabetes. Only 21.4 percent of the participants who later developed diabetes reported using vitamins during the 30 days before their baseline interview compared with 33.5 percent of participants who remained free of diabetes (p < 0.001).
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TABLE 1. Age-adjusted means or percentages (standard error) of selected characteristics from baseline examination by diabetes status among participants aged 2574 years, National Health and Nutrition Examination Survey I, 19721976 to 19921993
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Using answers to the question "Have you taken vitamins within the last 30 days?", I found that the age-adjusted incidence rate for diabetes mellitus was lower among participants who used vitamins than among those who did not (table 2). The proportional hazards model generally supported these patterns. After adjustment for age, race or ethnicity, education, cigarette smoking, systolic pressure, use of antihypertensive medication, serum cholesterol concentration, body mass index, recreational exercise, nonrecreational exercise, alcohol consumption, fruit and vegetable intake, percent calories from fat, and total energy intake, the hazard ratios for participants using vitamin supplements were 0.76 (95 percent confidence interval (CI): 0.63, 0.93, p = 0.007) for all participants, 0.70 (95 percent CI: 0.54, 0.92, p = 0.009) for men, and 0.84 (95 percent CI: 0.64, 1.11, p = 0.210) for women. The interaction term for sex and vitamin use was not significant (p = 0.405).
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TABLE 2. Incidence rates and hazard ratios for vitamin supplement use and diabetes mellitus incidence among participants aged 2574 years, National Health and Nutrition Examination Survey I, 19721976 to 19921993
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Results were similar when using answers to the question "Are you taking vitamins or minerals?" Compared with participants who did not use vitamins or minerals, adjusted odds ratios for all participants were 0.86 (95 percent CI: 0.62, 1.20) for those who used vitamins irregularly and 0.75 (95 percent CI: 0.60, 0.94) for regular vitamin or mineral users (n = 9,665). For men, the adjusted hazard ratios were 0.74 (95 percent CI: 0.43, 1.27) and 0.68 (95 percent CI: 0.48, 0.97) for those who used vitamins irregularly and regular vitamin users, respectively (n = 3,874). For women, the adjusted hazard ratios were 0.98 (95 percent CI: 0.66, 1.45) and 0.83 (95 percent CI: 0.62, 1.11), respectively (n = 5,791). The interaction term for sex and vitamin or mineral use was not significant (p = 0.523). Using the more detailed use data (n = 9,512), the adjusted hazard ratios for all participants were 0.89 (95 percent CI: 0.62, 1.29) for users of multiple vitamins or multiple vitamins with additional supplements; 0.67 (95 percent CI: 0.41, 1.10) for users of multiple vitamins and minerals or multiple vitamins and minerals with additional supplements; 1.19 (95 percent CI: 0.58, 2.43) for users of iron only; 0.74 (95 percent CI: 0.48, 1.14) for users of multiple vitamins with iron or iron with additional supplementsGeritol; 0.87 (95 percent CI: 0.65, 1.17) for users of vitamin E, vitamin E with additional supplements, vitamin A, vitamin A with additional supplements, vitamin D, or vitamin D with additional supplements; and 1.13 (95 percent CI: 0.55, 2.32) for users of vitamin C or vitamin C with additional supplements. Because the numbers of participants using calcium or related products with or without other products, vitamin B with or without additional supplements, or miscellaneous products were less than 100, I eliminated these subjects from the above analysis. Furthermore, because the sample size for some of the usage categories was small, I did not stratify these analyses by sex.
To estimate the risk of developing diabetes in function of reported vitamin use from the baseline ("Are you taking vitamins or minerals?") and follow-up interviews, I created a new variable with four levels: not using vitamins at baseline and follow-up, not using vitamins at baseline but reported using them at follow-up, using vitamins at baseline but not during follow-up, and using vitamins at baseline and follow-up.
Participants who used vitamins or minerals regularly or irregularly at baseline were defined as using vitamins or minerals. Persons who developed diabetes during the period between their baseline interview (19711975) and their first follow-up interview (19821984) were excluded. Of the 7,001 participants (2,508 men and 4,493 women) available for these analyses, 387 participants (145 men, 242 women) developed diabetes after their first follow-up interview. Compared with participants who reported not using vitamins at either time period, no significant reduction in risk was noted for persons who were not using vitamins at baseline but who reported using them at follow-up (all participants: adjusted hazard ratio (HR) = 0.72, 95 percent CI: 0.45, 1.16; men: adjusted HR = 0.72, 95 percent CI: 0.34, 1.51; women: adjusted HR = 0.64, 95 percent CI: 0.36, 1.14) or for those who were using vitamins at baseline but not during follow-up (all participants: adjusted HR = 0.81, 95 percent CI: 0.58, 1.11; men: adjusted HR = 0.65, 95 percent CI: 0.36, 1.18; women: adjusted HR = 0.96, 95 percent CI: 0.58, 1.60). A significant reduction in risk was noted for participants who reported using vitamins at baseline and follow-up (all participants: adjusted HR = 0.47, 95 percent CI: 0.27, 0.81; men: adjusted HR = 0.28, 95 percent CI: 0.09, 0.81; women: adjusted HR = 0.64, 95 percent CI: 0.36, 1.14), however.
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DISCUSSION
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Little is known about whether vitamin use or vitamin status may have a protective effect on diabetes mellitus. The findings from the NHEFS that vitamin use may be associated with lower risks for diabetes mellitus are intriguing. Although the reduction in risk of diabetes associated with the use of vitamins was significant only among men, the smaller reduction observed among women was not inconsistent with the results among men. The findings that participants who used vitamins regularly had a larger reduction in risk than those who used vitamins irregularly and that participants who reported using vitamins both at baseline and during the first-follow-up interviews had larger reductions in risk than those who either started or stopped vitamin use during that period suggest dose-response relations.
Several limitations of this study need to be recognized. Persons who use vitamins differ in known and unknown ways from those who do not (31
). Although I adjusted for various factors that are related to vitamin use, other unknown factors or residual confounding could account for some or all of the observed association. Unfortunately, limited information about the types, dosage, frequency, and duration of vitamin use was requested from the participants. Thus, it was impossible to assess whether particular vitamins or vitamin use patterns were responsible for the observed association. The endpoint of diabetes incidence was based on self-reports, hospital diagnoses, and death certificate information. Although hospital records and death certificates may underreport the diagnosis of diabetes mellitus (32
, 33
), self-reports of diabetes are generally good (34
). Up to one half of all persons with diabetes are unaware of their condition, however (35
, 36
). Finally, I was unable to distinguish persons with type 1 diabetes mellitus from those with type 2 diabetes mellitus. The vast majority of cases were very likely to have been type 2 diabetes mellitus, however. About 95 percent of the participants who developed diabetes were aged 40 years or more when they did so.
The antioxidant effects of vitamin C or E could account for the observed association between vitamin use and incidence of diabetes mellitus. Some research has suggested that oxidation and attendant free radical damage contribute to the pathogenesis of diabetes mellitus, although the mechanisms are unclear (37
, 38
). Beta cells are thought to be highly susceptible to damage from reactive oxygen species (39
) and are characterized by low concentrations of radical scavengers (40
). Vitamin E has been shown to block the formation of malondialdehyde, an end product of lipid peroxidation (41
). Although some studies have suggested that vitamin E has favorable effects on insulin action (42
, 43
) and could help maintain residual beta cell function in persons with insulin-dependent diabetes mellitus (44
), not all studies have produced similar results (45
). In at least one study, vitamins E and C were not significantly associated with insulin sensitivity (46
).
Only a few studies have prospectively examined the relations between dietary intakes or physiologic concentrations of vitamins and diabetes incidence. In a 20-year follow-up of 338 men of the Finnish and Dutch cohorts of the Seven Country Study, vitamin C intake was inversely related to the incidence of diabetes (n = 26) and impaired glucose tolerance (n = 71) (17
). Plasma vitamin E concentration was inversely related to the incidence of diabetes mellitus (n = 45) in a cohort of 944 men aged 4260 years who were followed for 4 years in Finland (15
). In a Finnish nested case-control study of 106 persons who developed diabetes and were matched to 201 controls, serum alpha-tocopherol was not significantly related to diabetes incidence after adjustment for a number of risk factors (16
).
Research suggests that some of the contents of mineral supplements such as chromium and magnesium may lower the risk for developing this disease. Chromium has been shown to improve insulin sensitivity in humans and animals and may improve glycemic control in patients with diabetes (47
). Several studies have suggested that dietary magnesium intake is inversely related to diabetes incidence (48
, 49
) and insulin resistance (50
, 51
). Furthermore, magnesium supplementation may improve glycemic control (52
).
Supplements containing iron did not appear to affect the risk for diabetes mellitus significantly in this study. Because iron is a prooxidant and because some evidence suggests that oxidation may play a role in the pathogenesis of diabetes mellitus, an increase in the risk for developing diabetes might have been expected. Hemochromatosis, a condition of iron overload, is associated with an increased risk of diabetes, and this has suggested to some that lower concentrations of excess iron might also increase the risk for diabetes. A few cross-sectional and prospective studies have shown associations between various indicators of elevated iron stores and diabetes (53
, 54
).
The NHEFS is one of only a few studies to suggest that vitamin use or vitamin status may have a beneficial effect on the incidence of diabetes mellitus. If future studies support the findings of this study, the vitamins responsible for any protective effect will need to be identified and mechanisms for such effects unraveled. Diabetes mellitus is the seventh leading cause of mortality in the United States. With 16 million Americans thought to have diabetes (55
) and the incidence and prevalence of this disease increasing (56
58
), new approaches to primary and secondary prevention need to be explored. Perhaps the judicious use of vitamins may play a role in the prevention of this disease.
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Received for publication January 13, 2000.
Accepted for publication September 7, 2000.