Richard P. Donahue

Effects of Long-Term Selenium Supplementation on the Incidence of Type 2 Diabetes: A Randomized Trial

Context Research suggests that selenium supplements may improve glucose metabolism. Contribution The investigators examined the incidence of type 2 diabetes among participants in a clinical trial designed to assess the effects of selenium supplementation on skin cancer. Participants randomly assigned to receive selenium were more likely to develop type 2 diabetes than were those assigned to placebo. Cautions Diabetes was a secondary outcome of the original trial. The diagnosis was self-reported, and most participants were older and white. Implication Long-term selenium supplementation appears to increase the risk for type 2 diabetes. The Editors Insulin resistance, impaired glucose tolerance, and type 2 diabetes are all linked to oxidative stress, which may be the pathogenic mechanism that links these conditions to cardiovascular disease (1). Observational epidemiologic studies show a protective association of dietary or plasma antioxidants against the development of type 2 diabetes (2, 3). However, the few clinical trials that have examined the efficacy of antioxidant supplementation in the prevention of type 2 diabetes or its complications have had negative results (46). Experimental evidence from animal models suggests that supplementation with low doses of the antioxidant selenium may exert beneficial effects on glucose metabolism, possibly through many insulin-like actions, and may delay complications of diabetes. The effects of high-dose selenium supplements, however, are less clear (710). Some studies in patients with diabetes suggest that selenium supplementation may help to prevent vascular complications (11) and that diabetic patients may be deficient in selenium relative to healthy persons (12). Conversely, recent findings from the SU.VI.MAX (Supplementation with Antioxidant Vitamins and Minerals) study (13) showed no effect of supplementation with a combination of antioxidants, including selenium (100 g/d), on fasting plasma glucose levels after 7.5 years of follow-up. Because no randomized, placebo-controlled clinical trials to date have tested the effect of long-term supplementation with selenium alone (200 g/d) on the risk for type 2 diabetes, we examined the efficacy of selenium supplementation in preventing new-onset type 2 diabetes in the NPC (Nutritional Prevention of Cancer) trial, a randomized, double-blind clinical trial designed primarily to evaluate the efficacy of selenium supplementation for prevention of cancer (14, 15). Specifically, we assessed the incidence of type 2 diabetes as a secondary end point throughout the blinded phase of the trial (19831996) among participants who did not have type 2 diabetes at baseline (n= 1202). Methods Design and Participants The rationale, design, and methods of the NPC trial are described in detail elsewhere (14). In brief, the NPC trial was a randomized, double-blind, placebo-controlled study of 1312 participants who were recruited in 1983 to 1991 from 7 dermatology clinics in areas of low selenium consumption of the eastern United States. Randomization was blocked by time and stratified by clinic. Persons were eligible if they had a confirmed history of nonmelanoma skin cancer in the year before randomization, had an estimated life expectancy of 5 years, and had no reported internal cancer in the previous 5 years. Participants with a history of clinically important liver or kidney disorders were excluded. Because the primary aim of the trial was to determine the effects of selenium supplementation on nonmelanoma skin cancer, we excluded nonwhite persons. This restriction served to control the effects of skin pigmentation on the risk for skin cancer recurrence. As a result, almost all participants in the NPC trial were non-Hispanic white persons; about 1.4% (n= 18) of persons who were randomly allocated were identified as Hispanic, and some persons were from other ethnic groups. Although recruitment was sex-neutral, about three quarters of the participants were male. Of the 1316 persons recruited, random assignment was successful for 1312. At the end of the blinded treatment period on 1 February 1996, no participant was lost to vital follow-up, generating a total of 9301 person-years of follow-up. Self-reported adherence indicated that 79.3% of participants (80.3% in the placebo group and 78.4% in the selenium group) adhered to the intervention (16). This was corroborated by the fact that plasma selenium levels remained constant throughout the trial in the placebo group but were substantially higher in the selenium group (Figure 1). Figure 1. Mean plasma selenium levels. We analyzed only participants with a valid baseline selenium value obtained within 4 days from the date of randomization (1250 of 1312 participants), a decision that is consistent with previously published studies from the NPC trial (1517). Baseline characteristics of the total NPC cohort of 1312 participants and the subsample of 1250 participants with valid baseline selenium levels did not statistically significantly differ (17), and our findings did not change substantially when analyses were expanded to include all 1312 participants (data not reported). We focus on the 1202 participants who did not have type 2 diabetes at baseline (600 selenium recipients and 602 placebo recipients). Ascertainment of prevalent type 2 diabetes at baseline was based on a self-reported diagnosis of type 2 diabetes before randomization, with subsequent evaluation of medical records (48 cases [21 in the selenium group and 27 in the placebo group]). Figure 2 shows the flow diagram of the NPC participants included in our analysis. Figure 2. Flow diagram of the Nutritional Prevention of Cancer Trial, 19831996. Clinical Examination and Laboratory Methods The intervention agent was 200 g of selenium daily, supplied in a 0.5-g, high-selenium bakers yeast tablet provided by Nutrition 21 (La Jolla, California) through 1995 and by Cypress Systems (Fresno, California) thereafter. The placebo group received a tablet containing yeast only. Selenium and placebo pills were coated with titanium oxide to ensure identical appearance and smell. Each patient was assigned a unique sequential treatment number. Treatment group assignment was made centrally by using sealed identical pill bottles that were distributed at the clinic. The coordinating center held all treatment information in blinded form (14). The selenium content of each batch of pills was determined in the laboratories of Dr. Combs and of I.S. Palmer, MD (South Dakota State University, Brookings, South Dakota), by the diaminonapthalene fluorometric procedure after nitricperchloric acid digestion (18). Plasma selenium level was determined in the laboratory of Dr. Combs by using an automated electrothermal atomic absorption spectrophotometer (Perkin Elmer 3030, Perkin-Elmer, Norwalk, Connecticut) equipped with an electrodeless discharge lamp and automatic Zeeman-effect background correction. Quality control included multiple aliquots of human plasma as external control samples. A coefficient of variation less than 7% (for duplicate analyses) was the criterion for acceptance (19). Participants visited their respective clinics biannually to provide blood samples and report new illnesses and medications. Patient medical records from both study and nonstudy visits were periodically reviewed to ensure completeness and accuracy. At the baseline interview, data were collected on sociodemographic, anthropometric, and behavioral characteristics, including education (0 to 18 years), body mass index (BMI), use of vitamin supplements, alcohol consumption (drinks consumed per day), smoking status (never, former, or current), and pack-years of smoking. For participants who became inactive, annual monitoring was attempted by using the National Death Index and ChoicePoint Services (formerly Equifax, Atlanta, Georgia) to determine vital status and identify diagnoses of new illnesses. Ascertainment of Type 2 Diabetes and Follow-up Participants who had a new diagnosis of type 2 diabetes during the blinded phase of the trial (15 September 1983 to 1 February 1996) were noted. The initial report of diabetes came from 3 sources: self-report during the clinical interview, reported use of drugs for diabetes, and reports in medical record documents. Medical record requests were then sent to the primary physicians for every patient with a report. This process of requesting and reviewing documentation was done in a blinded manner. About 92% of these reports, regardless of source, were corroborated with medical record documentation, as determined by registered nurse reviewers. Person-years of follow-up were accrued from the date of randomization as the start date to the date of an incident case of type 2 diabetes, the date of death, or the end of the blinded period of the trial. Statistical Analysis For continuous and categorical variables, we used t tests and chi-square tests, respectively, to determine the statistical significance of any difference in the distribution of baseline variables between treatment groups. Cumulative incidence curves of type 2 diabetes by treatment group were constructed by comparing NelsonAalen cumulative hazard function estimates that were calculated at different time points of the trial and by using the 2-sided log-rank test (20). In unadjusted analyses, incidence data were statistically analyzed by calculating relative risks as the ratios of the incidence density for the treatment groups, with corresponding 95% CIs. P values were derived from log-rank tests. In adjusted analyses, hazard ratios and 95% CIs were calculated by using the Cox proportional hazard model, which allowed adjustment for age, BMI (continuous variable), sex, and smoking status at baseline as covariates. We decided a priori to adjust for these diabetes risk factors regardless of whether they differed between treatment groups. Tests of proportional hazards assumptions were based on S

Postchallenge Glucose Concentration and Coronary Heart Disease in Men of Japanese Ancestry: Honolulu Heart Program

Since 1965, the Honolulu Heart Program has followed 8006 men of Japanese ancestry, aged 45–70 yr at study entry, for the development of cardiovascular disease. To investigate the role of glucose concentration 1 h after a 50-g challenge on the risk of fatal coronary heart disease (CHD) and nonfatal myocardial infarction (Ml), 6394 nondiabetic men were followed for 12 yr for the first development of CHD. The rate of fatal CHD increased linearly with amount of glucose. Men in the fourth quintile of postchallenge glucose (157–189 mg/dl) had twice the age-adjusted risk of fatal CHD of those in the lowest quintile (P < .05). Relative risk increased to threefold among those in the top quintile and remained statistically significant after adjustment for other risk factors including body mass, total cholesterol, hypertension, left ventricular hypertrophy, and hematocrit (P < .001). When glucose was considered as a linear term in the proportional hazards model, a highly significant relation was noted with fatal CHD alone and when combined with nonfatal Ml (P < .001). We conclude that a continuously increasing risk gradient exists between postchallenge glucose and subsequent CHD that is independent of other known risk factors.

Recruitment in the Coronary Artery Disease Risk Development in Young Adults (Cardia) study

Coronary Artery Disease Risk Development in Young Adults (CARDIA) is a longitudinal study designed to trace the development of risk factors for coronary heart disease in 5100 individuals 18-30 years old. The study will compare, by cross-sectional and longitudinal analyses, trends and processes involved in risk factor development by sex, race, age, and other sociodemographic characteristics. Participants for the approximately 4 1/2-hour baseline examination were randomly selected and recruited by telephone from census tracts in Minneapolis and Chicago, by telephone exchanges within the Birmingham city limit, and from lists of the Kaiser-Permanente Health Plan membership in Oakland and Berkeley. A major issue was the desirability of sampling approximately equal numbers by age, race, sex, and education as compared with sampling numbers representative of the population base. The recruitment goal of 5100 was achieved on schedule.

Diabetes Mellitus and Macrovascular Complications: An epidemiological perspective

It is clearly recognized that patients with NIDDM have an increased risk for CHD. Recent data indicate that persons with glucose concentrations in the nondiabetic range also may be at higher risk for CHD. These associations may not represent cause and effect, however. Emerging data suggest that hyperglycemia and CHD may both arise from hyperinsulinemia/insulin resistance. In support of this hypothesis are studies showing that NIDDM and CHD have many risk factors in common, including age, elevated blood pressure, dyslipidemia, adiposity, and a central pattern of fat distribution. Moreover, these risk factors are frequent concomitants of hyperinsulinemia, itself a risk factor for CHD and perhaps for NIDDM. Although the duration of NIDDM has been infrequently related to risk of CHD, the authors hypothesize that duration of hyperinsulinemia/insulin resistance would be a more sensitive marker for risk of CHD. The relation of IDDM to CHD is a different situation. The etiological process leading to IDDM, namely the destruction of β-cells in genetically predisposed persons, is not related to cardiovascular risk. However, IDDM patients still have an excess of CVD, the risk factors for which may vary according to the location of the diseases (e.g., LEAD vs. CHD). There is a strong relationship between proteinuria and CVD, which has led to a general theory of vascular complications in IDDM based on defective heparan sulfate metabolism (Steno hypothesis). Recent evidence challenges parts of this hypothesis, and the possibility is raised that a higher case-fatality rate in a subgroup of patients with both renal and CVD explains part of the renal connection, as does the general worsening of CVD risk factors.

Correlates of short and long sleep duration: a cross-cultural comparison between the United Kingdom and the United States: the Whitehall II Study and the Western New York Health Study.

The authors examined sociodemographic, lifestyle, and comorbidity factors that could confound or mediate U-shaped associations between sleep duration and health in 6,472 United Kingdom adults from the Whitehall II Study (1997-1999) and 3,027 US adults from the Western New York Health Study (1996-2001). Cross-sectional associations between short (<6 hours) and long (>8 hours) durations of sleep across several correlates were calculated as multivariable odds ratios. For short sleep duration, there were significant, consistent associations in both samples for unmarried status (United Kingdom: adjusted odds ratio (AOR) = 1.49, 95% confidence interval (CI): 1.15, 1.94; United States: AOR = 1.49, 95% CI: 1.10, 2.02), body mass index (AORs were 1.04 (95% CI: 1.01, 1.07) and 1.02 (95% CI: 1.00, 1.05)), and Short Form-36 physical (AORs were 0.96 (95% CI: 0.95, 0.98) and 0.97 (95% CI: 0.96, 0.98)) and mental (AORs were 0.95 (95% CI: 0.94, 0.96) and 0.98 (95% CI: 0.96, 0.99)) scores. For long sleep duration, there were fewer significant associations: age among men (AORs were 1.08 (95% CI: 1.01, 1.14) and 1.05 (95% CI: 1.02, 1.08)), low physical activity (AORs were 1.75 (95% CI: 0.97, 3.14) and 1.60 (95% CI: 1.09, 2.34)), and Short Form-36 physical score (AORs were 0.96 (95% CI: 0.93, 0.99) and 0.97 (95% CI: 0.95, 0.99)). Being unmarried, being overweight, and having poor general health are associated with short sleep and may contribute to observed disease associations. Long sleep may represent an epiphenomenon of comorbidity.

Association of fasting insulin with blood pressure and lipids in young adults. The CARDIA study.

The association of insulin with cardiovascular disease (CVD) may be mediated in part by the associations of insulin with CVD risk factors, particularly blood pressure and serum lipids. These associations were examined in 4576 black and white young adults in the CARDIA Study. Fasting insulin level was correlated in univariate analysis with systolic blood pressure (r = 0.16), diastolic blood pressure (r = 0.13), triglycerides (r = 0.27), total cholesterol (r = 0.10), high density lipoprotein (HDL) cholesterol (r = -0.25), and low density lipoprotein (LDL) cholesterol (r = 0.14), and with age, sex, race, glucose, body mass index, alcohol intake, cigarette use, physical activity, and treadmill duration (all p less than 0.0001). After adjustment for these covariates, insulin remained positively associated with blood pressure, triglycerides, total and LDL cholesterol, and apolipoprotein B and was negatively associated with HDL, HDL2 and HDL3 cholesterol, and apolipoprotein A-I in all four race-sex groups. Higher levels of fasting insulin are associated with unfavorable levels of CVD risk factors in young adults; these associations, though relatively small, can be expected to increase the risk of atherosclerosis. Demonstration of these relationships in a large, racially diverse, healthy population suggests that insulin may be an important intermediate risk factor for CVD in a broad segment of the U.S. population.

A population-based study of reduced sleep duration and hypertension: the strongest association may be in premenopausal women.

Objectives Recent evidence indicates that reduced sleep duration may be associated with an increased risk of hypertension with possibly stronger effects among women than men. We therefore examined cross-sectional sex-specific associations of sleep duration with hypertension in a large population-based sample from the Western New York Health Study (1996<2001). Methods Participants were 3027 white men (43.5%) and women (56.5%) without prevalent cardiovascular disease (median age 56 years). Hypertension was defined as blood pressure at least 140 or at least 90&mmHg or regular use of antihypertensive medication. Multivariate logistic regression analyses were performed to estimate odds ratios (ORs) of hypertension comparing less than 6&h of sleep per night versus the reference category (&6&h) while accounting for a number of potential confounders. Results In multivariate analyses, less than 6&h of sleep was associated with a significant increased risk of hypertension compared to sleeping at least 6&h per night, only among women [OR&=&1.66 (1.09 to 2.53)]. No significant association was found among men [OR&=&0.93 (0.62 to 1.41)]. In subgroup analyses by menopausal status, the effect was stronger among premenopausal women [OR&=&3.25 (1.37 to 7.76)] than among postmenopausal women [OR&=&1.49 (0.92 to 2.41)]. Conclusion Reduced sleep duration, by increasing the risk of hypertension, may produce detrimental cardiovascular effects among women. The association is independent of socioeconomic status, traditional cardiovascular risk factors, and psychiatric comorbidities, and is stronger among premenopausal women. Prospective and mechanistic evidence is necessary to support causality.

Cholesterol screening in childhood: Does it predict adult hypercholesterolemia? The Beaver County experience

To establish the value of screening children for hypercholesterolemia in terms of identifying future adults with hypercholesterolemia, we studied 611 individuals 9 years after they were initially screened at age 12 years. They represent 61% of a stratified sample of the original cohort, which was drawn from all seventh graders in a countywide school district. Overall, the correlation between baseline and follow-up cholesterol concentration was r = 0.52 (P less than 0.0001). Forty-nine percent of the top cholesterol quintile at baseline were similarly placed at follow-up, with 70% in the top two quintiles. Children who dropped out of the top quintile had lower body mass index at follow-up (P less than 0.05), were less frequently smokers, and tended to be more active than those who were only in the top quintile as adults.

Cigarette Smoking, Alcohol Use, and Physical Activity in Relation to Serum Leptin Levels in a Multiethnic Population: The Miami Community Health Study

PURPOSE To examine the correlates of plasma leptin, including fasting insulin, adiposity, and several health habits and behaviors among a nondiabetic multiethnic population. METHODS A cross-sectional study was conducted among 25-44 year old African-Americans (n = 126), Cuban-Americans (n = 107), and non-Hispanic whites (n = 189) randomly selected from Dade County Florida. Fasting leptin levels were correlated with fasting insulin, percent body fat, smoking, alcohol use, and physical activity within each sex. Multiple linear regression and analysis of covariance were used to estimate the independent determinants of plasma leptin concentration separately among men and women. RESULTS Stepwise linear regression analyses revealed statistically significant associations of leptin with percent body fat, fasting insulin, cigarette smoking, and physical activity (both inversely) among men (p < 0.05 for each). Among women, percent body fat, fasting insulin (both positively), cigarette smoking, and alcohol use (inversely) were independent predictors of leptin levels explaining over 70% of the variance. Analyses of covariance revealed that women had higher adjusted mean leptin levels than men (13.1 ng/ml vs. 5.9 ng/ml; p < 0.001), whereas no separate effect of ethnicity was noted. CONCLUSIONS Although adiposity was the strongest correlate of leptin levels, fasting insulin and several health habits and behaviors were independently associated with leptin. After adjustment for these factors, women had significantly higher mean leptin levels than men. The independent association among leptin and insulin levels is intriguing and suggests additional avenues for epidemiologic research.

Body Fat Distribution, Liver Enzymes, and Risk of Hypertension. Evidence From the Western New York Study

&ggr;-Glutamyltransferase (GGT) has been associated with hypertension (HTN); however, the nature of this association remains unclear. GGT is a marker of alcohol consumption, but it is also related to the infiltration of fat in the liver (fatty liver). The association between GGT and HTN was examined in a 6-year longitudinal investigation among 1455 men and women who returned for the follow-up visit. Baseline variables included serum GGT, blood pressure, and anthropometric measures. Incident HTN was defined as blood pressure ≥140/90 or on antihypertensive medication at the follow-up visit. To eliminate individuals with potential liver pathology, analyses focused only on individuals with GGT within its normal range (n=897). Participants were divided in quintiles (Q) based on their baseline GGT levels. Multiple logistic regression analyses [odds ratio (95% confidence intervals)] revealed a significant association of GGT with incident hypertension [2.1 (1.1 to 4.0) Q5 versus Q1]. In subgroup analyses, GGT and HTN were significantly associated among both noncurrent and current drinkers, but only for participants above the median of anthropometric measures [eg, body mass index >26.4, 2.3 (0.9 to 5.7), waist circumference >86.1 cm, 3.7 (1.4 to 9.9), and abdominal height >19.8 cm, 3.1 (1.2 to 8.5), for Q5 versus Q1, in fully adjusted models]. These findings suggest that the association between GGT and hypertension is not caused solely by alcohol consumption and indicate that serum GGT, within its normal range, may predict hypertension among individuals with increased central fat distribution, suggesting that fatty liver may represent an important underlying mechanism for this association.