Denis C. Muller

Predictors of Progression From Impaired Glucose Tolerance to NIDDM: An Analysis of Six Prospective Studies

Risk factors associated with the progression from impaired glucose tolerance (IGT) to NIDDM were examined in data from six prospective studies. IGT and NIDDM were defined in all studies by World Health Organization (WHO) criteria, and baseline risk factors were measured at the time of first recognition of IGT. The studies varied in size from 177 to 693 participants with IGT, and included men and women followed from 2 to 27 years after the recognition of IGT. Across the six studies, the incidence rate of NIDDM was 57.2/1,000 person-years and ranged from 35.8/1,000 to 87.3/1,000 person-years. Although baseline measures of fasting and 2-h postchallenge glucose levels were both positively associated with NIDDM incidence, incidence rates were sharply higher for those in the top quartile of fasting plasma glucose levels, but increased linearly with increasing 2-h postchallenge glucose quartiles. Incidence rates were higher among the Hispanic, Mexican-American, Pima, and Nauruan populations than among Caucasians. The effect of baseline age on NIDDM incidence rates differed among the studies; the rates did not increase or rose only slightly with increasing baseline age in three of the studies and formed an inverted U in three studies. In all studies, estimates of obesity (including BMI, waist-to-hip ratio, and waist circumference) were positively associated with NIDDM incidence. BMI was associated with NIDDM incidence independently of fasting and 2-h post challenge glucose levels in the combined analysis of all six studies and in three cohorts separately, but not in the three studies with the highest NIDDM incidence rates. Sex and family history of diabetes were generally not related to NIDDM progression. This analysis indicates that persons with IGT are at high risk and that further refinement of risk can be made by other simple measurements. The ability to identify persons at high risk of NIDDM should facilitate clinical trials in diabetes prevention.

Metabolic Syndrome in Men With Prostate Cancer Undergoing Long-Term Androgen-Deprivation Therapy

PURPOSE Prostate cancer (PCa) is one of the most common cancers in men. Men with recurrent or metastatic PCa are treated with androgen-deprivation therapy (ADT), resulting in profound hypogonadism. Because male hypogonadism is a risk factor for metabolic syndrome and men with PCa have high cardiovascular mortality, we evaluated the prevalence of metabolic syndrome in men undergoing long-term ADT. PATIENTS AND METHODS This was a cross-sectional study. We evaluated 58 men, including 20 with PCa undergoing ADT for at least 12 months (ADT group), 18 age-matched men with nonmetastatic PCa who had received local treatment and were recently found to have an increasing prostate-specific antigen (non-ADT group), and 20 age-matched controls (control group). Men in the non-ADT and control groups were eugonadal. Metabolic syndrome was defined according to the Adult Treatment Panel III criteria. RESULTS Mean age was similar among the groups. Men on ADT had significantly higher body mass index and lower total and free testosterone levels. The prevalence of metabolic syndrome was higher in the ADT group compared with the non-ADT (P < .01) and control (P = .03) groups. Among the components of metabolic syndrome, men on ADT had a higher prevalence of abdominal obesity and hyperglycemia. Androgen-deprived men also had elevated triglycerides compared with controls (P = .02). The prevalence of hypertension and low high-density lipoprotein levels were similar. CONCLUSION These data suggest that metabolic syndrome was present in more than 50% of the men undergoing long-term ADT, predisposing them to higher cardiovascular risk. Abdominal obesity and hyperglycemia were responsible for this higher prevalence. We recommend prospective studies to further delineate this association.

Pulse Wave Velocity Is an Independent Predictor of the Longitudinal Increase in Systolic Blood Pressure and of Incident Hypertension in the Baltimore Longitudinal Study of Aging

OBJECTIVES This study sought to evaluate whether pulse wave velocity (PWV), a noninvasive index of arterial stiffness, is a predictor of the longitudinal changes in systolic blood pressure (SBP) and of incident hypertension. BACKGROUND Although arterial stiffness is believed to underlie, in part, the age-associated changes in SBP, particularly at older ages, few longitudinal studies in humans have examined the relationship between arterial stiffness and blood pressure. METHODS Pulse wave velocity was measured at baseline in 449 normotensive or untreated hypertensive volunteers (age 53 +/- 17 years). Repeated measurements of blood pressure were performed during an average follow-up of 4.9 +/- 2.5 years. RESULTS After adjusting for covariates including age, body mass index, and mean arterial pressure, linear mixed effects regression models showed that PWV was an independent determinant of the longitudinal increase in SBP (p = 0.003 for the interaction term with time). In a subset of 306 subjects who were normotensive at baseline, hypertension developed in 105 (34%) during a median follow-up of 4.3 years (range 2 to 12 years). By stepwise Cox proportional hazards models, PWV was an independent predictor of incident hypertension (hazard ratio 1.10 per 1 m/s increase in PWV, 95% confidence interval 1.00 to 1.30, p = 0.03) in individuals with a follow-up duration greater than the median. CONCLUSIONS Pulse wave velocity is an independent predictor of the longitudinal increase in SBP and of incident hypertension. This suggests that PWV could help identify normotensive individuals who should be targeted for the implementation of interventions aimed at preventing or delaying the progression of subclinical arterial stiffening and the onset of hypertension.

Impact of Age on Weight Goals

Although the health hazards due to excessive obesity and excessive leanness are multiple and diverse, weight recommendations for over 40 years have been based solely on the risk of dying. The weight recommendation tables in nearly universal usage have been derived from the experience of the life insurance industry. Those tables have not recommended any weight adjustments for age. An analysis of the actuarial data on which the most recent tables are based shows that minimal mortality occurs at progressively increasing body weight as age advances (20 to 29, through 60 to 69 years). There is, furthermore, no systematic sex difference in those weights. We have prepared height-weight tables that are age-specific and delete sex and body frame type as variables. These weight standards are lower for young adults and higher for older adults than those previously recommended. A review of 23 other reported populations confirms the need to adjust weight standards for age.

Plasma selenium level before diagnosis and the risk of prostate cancer development.

PURPOSE Epidemiological studies and a randomized intervention trial suggest that the risk of prostate cancer may be reduced by selenium intake. We investigated whether plasma selenium level before diagnosis correlated with the risk of later developing prostate cancer. MATERIALS AND METHODS A case control study was performed on men from the Baltimore Longitudinal Study of Aging registry, including 52 with known prostate cancer and 96 age matched controls with no detectable prostatic disease. Plasma selenium was measured at an average time plus or minus standard deviation of 3.83 +/- 1.85 years before the diagnosis of prostate cancer by graphite furnace atomic absorption spectrophotometry. Adjusted odds ratio and 95% confidence interval were computed with logistic regression. RESULTS After correcting for years before diagnosis, body mass index, and smoking and alcohol use history, higher selenium was associated with a lower risk of prostate cancer. Compared with the lowest quartile of selenium (range 8.2 to 10.7 microg./dl.), the odds ratios of the second (10.8 to 11.8), third (11.9 to 13.2) and fourth (13.3 to 18.2) quartiles were 0.15 (95% confidence interval 0.05 to 0.50), 0.21 (0.07 to 0.68) and 0.24 (0.08 to 0.77, respectively, p =0.01). Furthermore, plasma selenium decreased significantly with patient age (p <0.001). CONCLUSIONS Low plasma selenium is associated with a 4 to 5-fold increased risk of prostate cancer. These results support the hypothesis that supplemental selenium may reduce the risk of prostate cancer. Because plasma selenium decreases with patient age, supplementation may be particularly beneficial to older men.

Long-Term Effects of Change in Body Weight on All-Cause Mortality: A Review

Many studies have described body weight as a risk factor for or a predictor of subsequent death. The clear consensus of these population studies is that a quadratic or U-shaped relation exists between weight and death. Furthermore, the nadir of the U, that is, the body weight associated with lowest mortality rate, is generally considerably lower in young adults than in middle-aged or older adults. Many theoretic complexities exist in the interpretation of this finding, including two major potential confounders: 1) because cigarette smoking is associated with low body weight and high mortality rate, decreases in smoking with advancing age could variably distort the association between weight and death at different ages; and 2) serious illness influences weight and death and is more prevalent with age. Results of studies that attempted to control for these complicating factors support the basic finding that body weight associated with minimal mortality rate increases with age. The implication of this result is unexpected and disturbing: If body weight for optimal survival increases with age, then some weight gain over time is not only permissible but can even be recommended for persons who are not overweight in early adult life. A test of this controversial conclusion is to examine persons on two occasions, to compute their changes in body weight, to follow these persons for specific outcomes, and to relate the observed weight changes to outcome. Such studies have the same potential confounders as those noted previously. Why was weight gained or lost? Although most potentially lethal illnesses lead to weight loss, weight gain is also possible (for example, edema in heart failure and inactivity due to illness). Weight may also be lost, however, in a purposeful program of health promotion that includes increased activity and a healthful diet. Unexplained weight loss in older persons is known to be an ominous symptom just as weight loss in elderly rodents is a harbinger of death. Despite these complexities, results of studies that quantify weight change must be examined. This review examines only the effects of weight change on all-cause mortality. Studies of the effects of long-term weight change on diabetes, coronary heart disease, cancer, and cause-specific death will not be reported in detail. Methods Change in weight is sometimes reported in kilograms, sometimes in body mass index (BMI, kg/m2), and sometimes as a percentage. For ease of comparison, data were converted, when feasible, to metric BMI units. It was assumed that the average height of men was 1.75 m (69 in) and of women was 1.63 m [64 in]. This report is limited to all published population studies that 1) assessed change in weight as the independent variable, 2) determined overall mortality rate as the dependent variable, and 3) had not been reported elsewhere in these proceedings. Studies were identified through a comprehensive bibliographic search of the literature. Williamson and Pamuk [1] critically summarized the results of six published studies that specifically purported to show increased longevity in association with long-term weight loss. We report results from 13 other published studies [214]. Their salient characteristics are summarized in Table 1. Publications [214] should be referred to for more detailed descriptions. The order of presentation was determined alphabetically by author. Descriptors included in the tables are not repeated in the brief summaries that follow. Table 1. Studies Reporting Change in Weight and All-Cause Mortality* Each study examined participants at two distinct periods in life. In the first, changes in body weight were determined; in the second, mortality rates were determined. In addition, 7 of the 13 studies included a period of temporal separation in the analytic scheme (Table 1). Although monitoring for death started at the end of the weight change period, data from participants who died in the early years of the mortality follow-up period were excluded from the analysis. Thus in the seven studies that included a temporal separation period, persons who had an illness that had caused weight loss and subsequent death were omitted to minimize the effects of serious illness on weight change and death. Results The Paris Prospective Study [2] of civil servants working in the Paris Police Administration computed BMI at 20 years of age from weight at the age of military service and height measured in middle-age at study entry. Participants were divided into quintiles of change in BMI between 20 and 43 to 53 years of age. Minimal mortality (6.7 deaths per 1000 person-years) occurred in the third quintile of BMI change (gains of 2.5 to 4.4 kg/m2). Highest mortality rates (10.8 and 9.3) occurred in the lowest quintile of weight change (a gain of 0.5 kg/m2 and in those who gained the most weight [> 6.5 kg/m2]). The Dutch Longitudinal Study among the Elderly [3], conducted between 1955 and 1957, examined a probability sample of elderly men and women. They were re-examined between 1960 and 1962, and five categories of weight change were then computed. Vital status was ascertained in 1983. Longevity was expressed as the realized probability of dying [3]. Additional analyses were limited to only those participants surviving 2 or more years after the end of the weight-change period. Data were analyzed separately for persons 65 to 74 years old and for those 75 years or older. Separate analyses were done for men and women. Both age groups and sexes showed a quadratic relation between weight change and death, but none of these patterns was statistically significant. The Western Electric Study by Hamm and colleagues [4] was directed primarily at fluctuations in weight and therefore used rather selective and unusual weight-change categories (see Table 1). Of 1959 employees studied, only 178 met the no weight change definition, and 133 met the gain only criteria. Only these groups provided data pertinent to this report. The weight-gain group had a relative mortality risk of 1.4 compared with the no-change group [95% CI, 1.0 to 2.1]. Weight gains averaged 37% and thus represented a serious degree of increase. No data on weight loss or on lesser degrees of weight gain were described in the report. The Framingham Heart Study [5] examined residents of Framingham, Massachusetts, and excluded persons who reported smoking cigarettes at any visit. Participants were placed in one of four BMI change groups. Lowest mortality rates occurred in men and women who gained from 0% to 9% in BMI. Men and women who lost 10% or more and men who lost 0% to 9% had significantly increased mortality rates. An analysis of weight change in this population at an earlier age is presented later in this report. In the Harvard Alumni Study by Lee and Paffenbarger [6], change in weight was monitored after participants had reached ages 35 to 74 years. Weight changes during an earlier phase of the life cycle were reported in a separate report. Participants were divided into five weight-change categories (loss of > 5 kg, loss of 1 to 5 kg, no change [ 1 kg], gain of 1 to 5 kg, and gain of > 5 kg). Relative risks for death (with the no change group set at 1.0) were 1.6, 1.25, 1.0, 1.0, and 1.3 for the five groups, respectively. They further showed similar patterns when analyses were stratified for initial BMI (more and less than 25 kg/m2). When participants were stratified by smoking pattern, nonsmokers showed significantly increased mortality rates in the two weight-loss groups and among those who gained more than 5 kg. Smokers showed the lowest mortality rate with 1 to 5 kg weight gain, and only those who lost more than 5 kg had a significant increase in mortality rate. In the Baltimore Longitudinal Study of Aging [7], change in BMI among community-dwelling volunteers was computed as a slope for each participant from four consecutive measurements made during a period that averaged 3.9 years. A significant (P = 0.05) negative association was noted between weight change and mortality rate; that is, weight loss was associated with increased mortality rate. To test for a quadratic (U-shaped) association, we used further analyses to show that, when participants were divided by quintiles of BMI change (from a loss of > 1.1 kg/m2 to a gain of > 0.8 kg/m2), a corresponding decrease was seen in relative risk for death. The values were 1.00 (referent), 0.94, 0.90, 0.78, and 0.75 for the five groups, respectively. A test for linear trend (orthogonal polynomials) showed the results analyzed by quintiles to be of borderline significance (P = 0.058). The Gothenburg prospective studies [8] combined two separate population studies. In women, a multiple logistic regression analysis showed that change in BMI was negatively associated with death (weight loss predicted death) (P < 0.03); in men, results were similar (P < 0.001). Addition of smoking to the model did not change either result. In addition to the weight-change analysis of persons 55 to 65 years old presented by Harris and colleagues [5], an analysis of the Framingham data based on weight changes occurring between 25 and 44-76 years of age has been published [9]. Highly significant effects of the slope of BMI change with time on total mortality rate were present in men and in women (P < 0.001 for both groups). These findings persisted despite the inclusion of five other risk factors for cardiovascular disease: smoking, serum cholesterol level, systolic blood pressure, glucose tolerance, and physical activity. Results remained statistically significant with temporal separation periods of either 4 or 6 years. The Harvard Alumni Study by Paffenbarger and coworkers [10] measured the height and weight of incoming Harvard freshmen during the years 1916 to 1959. Participants were enrolled in a follow-up study at ages 35 to 74 years, when weight was obtained by questionnaire. They were then placed into quintiles according to chan

Age as independent determinant of glucose tolerance.

It has been proposed that the decline in glucose tolerance with age is not a primary aging effect but is secondary to a combination of other age-associated characteristics, i.e., disease, medication, obesity, central and upper-body fat deposition, and inactivity. To test this hypothesis, we first eliminated from analysis the Baltimore Longitudinal Study of Aging participants with identifiable diseases or medications known to influence glucose tolerance. Seven hundred forty-three men and women, aged 17–92 yr, remained for analysis. As indices of fatness, body mass index and percent body fat were determined. As indices of body fat distribution, waist-hip ratio and subscapular triceps skin-fold ratio were calculated. As indices of fitness, physical activity level, determined by detailed questionnaire, and maximum 02 consumption were calculated. We tested whether the effect of age on glucose tolerance remains when data were adjusted for fatness, fitness, and fat distribution; 2-h glucose values were 6.61, 6.78, and 7.83 mM for young (17–39 yr), middle-aged (40–59 yr), and old (60–92 yr) men and 6.22, 6.22, and 7.28 mM for the three groups of women, respectively. The differences between the young and middle-aged groups were not significant, but the old groups had significantly higher values than young or middle-aged groups. Fatness, fitness, and fat distribution can account for the decline in glucose tolerance from the young adult to the middle-aged years. However, age remains a significant determinant of the further decline in glucose tolerance of healthy old subjects.

Plasma antioxidants and risk of cortical and nuclear cataract.

We evaluated nutritional risk factors for cataract in 660 subjects enrolled in the Baltimore Longitudinal Study on Aging. As a part of a regular cycle of visits, nuclear and cortical lens photographs were taken over a 2-year period. Measurements of plasma antioxidants (beta-carotene, ascorbic acid, and alpha-tocopherol) were obtained in this cohort as part of the study protocol up to 4 years before lens photographs were taken. We found that plasma beta-carotene and ascorbic acid levels were not associated with risk of nuclear or cortical lens opacities. Higher levels of plasma alpha-tocopherol, however, were associated with a reduced risk of nuclear opacity [odds ratio (OR) for highest quartile vs lowest quartile = 0.52, 95% confidence interval (CI) = 0.27–0.98; OR for middle two quartiles vs lowest quartile = 0.55, 95% CI = 0.30–0.98], after adjusting for age, sex, and history of diabetes. Middle levels of alpha-tocopherol were associated with a reduced risk of cortical opacity (OR = 0.57, 95% CI = 0.32–1.02), but no such association was observed for high levels of alpha-tocopherol. We constructed an index of overall antioxidant status, which indicated that higher levels of plasma antioxidants were not associated with risk of nuclear or cortical opacities.

Abnormal body composition phenotypes in older rheumatoid arthritis patients: association with disease characteristics and pharmacotherapies.

OBJECTIVE To compare measures of body fat and lean mass and the prevalence of abnormal body composition phenotypes (sarcopenia, overfat, and sarcopenic obesity) in men and women with rheumatoid arthritis (RA) versus matched controls, and to explore the disease-related predictors of abnormal body composition in patients with RA. METHODS A total of 189 men and women with RA and 189 age-, sex-, and race-matched non-RA controls underwent dual-energy x-ray absorptiometry for measurement of total and regional body fat and lean mass. Continuous and categorical measures of body composition were compared between RA and control subjects by sex and according to categories of body mass index (BMI). Within the group of RA patients, demographic, lifestyle, and RA disease and treatment characteristics were compared for RA patients with healthy body composition versus those with abnormal body composition phenotypes. RESULTS Compared with non-RA controls, RA status was significantly associated with greater odds of sarcopenia, overfat, and sarcopenic obesity in women, but not in men. Relative differences in body composition phenotypes between RA and control subjects were greatest for patients in the normal weight BMI category (<25 kg/m(2)). Among RA characteristics, increasing joint deformity, self-reported disability scores, C-reactive protein levels, rheumatoid factor seropositivity, and a lack of current treatment with disease-modifying antirheumatic drugs were significantly associated with abnormal body composition. CONCLUSION Abnormal body composition phenotypes are overrepresented in patients with RA, particularly in those in the normal weight BMI range. RA-associated disease and treatment characteristics contribute to this increase in abnormal body composition.

Reduced risk of Alzheimer’s disease with high folate intake: The Baltimore Longitudinal Study of Aging

Study findings have suggested an association between Alzheimers disease (AD) risk and several vitamins and have speculated about their use as preventive agents. Here, we examine whether total intake (intake from diet plus supplements) of antioxidant vitamins (E, C, carotenoids) and B vitamins (folate, B6, and B12) is associated with a reduced risk of AD.