Alka M. Kanaya

Glycemic Effects of Postmenopausal Hormone Therapy: The Heart and Estrogen/progestin Replacement Study: A Randomized, Double-Blind, Placebo-Controlled Trial

Context In observational studies, postmenopausal hormone therapy has been associated with lower fasting glucose levels. No prospective, controlled trial has evaluated the effect of postmenopausal hormone therapy on the development of diabetes mellitus. Contribution Among the 2029 women in the Heart and Estrogen/progestin Replacement Study who had coronary disease but no diabetes at baseline, 6.2% of those receiving 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate and 9.5% of those receiving placebo developed diabetes. Implications Recommendations about combination postmenopausal hormone therapy should consider that for every 30 women treated for 4 years, therapy might prevent one case of diabetes. The Editors Several clinical studies have evaluated the effect of postmenopausal hormone therapy on glucose metabolism and have had disparate results. Results from randomized, controlled trials performed primarily in women without diabetes have found decreased mean fasting glucose or insulin levels among those assigned to hormone therapy (1-5) or no difference between those assigned to hormones and those assigned to placebo (6-10). Fewer clinical trials have evaluated the effect of postmenopausal hormones on fasting glucose and insulin levels among women with type 2 diabetes mellitus, but again, the results have been mixed (11-16). Observational studies have more consistently found that postmenopausal women taking hormone therapy have lower fasting glucose or hemoglobin A1c levels than those not taking hormones (17-24). In addition, some (25, 26) but not all (24, 27) observational studies have noted a decreased incidence of diabetes among users of postmenopausal hormone therapy. No randomized, controlled trial has evaluated the long-term effect of hormone therapy on diabetes incidence. To determine the effect of hormone therapy on subsequent diabetes, we analyzed data from the Heart and Estrogen/progestin Replacement Study (HERS), in which 2763 postmenopausal women with documented coronary heart disease (CHD) were randomly assigned to daily estrogen plus progestin therapy or to placebo. We evaluated the effect of hormone therapy on fasting glucose levels and incident diabetes over 4 years of follow-up. Methods Study Setting, Participants, and Design The design, methods, baseline characteristics (28), and main findings (29) of HERS have been published elsewhere. Briefly, HERS was a randomized, double-blind, placebo-controlled trial performed to evaluate daily doses of 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate for the prevention of coronary events in postmenopausal women with established CHD. The trial enrolled 2763 women at 20 clinical centers in the United States between January 1993 and September 1994 and followed participants for a mean of 4.1 years. To be included in the trial, women had to be younger than 80 years of age and have CHD, as evidenced by previous myocardial infarction, coronary artery bypass graft surgery, mechanical revascularization, or angiographic evidence of coronary stenosis. Women who reported a CHD event within 6 months of randomization or who had used postmenopausal hormone therapy within 3 months of the initial screening were excluded. Those with serum triglyceride levels of 3.39 mmol/L or greater ( 300 mg/dL), fasting blood glucose levels of 16.5 mmol/L or greater ( 300 mg/dL), or uncontrolled hypertension (systolic blood pres sure 200 mg Hg or diastolic blood pressure 105 mm Hg) were also excluded. Computer-generated random numbers were used to specify the allocation sequence. Women were randomly assigned to the two treatment groups by use of a tamper-proof blocked randomization stratified by clinical center. Participants, investigators, and staff at the clinical centers; Wyeth-Ayerst Research; and those adjudicating study outcomes were blinded to medication assignment. Additional details about sample size calculations, randomization, and blinding procedures have been published elsewhere (29). For our analysis, women were classified as having diabetes at the baseline visit if they reported a physician diagnosis of diabetes, were taking diabetes medication, or had a fasting plasma glucose level of 6.9 mmol/L or greater ( 126 mg/dL). Women were classified as having impaired fasting glucose if they had a fasting glucose level of 6.0 to 6.9 mmol/L (110 to 125 mg/dL) at baseline. The remaining women were considered to have normal glucose metabolism. Data Collection At baseline, participants completed a questionnaire to ascertain age, race or ethnicity, education, smoking habits (current, former, or never), alcohol consumption (drinks per week), and exercise or walking activity. Physical examination variables measured at baseline were body weight, height, waist and hip circumference, and systolic and diastolic blood pressure. At baseline, at year 1, and at the end-of-trial visit, participants had fasting blood tests for levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and lipoprotein(a) measured by the Lipoprotein Analytical Laboratory at Johns Hopkins Hospital, Baltimore, Maryland. Fasting serum glucose level was measured at baseline, at year 1, and at the end-of-trial visit. Venous blood was obtained in the morning after a 12-hour fast, and SmithKline Beecham Clinical Laboratory, Van Nuys, California, analyzed the samples using the hexokinase enzymatic method. We determined coefficients of variation by using ChemTrac (Medical Analysis Systems, Inc., Camarillo, California) control. The coefficient of variation for serum glucose level was 1.6% at a mean value (SD) of 4.2 0.05 mmol/L (77 1.0 mg/dL) and 1.1% at a mean value (SD) of 14.6 0.16 mmol/L (266 3.0 mg/dL). Adherence to study medication was reassessed every 4 months, at each visit. Ascertainment of Outcomes Diabetes incidence was not a secondary end point of the main HERS trial, but blood glucose level was prespecified as a variable that may mediate the effects of hormone therapy on CHD outcomes. We defined incident cases of diabetes by the presence of a fasting glucose level of 6.9 mmol/L or greater ( 126 mg/dL) at year 1 or at the end-of-trial visit, self-report of new diabetes or a complication directly related to diabetes, or initiation of hypoglycemic medication at any point during follow-up. Self-reported complications included diabetic neuropathy, diabetic retinopathy, diabetic foot ulcer, and diabetic renal disease. Hypoglycemia was considered a complication of diabetes if a participant taking an antidiabetic medication reported it to the study staff as an adverse event. Statistical Analysis To compare fasting glucose levels by treatment assignment at baseline, at year 1, and at the end-of-trial visit, t-tests were used. In addition, mixed linear models for repeated measures were used to assess treatment effects on fasting glucose level measured at year 1 and at the end-of-trial visit. Since mean values changed little after the year 1 visit, treatment effects were modeled by using the interaction between treatment assignment and an indicator for follow-up compared with baseline. These analyses were repeated after stratification by baseline diabetes status (diabetes, impaired fasting glucose, or normal glucose metabolism). We calculated the number needed to treat for benefit by taking the inverse of the absolute risk reduction of incident diabetes between the treatment groups. The effect of treatment assignment on incident diabetes was assessed by using Cox proportional-hazards models. Primary analyses used unadjusted intention-to-treat models; in supplementary analyses, we adjusted first for age and then for a range of potential confounders selected a priori, including age; ethnicity; education; current smoking; alcohol use; exercise; body mass index; waist circumference; and baseline use of diuretics, -blockers, angiotensin-converting enzyme inhibitors, and statins. In addition to intention-to-treat analyses, we also performed as treated analyses to determine whether the observed effect of hormone therapy on glucose levels and incident diabetes was also seen among women who adhered to the study medication. In these analyses, follow-up was censored at the beginning of the first 2-week period in which participants did not adhere to medication. To minimize potential confounding, these analyses were adjusted for baseline variables that differed between adherent and nonadherent women. We hypothesized that certain characteristics (body mass index, waist circumference, weight change, smoking, triglyceride level, high-density lipoprotein cholesterol level, hypertension, and certain cardiac medications) may mediate the effect of hormone therapy on fasting glucose level and diabetes incidence. To test this theory, we added postrandomization values of one or more hypothesized mediators as covariates to Cox regression models for incident diabetes. All analyses were conducted by using SAS software, version 8.02 (SAS Institute, Inc., Cary, North Carolina). A P value less than 0.05 was considered statistically significant. Role of the Funding Sources The funding sources had no role in the design or conduct of this analysis or in the decision to submit the paper for publication. Results Characteristics of women enrolled in HERS did not differ substantially between the hormone therapy group and the placebo group (Table 1). At the baseline examination, 734 women (26.6%) were classified as diabetic based on self-report of diagnosis or medication use (n = 640 [87.2%]) or by a fasting serum glucose level of 6.9 mmol/L or greater ( 126 mg/dL) (n = 101 [13.8%]). Impaired fasting glucose (fasting serum glucose level, 6.0 to 6.9 mmol/L [110 to 125 mg/dL]) was noted in 218 women (7.9%), and 1811 women (65.5%) were classified as nondiabetic (Table 2). Women with diabetes had higher body mass index, waist circumference, systolic

Diabetes, impaired fasting glucose, and development of cognitive impairment in older women

Objective: To investigate the association between diabetes and impaired fasting glucose (IFG) and cognition and risk of developing both dementia and mild cognitive impairment (MCI) in older women. Methods: The authors analyzed data from a 4-year randomized trial of raloxifene among 7,027 osteoporotic postmenopausal women (mean age, 66.3 years) at 178 sites. Diabetes was defined by history, fasting blood glucose ≥7.0 mmol/L (≥126 mg/dL), or use of hypoglycemic agents; IFG was defined as fasting glucose <7.0 mmol/L but >6.11 mmol/L (110 mg/dL); all others were considered to have normal glucose (NG). The main outcome was baseline and 4-year change on five standardized cognitive tests (z scores with lower scores indicating worse performance) and risk of developing clinically significant impairment (dementia, mild cognitive impairment, or very low cognitive score). Results: A total of 267 (3.8%) women had diabetes and 297 (4.2%) had IFG. Women with IFG had worse baseline cognitive scores compared to women with NG but better scores than diabetics (age-adjusted composite z score based on five tests: NG 0.40, 95% CI 0.30 to 0.49; IFG 0.14, 95% CI −0.36 to 0.64; diabetics −0.78, 95% CI −1.23 to −0.33; p < 0.001). There was greater 4-year decline among diabetics (age and treatment-adjusted composite z score: NG −0.05, 95% CI −0.16 to 0.05; IFG 0.11, 95% CI −0.53 to 0.75; diabetics −1.00, 95% CI −1.50 to −0.50; p = 0.001). Further adjustment for education, race, and depression led to similar results. Risk of developing cognitive impairment among women with IFG or diabetes was increased by almost twofold (age and treatment-adjusted OR = 1.64; 95% CI 1.03 to 2.61 for IFG; OR = 1.79; 95% CI 1.14 to 2.81 for diabetics). Conclusions: Diabetic as well as pre-diabetic women have impaired cognitive performance and greater risk of developing cognitive impairment.

Low subcutaneous thigh fat is a risk factor for unfavourable glucose and lipid levels, independently of high abdominal fat. The Health ABC Study

AimsWe investigated whether low subcutaneous thigh fat is an independent risk factor for unfavourable glucose and lipid levels, and whether these associations differ between sexes, and between white and black adults. Our secondary aim was to investigate which body composition characteristics (lean tissue, fat tissue) are reflected by anthropometric measures (waist and thigh circumference).MethodsAnthropometric measurements and computed tomography of the abdomen and of the thigh were performed for all participants of the Health, Aging and Body Composition Study, who were aged 70–79 years. Fasting glucose, triglycerides and HDL-cholesterol, and 2-h postload glucose were determined.ResultsAfter excluding those already diagnosed with diabetes or dyslipidaemia, we analysed data from 2,106 participants. After adjustment for abdominal subcutaneous and visceral fat, and intermuscular thigh fat, larger thigh subcutaneous fat area was statistically significantly associated with lower ln-transformed triglycerides [standardised beta (95% CI) −0.12 (−0.20 to −0.04) in men and −0.13 (−0.21 to −0.05) in women] and higher ln-HDL-cholesterol [0.10 (0.02 to 0.19) and 0.09 (0.01 to 0.18), respectively]. The associations with lower glucose levels were strong in men [−0.11 (−0.20 to −0.02) for fasting and −0.14 (−0.23 to −0.05) for postload glucose], but not statistically significant in women [−0.02 (−0.10 to 0.07) and −0.04 (−0.13 to 0.05), respectively]. There were no differences in the associations between white and black persons. Waist circumference was more strongly associated with abdominal subcutaneous fat, and this association became stronger with increasing BMI, whereas the association with visceral fat became weaker. Thigh circumference was equally dependent on thigh fat and thigh muscle in men, whereas in women the fat component was the main contributor.ConclusionLarger subcutaneous thigh fat is independently associated with more favourable glucose (in men) and lipid levels (in both sexes) after accounting for abdominal fat depots, which are associated with unfavourable glucose and lipid levels. Anthropometric measures reflect different fat depots at different levels of BMI at the abdomen, and reflect both fat and lean tissue at the thigh. These results emphasise the importance of accurate measures of regional body composition when investigating potential health risks.

Fetuin-A and Incident Diabetes Mellitus in Older Persons

CONTEXT Fetuin-A is a hepatic secretory protein that binds the insulin receptor and inhibits insulin action in vitro. In prior cross-sectional studies in humans, higher fetuin-A levels were associated with insulin resistance. However, the longitudinal association of fetuin-A with incident type 2 diabetes mellitus is unknown. OBJECTIVE To determine whether fetuin-A levels are associated with incident diabetes in older persons. DESIGN, SETTING, AND PARTICIPANTS Observational study among 3075 well-functioning persons aged 70 to 79 years. In this case-cohort study, we retrospectively measured fetuin-A levels in baseline serum among 406 randomly selected participants without prevalent diabetes, and all participants who developed incident diabetes mellitus during a 6-year follow-up (to August 31, 2005). MAIN OUTCOME MEASURE Incident diabetes mellitus. RESULTS Incident diabetes developed in 135 participants (10.1 cases/1000 person-years). Participants with fetuin-A levels within the highest tertile (> 0.97 g/L) had an increased risk of incident diabetes (13.3 cases/1000 person-years) compared with participants in the lowest tertile (< or = 0.76 g/L) (6.5 cases/1000 person-years) in models adjusted for age, sex, race, waist circumference, body weight, physical activity, blood pressure level, fasting glucose level, high-density lipoprotein cholesterol concentration, triglyceride concentration, and C-reactive protein level (adjusted hazard ratio, 2.41; 95% confidence interval, 1.28-4.53; P = .007). The association was not affected by adipocytokine levels but was moderately attenuated by adjustment for visceral adiposity (adjusted hazard ratio of highest vs lowest tertile 1.72; 95% confidence interval, 0.98-3.05; P = .06). CONCLUSION Among well-functioning older persons, serum fetuin-A is associated with incident diabetes, independent of other markers of insulin resistance.

Urinary Incontinence in Elderly Women: Findings From the Health, Aging, and Body Composition Study

OBJECTIVE: To estimate the prevalence of and risk factors for stress and urge incontinence in a biracial sample of well-functioning older women. METHODS: We performed a cross-sectional analysis of 1,584 white and black women, aged 70–79 years, enrolled in a longitudinal cohort study. Participants were asked about incontinence, medical problems, and demographic and reproductive characteristics and underwent physical measurements. Using multivariable logistic regression, we compared women reporting at least weekly incontinence with those without incontinence. RESULTS: Overall, 21% reported incontinence at least weekly. Of these, 42% reported predominantly urge incontinence, and 40% reported stress. Nearly twice as many white women as black women reported weekly incontinence (27% versus 14%, P < .001). Factors associated with urge incontinence included white race (odds ratio [OR] 3.1, 95% confidence interval [CI] 2.0–4.8), diabetes treated with insulin (OR 3.5, 95% CI 1.6–7.9), depressive symptoms (OR 2.7, 95% CI 1.4–5.3), current oral estrogen use (OR 1.7, 95% CI 1.1–2.6), arthritis (OR 1.7, 95% CI 1.1–2.6), and decreased physical performance (OR 1.6 per point on 0–4 scale, 95% CI 1.1–2.3). Factors associated with stress incontinence were chronic obstructive pulmonary disease (OR 5.6, 95% CI 1.3–23.2), white race (OR 4.1, 95% CI 2.5–6.7), current oral estrogen use (OR 2.0, 95% CI 1.3–3.1), arthritis (OR 1.6, 95% CI 1.0–2.4), and high body mass index (OR 1.3 per 5 kg/m2, 95% CI 1.1–1.6). CONCLUSION: Urinary incontinence is highly prevalent, even in well-functioning older women, whites in particular. Many risk factors differ for stress and urge incontinence, suggesting differing etiologies and prevention strategies. LEVEL OF EVIDENCE: II-2

Abdominal Obesity Is an Independent Risk Factor for Chronic Heart Failure in Older People

OBJECTIVES: To examine whether total and abdominal adiposity are risk factors for the development of chronic heart failure (CHF) in older men and women.

Combining Body Mass Index With Measures of Central Obesity in the Assessment of Mortality in Subjects With Coronary Disease : Role of “Normal Weight Central Obesity”

OBJECTIVES This study sought to assess the mortality risk of patients with coronary artery disease (CAD) based ona combination of body mass index (BMI) with measures of central obesity. BACKGROUND In CAD patients, mortality has been reported to vary inversely with BMI (“obesity paradox”). In contrast,central obesity is directly associated with mortality. Because of this bidirectionality, we hypothesized that CAD patients with normal BMI but central obesity would have worse survival compared to individuals with other combinations of BMI and central adiposity. METHODS We included 15,547 participants with CAD who were part of 5 studies from 3 continents. Multivariate stratifiedCox-proportional hazard models adjusted for potential confounders were used to assess mortality risk according to different patterns of adiposity that combined BMI with measures of central obesity. RESULTS Mean age was 66 years, 60% were men. There were 5,507 deaths over a median follow-up of 2.4 years (IQR: 0.5 to 7.4 years). Individuals with normal weight central obesity had the worst long-term survival: a person with BMI of 22 kg/m2 and waist circumference (WC) of 101 cm had higher mortality than a person with similar BMI but WC of 85 cm (HR: 1.10[95% CI: 1.05 to 1.17]), than a person with BMI of 26 kg/m2 and WC of 85 cm (HR: 1.20 [95% CI: 1.09 to 1.31]), than a person with BMI of 30 kg/m2 and WC of 85 cm (HR: 1.61 [95% CI: 1.39 to 1.86]) and than a person with BMI of 30kg/m2 and WC of 101 cm (HR: 1.27 [95% CI: 1.18 to 1.39), p < 0.0001 for all). CONCLUSIONS In patients with CAD, normal weight with central obesity is associated with the highest risk of mortality [corrected].

BMI Cut Points to Identify At-Risk Asian Americans for Type 2 Diabetes Screening

According to the U.S. Census Bureau, an Asian is a person with origins from the Far East (China, Japan, Korea, and Mongolia), Southeast Asia (Cambodia, Malaysia, the Philippine Islands, Thailand, Vietnam, Indonesia, Singapore, Laos, etc.), or the Indian subcontinent (India, Pakistan, Bangladesh, Bhutan, Sri Lanka, and Nepal); each region has several ethnicities, each with a unique culture, language, and history. In 2011, 18.2 million U.S. residents self-identified as Asian American, with more than two-thirds foreign-born (1). In 2012, Asian Americans were the nation’s fastest-growing racial or ethnic group, with a growth rate over four times that of the total U.S. population. International migration has contributed >60% of the growth rate in this population (1). Among Asian Americans, the Chinese population was the largest (4.0 million), followed by Filipinos (3.4 million), Asian Indians (3.2 million), Vietnamese (1.9 million), Koreans (1.7 million), and Japanese (1.3 million). Nearly three-fourths of all Asian Americans live in 10 states—California, New York, Texas, New Jersey, Hawaii, Illinois, Washington, Florida, Virginia, and Pennsylvania (1). By 2060, the Asian American population is projected to more than double to 34.4 million, with its share of the U.S. population climbing from 5.1 to 8.2% in the same period (2). Although it is clear that increased body weight is a risk factor for type 2 diabetes, the relationship between body weight and type 2 diabetes is more properly attributable to the quantity and distribution of body fat (3–5). Abdominal circumference and waist and hip measurements, although highly correlated with cardiometabolic risk (6,7), do not differentiate subcutaneous from visceral adipose abdominal depots and are subject to interobserver variability. Imaging and other approaches can be used to more accurately assess fat distribution and quantify adiposity (4,8), but they are not readily available, economical, or useable on …

Body fat distribution and inflammation among obese older adults with and without metabolic syndrome.

The protective mechanisms by which some obese individuals escape the detrimental metabolic consequences of obesity are not understood. This study examined differences in body fat distribution and adipocytokines in obese older persons with and without metabolic syndrome. Additionally, we examined whether adipocytokines mediate the association between body fat distribution and metabolic syndrome. Data were from 729 obese men and women (BMI ≥30 kg/m2), aged 70–79 participating in the Health, Aging and Body Composition (Health ABC) study. Thirty‐one percent of these obese men and women did not have metabolic syndrome. Obese persons with metabolic syndrome had significantly more abdominal visceral fat (men: P = 0.04; women: P < 0.01) and less thigh subcutaneous fat (men: P = 0.09; women: P < 0.01) than those without metabolic syndrome. Additionally, those with metabolic syndrome had significantly higher levels of interleukin‐6 (IL‐6), tumor necrosis factor‐α (TNF‐α), and plasminogen activator inhibitor‐1 (PAI‐1) than individuals without metabolic syndrome. Per standard deviation higher in visceral fat, the likelihood of metabolic syndrome significantly increased in women (odds ratio (OR): 2.16, 95% confidence interval (CI): 1.59–2.94). In contrast, the likelihood of metabolic syndrome decreased in both men (OR: 0.56, 95% CI: 0.39–0.80) and women (OR: 0.49, 95% CI: 0.34–0.69) with each standard deviation higher in thigh subcutaneous fat. These associations were partly mediated by adipocytokines; the association between thigh subcutaneous fat and metabolic syndrome was no longer significant in men. In summary, metabolically healthy obese older persons had a more favorable fat distribution, characterized by lower visceral fat and greater thigh subcutaneous fat and a more favorable inflammatory profile compared to their metabolically unhealthy obese counterparts.

Differences in Medical Care and Disease Outcomes Among Black and White Women With Heart Disease

Background—The risk of cardiovascular mortality is higher among black women than white women, and the reasons for this disparity are largely unexplored. We sought to evaluate differences in medical care and clinical outcomes among black and white women with established coronary artery disease. Methods and Results—Among the 2699 women enrolled in the Heart and Estrogen/progestin Replacement Study (HERS), we used Cox proportional hazards models to determine the association of race with risk of coronary heart disease (CHD) events independent of major cardiovascular risk factors or medical therapies. During an average of 4.1 years of follow-up, CHD events were twice as likely in black compared with white women (6.4 versus 3.1 per 100 person-years, hazard ratio, 2.1; 95% confidence interval, 1.5 to 2.8; P <0.001). Black women had higher rates of hypertension, diabetes, and hypercholesterolemia, yet were less likely to receive aspirin or statins. Black women less often had optimal blood pressure (56% versus 63%; P =0.01) and LDL cholesterol (30% versus 38%; P =0.04) control at baseline and during follow-up. After adjusting for these and other differences, black women still had >50% higher CHD event risk (hazard ratio, 1.52; 95% confidence interval, 1.1 to 2.1; P =0.03). Conclusions—In a large cohort of women with heart disease, black women less often received appropriate preventive therapy and adequate risk factor control despite a greater CHD event risk. Interventions to improve appropriate therapy and risk factor control in all women, and especially black women, are needed.