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1.  CHD Events in the WHI Hormone Trials: Effect Modification by Metabolic Syndrome A Nested Case/Control Study within the WHI RCTs 
Menopause (New York, N.Y.)  2013;20(3):254-260.
Objective
Our objective was to determine if metabolic syndrome (MetS), or its components, modified the effect of HT on risk of CHD events in the Women’s Health Initiative (WHI) clinical trials.
Methods
We performed a nested case/control study of incident CHD events during the first 4 years of follow up in the WHI HT trials (estrogen plus progestin [E+P] and estrogen-alone [E-alone]). There were 359 incident cases of CHD during follow up. After excluding women with cardiovascular disease (CVD) (n=90), diabetes or hypertension at baseline (n=103), 166 CHD cases were matched to 524 controls on age, randomization date, and hysterectomy status. MetS classification required at least 3 of 5 ATPIII criteria. Analyses by Chi-square, t-tests for heterogeneity and logistic regression were performed. Postmenopausal women (n=27,347) ages 50 to 79 from 40 US clinical centers participated.
Daily conjugated equine estrogens (0.625 mg) and medroxyprogesterone acetate (2.5mg) (EPT) or conjugated equine estrogens (0.625 mg) (ET) was compared to placebo. The Main Outcome Measure was the odds for CHD with HT use vs. placebo by MetS status.
Results
MetS modified the risk of CHD events with HT. In the pooled analysis, with MetS, risk was increased with HT vs. placebo (OR=2.26[95% CI, 1.26, 4.07]), whereas women without MetS were not found to have increased risk for a CHD event with HT (OR=0.97 [95% CI, 0.58, 1.61]) (p for interaction = 0. 03). Results were similar in the EPT and ET trials, when examined separately. The constellation of MetS variables was more predictive of risk from HT than Mets components assessed individually. When patients with diabetes or hypertension were included in the analysis we could not detect statistically significant effect modification.
Conclusion
MetS at baseline, in women without prior CVD, diabetes, or hypertension at baseline, identified women more likely to have had adverse coronary outcomes on HT. CHD risk stratification is recommended prior to initiating HT. The basis for the greater risk of CHD events with HT among patients with the metabolic syndrome requires further study.
doi:10.1097/GME.0b013e31826f80e0
PMCID: PMC4279916  PMID: 23435021
WHI; CHD; HT; Metabolic syndrome; Effect Modification
2.  All-Cause, Cardiovascular, and Cancer Mortality Rates in Postmenopausal White, Black, Hispanic, and Asian Women With and Without Diabetes in the United States 
American Journal of Epidemiology  2013;178(10):1533-1541.
Using data from the Women's Health Initiative (1993–2009; n = 158,833 participants, of whom 84.1% were white, 9.2% were black, 4.1% were Hispanic, and 2.6% were Asian), we compared all-cause, cardiovascular, and cancer mortality rates in white, black, Hispanic, and Asian postmenopausal women with and without diabetes. Cox proportional hazard models were used for the comparison from which hazard ratios and 95% confidence intervals were computed. Within each racial/ethnic subgroup, women with diabetes had an approximately 2–3 times higher risk of all-cause, cardiovascular, and cancer mortality than did those without diabetes. However, the hazard ratios for mortality outcomes were not significantly different between racial/ethnic subgroups. Population attributable risk percentages (PARPs) take into account both the prevalence of diabetes and hazard ratios. For all-cause mortality, whites had the lowest PARP (11.1, 95% confidence interval (CI): 10.1, 12.1), followed by Asians (12.9, 95% CI: 4.7, 20.9), blacks (19.4, 95% CI: 15.0, 23.7), and Hispanics (23.2, 95% CI: 14.8, 31.2). To our knowledge, the present study is the first to show that hazard ratios for mortality outcomes were not significantly different between racial/ethnic subgroups when stratified by diabetes status. Because of the “amplifying” effect of diabetes prevalence, efforts to reduce racial/ethnic disparities in the rate of death from diabetes should focus on prevention of diabetes.
doi:10.1093/aje/kwt177
PMCID: PMC3888272  PMID: 24045960
diabetes; health disparities; menopause; mortality; obesity; women's health
3.  Sex Hormone Levels and Risk of Breast Cancer With Estrogen Plus Progestin 
Background
Although high endogenous sex hormone levels and estrogen plus progestin (E+P) therapy are associated with increased breast cancer risk, it is unknown whether pretreatment levels of sex hormones modify E+P effect on breast cancer.
Methods
We conducted a nested case–control study within the Women’s Health Initiative randomized clinical trial of E+P. The trial enrolled 16608 postmenopausal women aged 50 to 79 years with intact uterus and no breast cancer history. During a mean of 5.6 years of follow-up, 348 incident breast cancer case subjects were identified and matched with 348 control subjects. Case and control subjects had their sex hormone levels measured at baseline (estrogens, testosterone, progesterone, and sex hormone–binding globulin [SHBG]) and year 1 (estrogens and SHBG) using sensitive assays. All statistical tests were two-sided.
Results
Statistically significant elevations in breast cancer risk were seen with greater pretreatment levels of total estradiol (P trend = .04), bioavailable estradiol (P trend = .03), estrone (P trend = .007), and estrone sulfate (P trend = .007). E+P increased all measured estrogens and SHGB at year 1 (all P < .001). The effect of E+P on breast cancer risk was strongest in women whose pretreatment levels of total estradiol, bioavailable estradiol, and estrone were in the lowest quartiles. For example, the odds ratio for E+P relative to placebo was 2.47 (95% confidence interval [CI] = 1.28 to 4.79) in the lowest total estradiol quartile, compared with 0.96 (95% CI = 0.44 to 2.09) in the highest total estradiol quartile; P interaction = .04).
Conclusions
Women with lower pr-treatment endogenous estrogen levels were at greater risk of breast cancer during E+P therapy compared with those with higher levels. Further studies are warranted to confirm these findings.
doi:10.1093/jnci/djt243
PMCID: PMC3787910  PMID: 24041978
4.  Evidence of Reduced β-Cell Function in Asian Indians With Mild Dysglycemia 
Diabetes Care  2013;36(9):2772-2778.
OBJECTIVE
To examine β-cell function across a spectrum of glycemia among Asian Indians, a population experiencing type 2 diabetes development at young ages despite low BMI.
RESEARCH DESIGN AND METHODS
One-thousand two-hundred sixty-four individuals without known diabetes in the Diabetes Community Lifestyle Improvement Program in Chennai, India, had a 75-g oral glucose tolerance test, with glucose and insulin measured at 0, 30, and 120 min. Type 2 diabetes, isolated impaired fasting glucose (iIFG), isolated impaired glucose tolerance (iIGT), combined impaired fasting glucose and impaired glucose tolerance, and normal glucose tolerance (NGT) were defined by American Diabetes Association guidelines. Measures included insulin resistance and sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR], modified Matsuda Index, 1/fasting insulin) and β-cell function (oral disposition index = [Δinsulin0–30/Δglucose0–30] × [1/fasting insulin]).
RESULTS
Mean age was 44.2 years (SD, 9.3) and BMI 27.4 kg/m2 (SD, 3.8); 341 individuals had NGT, 672 had iIFG, IGT, or IFG plus IGT, and 251 had diabetes. Patterns of insulin resistance or sensitivity were similar across glycemic categories. With mild dysglycemia, the absolute differences in age- and sex-adjusted oral disposition index (NGT vs. iIFG, 38%; NGT vs. iIGT, 32%) were greater than the differences in HOMA-IR (NGT vs. iIFG, 25%; NGT vs. iIGT, 23%; each P < 0.0001). Compared with NGT and adjusted for age, sex, BMI, waist circumference, and family history, the odds of mild dysglycemia were more significant per SD of oral disposition index (iIFG: odds ratio [OR], 0.36; 95% CI, 0.23–0.55; iIGT: OR, 0.37; 95% CI, 0.24–0.56) than per SD of HOMA-IR (iIFG: OR, 1.69; 95% CI, 1.23–2.33; iIGT: OR, 1.53; 95% CI, 1.11–2.11).
CONCLUSIONS
Asian Indians with mild dysglycemia have reduced β-cell function, regardless of age, adiposity, insulin sensitivity, or family history. Strategies in diabetes prevention should minimize loss of β-cell function.
doi:10.2337/dc12-2290
PMCID: PMC3747932  PMID: 23596180
5.  Relations of Depressive Symptoms and Antidepressant Use to Body Mass Index and Selected Biomarkers for Diabetes and Cardiovascular Disease 
American journal of public health  2013;103(8):e34-e43.
Objectives
We investigated whether depressive symptoms and antidepressant use are associated with biomarkers for glucose dysregulation and inflammation, body mass index (BMI), and waist circumference.
Methods
Postmenopausal women were recruited into the Women’s Health Initiative from 1993 to 1998, and data were collected at regular intervals through 2005. We used multiple linear regression models to examine whether depressive symptoms and antidepressant use are associated with BMI, waist circumference, and biomarkers.
Results
Analysis of data from 71 809 women who completed all relevant baseline and year 3 assessments showed that both elevated depressive symptoms and antidepressant use were significantly associated with higher BMI and waist circumference. Among 1950 women, elevated depressive symptoms were significantly associated with increased insulin levels and measures of insulin resistance. Analyses of baseline data from 2242 women showed that both elevated depressive symptoms and antidepressant use were associated with higher C-reactive protein levels.
Conclusions
Monitoring body habitus and other biomarkers among women with elevated depression symptoms or taking antidepressant medication may be prudent to prevent diabetes and cardiovascular disease.
doi:10.2105/AJPH.2013.301394
PMCID: PMC3791588  PMID: 23763394
6.  Hyperglycemia, Insulin Resistance, Impaired Pancreatic β-Cell Function, and Risk of Pancreatic Cancer 
Background
Obesity and diabetes mellitus are associated with an increased risk of pancreatic cancer. These associations may be secondary to consequences of peripheral insulin resistance, pancreatic β-cell dysfunction, or hyperglycemia itself. Hemoglobin A1c (HbA1c) is a measure of hyperglycemia, whereas plasma insulin and proinsulin are markers of peripheral insulin resistance, and the proinsulin to insulin ratio marks pancreatic β-cell dysfunction.
Methods
This was a prospective, nested case-control study of 449 case patients and 982 control subjects with prediagnostic blood samples and no diabetes history from five prospective US cohorts followed through 2008. Two or three control subjects were matched to each case patient by year of birth, cohort, smoking, and fasting status. Pancreatic cancer risk was assessed by prediagnostic HbA1c, insulin, proinsulin, and proinsulin to insulin ratio with multivariable-adjusted logistic regression. All P values were two-sided.
Results
The highest vs lowest quintiles of HbA1c, insulin, and proinsulin were associated with with an increased risk for pancreatic cancer (odds ratio [OR] = 1.79; 95% confidence interval [CI] = 1.17 to 2.72, P trend = .04 for HbA1c; OR = 1.57; 95% CI = 1.08 to 2.30; Ptrend = .002 for insulin; and OR = 2.22; 95% CI = 1.50 to 3.29; P trend < .001 for proinsulin). Proinsulin to insulin ratio was not associated with pancreatic cancer risk. Results were similar across studies (all P heterogeneity > .29). In cancers developing 10 or more years after blood collection, the associations with insulin and proinsulin became stronger (highest vs lowest quintile, OR = 2.77; 95% CI = 1.28 to 5.99 for insulin and OR = 3.60; 95% CI = 1.68 to 7.72 for proinsulin). In mutually adjusted models including HbA1c, insulin, and proinsulin, only proinsulin remained statistically significant ( highest vs lowest quintile, OR = 2.55; 95% CI = 1.54 to 4.21; Ptrend < .001).
Conclusions
Among participants from five large prospective cohorts, circulating markers of peripheral insulin resistance, rather than hyperglycemia or pancreatic β-cell dysfunction, were independently associated with pancreatic cancer risk.
doi:10.1093/jnci/djt123
PMCID: PMC3714020  PMID: 23847240
7.  Screening for Diabetes and Prediabetes Should Be Cost-Saving in Patients at High Risk 
Diabetes Care  2013;36(7):1981-1987.
OBJECTIVE
Although screening for diabetes and prediabetes is recommended, it is not clear how best or whom to screen. We therefore compared the economics of screening according to baseline risk.
RESEARCH DESIGN AND METHODS
Five screening tests were performed in 1,573 adults without known diabetes—random plasma/capillary glucose, plasma/capillary glucose 1 h after 50-g oral glucose (any time, without previous fast, plasma glucose 1 h after a 50-g oral glucose challenge [GCTpl]/capillary glucose 1 h after a 50-g oral glucose challenge [GCTcap]), and A1C—and a definitive 75-g oral glucose tolerance test. Costs of screening included the following: costs of testing (screen plus oral glucose tolerance test, if screen is positive); costs for false-negative results; and costs of treatment of true-positive results with metformin, all over the course of 3 years. We compared costs for no screening, screening everyone for diabetes or high-risk prediabetes, and screening those with risk factors based on age, BMI, blood pressure, waist circumference, lipids, or family history of diabetes.
RESULTS
Compared with no screening, cost-savings would be obtained largely from screening those at higher risk, including those with BMI >35 kg/m2, systolic blood pressure ≥130 mmHg, or age >55 years, with differences of up to −46% of health system costs for screening for diabetes and −21% for screening for dysglycemia110, respectively (all P < 0.01). GCTpl would be the least expensive screening test for most high-risk groups for this population over the course of 3 years.
CONCLUSIONS
From a health economics perspective, screening for diabetes and high-risk prediabetes should target patients at higher risk, particularly those with BMI >35 kg/m2, systolic blood pressure ≥130 mmHg, or age >55 years, for whom screening can be most cost-saving. GCTpl is generally the least expensive test in high-risk groups and should be considered for routine use as an opportunistic screen in these groups.
doi:10.2337/dc12-1752
PMCID: PMC3687271  PMID: 23393215
8.  Lessons learned from MPI and physiologic testing in randomized trials of stable ischemic heart disease: COURAGE, BARI 2D, FAME, and ISCHEMIA 
There is a preponderance of evidence that, in the setting of an acute coronary syndrome, an invasive approach using coronary revascularization has a morbidity and mortality benefit. However, recent stable ischemic heart disease (SIHD) randomized clinical trials testing whether the addition of coronary revascularization to guideline-directed medical therapy (GDMT) reduces death or major cardiovascular events have been negative. Based on the evidence from these trials, the primary role of GDMT as a front line medical management approach has been clearly defined in the recent SIHD clinical practice guideline; the role of prompt revascularization is less precisely defined. Based on data from observational studies, it has been hypothesized that there is a level of ischemia above which a revascularization strategy might result in benefit regarding cardiovascular events. However, eligibility for recent negative trials in SIHD has mandated at most minimal standards for ischemia. An ongoing randomized trial evaluating the effectiveness of randomization of patients to coronary angiography and revascularization as compared to no coronary angiography and GDMT in patients with moderate-severe ischemia will formally test this hypothesis. The current review will highlight the available evidence including a review of the published and ongoing SIHD trials.
doi:10.1007/s12350-013-9773-4
PMCID: PMC3954506  PMID: 23963599
Myocardial perfusion imaging; ischemia; coronary artery disease; clinical trials
9.  Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium 
Cancer causes & control : CCC  2012;24(1):13-25.
Purpose
Diabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan).
Methods
The pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case–control study design. Subjects who were diagnosed with diabetes near the time (<2 years) of pancreatic cancer diagnosis were excluded from all analyses. All analyses were adjusted for age, race, gender, study, alcohol use, smoking, BMI, and family history of pancreatic cancer.
Results
Self-reported diabetes was associated with a forty percent increased risk of pancreatic cancer (OR = 1.40, 95 % CI: 1.07, 1.84). The association differed by duration of diabetes; risk was highest for those with a duration of 2–8 years (OR = 1.79, 95 % CI: 1.25, 2.55); there was no association for those with 9+ years of diabetes (OR = 1.02, 95 % CI: 0.68, 1.52).
Conclusions
These findings provide support for a relationship between diabetes and pancreatic cancer risk. The absence of association in those with the longest duration of diabetes may reflect hypoinsulinemia and warrants further investigation.
doi:10.1007/s10552-012-0078-8
PMCID: PMC3529822  PMID: 23112111
Diabetes; Risk factor; Cohort consortium; Pancreatic cancer
10.  Determinants of Racial/Ethnic Disparities in Incidence of Diabetes in Postmenopausal Women in the U.S. 
Diabetes Care  2012;35(11):2226-2234.
OBJECTIVE
To examine determinants of racial/ethnic differences in diabetes incidence among postmenopausal women participating in the Women’s Health Initiative.
RESEARCH DESIGN AND METHODS
Data on race/ethnicity, baseline diabetes prevalence, and incident diabetes were obtained from 158,833 women recruited from 1993–1998 and followed through August 2009. The relationship between race/ethnicity, other potential risk factors, and the risk of incident diabetes was estimated using Cox proportional hazards models from which hazard ratios (HRs) and 95% CIs were computed.
RESULTS
Participants were aged 63 years on average at baseline. The racial/ethnic distribution was 84.1% non-Hispanic white, 9.2% non-Hispanic black, 4.1% Hispanic, and 2.6% Asian. After an average of 10.4 years of follow-up, compared with whites and adjusting for potential confounders, the HRs for incident diabetes were 1.55 for blacks (95% CI 1.47–1.63), 1.67 for Hispanics (1.54–1.81), and 1.86 for Asians (1.68–2.06). Whites, blacks, and Hispanics with all factors (i.e., weight, physical activity, dietary quality, and smoking) in the low-risk category had 60, 69, and 63% lower risk for incident diabetes. Although contributions of different risk factors varied slightly by race/ethnicity, most findings were similar across groups, and women who had both a healthy weight and were in the highest tertile of physical activity had less than one-third the risk of diabetes compared with obese and inactive women.
CONCLUSIONS
Despite large racial/ethnic differences in diabetes incidence, most variability could be attributed to lifestyle factors. Our findings show that the majority of diabetes cases are preventable, and risk reduction strategies can be effectively applied to all racial/ethnic groups.
doi:10.2337/dc12-0412
PMCID: PMC3476929  PMID: 22833490
11.  A Prospective Study of Leukocyte Telomere Length and Risk of Type 2 Diabetes in Postmenopausal Women 
Diabetes  2012;61(11):2998-3004.
Telomere length (TL) has been implicated in the pathogenesis of age-related disorders. However, there are no prospective studies directly investigating the role of TL and relevant genes in diabetes development. In the multiethnic Women’s Health Initiative, we identified 1,675 incident diabetes case participants in 6 years of follow-up and 2,382 control participants matched by age, ethnicity, clinical center, time of blood draw, and follow-up duration. Leukocyte TL at baseline was measured using quantitative PCR, and Mendelian randomization analysis was conducted to test whether TL is causally associated with diabetes risk. After adjustment for matching and known diabetes risk factors, odds ratios per 1-kilobase increment were 1.00 (95% CI 0.90–1.11) in whites, 0.95 (0.85–1.06) in blacks, 0.96 (0.79–1.17) in Hispanics, and 0.88 (0.70–1.10) in Asians. Of the 80 single nucleotide polymorphisms (SNPs) in nine genes involved in telomere regulation, 14 SNPs were predictive of TL, but none were significantly associated with diabetes risk. Using ethnicity-specific SNPs as randomization instruments, we observed no statistically significant association between TL and diabetes risk (P = 0.52). Although leukocyte TL was weakly associated with diabetes risk, this association was not independent of known risk factors. These prospective findings indicate limited clinical utility of TL in diabetes risk stratification among postmenopausal women.
doi:10.2337/db12-0241
PMCID: PMC3478524  PMID: 22829448
12.  Ethnic heterogeneity in glucoregulatory function during treatment with atypical antipsychotics in patients with schizophrenia✩  
Journal of psychiatric research  2008;42(13):1076-1085.
Objective
Atypical antipsychotics induce weight gain and are linked to increased diabetes risk, but their relative impact on factors that elevate disease risk are unknown.
Methods
We performed a 6-month, randomized, double-blind study to evaluate the effects of risperidone and olanzapine in patients with schizophrenia. At baseline and weeks 6 and 24, we quantified: (1) total adiposity by DEXA, (2) visceral adiposity by abdominal CT, and (3) insulin sensitivity (SI) and (4) pancreatic function (“disposition index”, DI) by intravenous glucose tolerance test.
Results
At baseline, groups (risperidone: n = 28; olanzapine: n = 31) were overweight or obese by body mass index (risperidone: 28.4 ± 5.4, olanzapine: 30.6 ± 7.0 kg/m2). Both drugs induced weight gain (p < 0.004). Total adiposity was increased by olanzapine at 6 weeks (p = 0.0006) and by both treatments at 24 weeks (p < 0.003). Visceral adiposity was increased by olanzapine and risperidone by 24 weeks (p < 0.003). SI did not deteriorate appreciably, although a downward trend was observed with risperidone. Given known ethnic differences in adiposity and SI, we performed secondary analysis in African American and Hispanic subjects. In this subset, olanzapine expanded both total and visceral adiposity (p < 0.02); no increase was observed with risperidone. There were modest downward trends for SI with both treatments. By week 24, olanzapine-treated subjects exhibited diminished DI (p = 0.033), indicating inadequate pancreatic compensation for insulin resistance.
Conclusions
This is the first prospective study in psychiatric patients that quantified antipsychotic effects on the multiple metabolic processes that increase diabetes risk. Results indicate that ethnic minorities may have greater susceptibility to antipsychotic-induced glucoregulatory complications.
doi:10.1016/j.jpsychires.2008.01.004
PMCID: PMC3769976  PMID: 18295798
Risperidone; Olanzapine; Schizophrenia; Diabetes; Minorities
13.  Sagittal Abdominal Diameter and Visceral Adiposity 
Obesity surgery  2013;23(7):874-881.
Background
In the context of increasing obesity prevalence, the relationship between large visceral adipose tissue (VAT) volumes and type 2 diabetes mellitus (T2DM) is unclear. In a clinical sample of severely obese women (mean body mass index [BMI], 46 kg/m2) with fasting normoglycemia (n=40) or dysglycemia (impaired fasting glucose+diabetes; n=20), we sought to determine the usefulness of anthropometric correlates of VAT and associations with dysglycemia.
Methods
VAT volume was estimated using multi-slice computer tomography; anthropometric surrogates included sagittal abdominal diameter (SAD), waist circumference (WC) and BMI. Insulin sensitivity (Si), and beta-cell dysfunction, measured by insulin secretion (AIRg) and the disposition index (DI), were determined by frequently sampled intravenous glucose tolerance test.
Results
Compared to fasting normoglycemic women, individuals with dysglycemia had greater VAT (P<0.001) and SAD (P=0.04), but BMI, total adiposity and Si were similar. VAT was inversely associated with AIRg and DI after controlling for ancestry, Si, and total adiposity (standardized beta, −0.32 and −0.34, both P<0.05). In addition, SAD (beta=0.41, P=0.02) was found to be a better estimate of VAT volume than WC (beta=0.32, P=0.08) after controlling for covariates. Receiver operating characteristic analysis showed that VAT volume, followed by SAD, outperformed WC and BMI in identifying dysglycemic participants.
Conclusions
Increasing VAT is associated with beta-cell dysfunction and dysglycemia in very obese women. In the presence of severe obesity, SAD is a simple surrogate of VAT, and an indicator of glucose dysregulation.
doi:10.1007/s11695-013-0874-6
PMCID: PMC3750719  PMID: 23408092
Obesity; Type 2 diabetes; Waist circumference; Anthropometry; Intra-abdominal fat; Insulin resistance; Sagittal abdominal diameter
14.  Diabetes, Metformin, and Breast Cancer in Postmenopausal Women 
Journal of Clinical Oncology  2012;30(23):2844-2852.
Purpose
Emerging evidence suggests that metformin may reduce breast cancer incidence, but reports are mixed and few provide information on tumor characteristics. Therefore, we assessed associations among diabetes, metformin use, and breast cancer in postmenopausal women participating in Women's Health Initiative clinical trials.
Patients and Methods
In all, 68,019 postmenopausal women, including 3,401 with diabetes at study entry, were observed over a mean of 11.8 years with 3,273 invasive breast cancers diagnosed. Diabetes incidence status was collected throughout follow-up, with medication information collected at baseline and years 1, 3, 6, and 9. Breast cancers were confirmed by review of central medical records and pathology reports. Cox proportional hazards regression, adjusted for breast cancer risk factors, compared breast cancer incidence in women with diabetes who were metformin users or nonusers with breast cancer incidence in women without diabetes.
Results
Compared with that in women without diabetes, breast cancer incidence in women with diabetes differed by diabetes medication type (P = .04). Women with diabetes receiving medications other than metformin had a slightly higher incidence of breast cancer (hazard ratio [HR], 1.16; 95% CI, 0.93 to 1.45), and women with diabetes who were given metformin had lower breast cancer incidence (HR, 0.75; 95% CI, 0.57 to 0.99). The association was observed for cancers positive for both estrogen receptor and progesterone receptor and those that were negative for human epidermal growth factor receptor 2.
Conclusion
Metformin use in postmenopausal women with diabetes was associated with lower incidence of invasive breast cancer. These results can inform future studies evaluating metformin use in breast cancer management and prevention.
doi:10.1200/JCO.2011.39.7505
PMCID: PMC3826090  PMID: 22689798
15.  Diabetes Management in Urban African Americans: Review of a Public Hospital Experience 
Ethnicity & disease  2008;18(3):336-341.
Objective
To review characteristics of an urban (primarily African American) diabetes patient population and discuss experience with treatment strategies, we summarize key retrospective and prospective analyses conducted during 15 years.
Results
Severe socioeconomic and personal barriers to diabetes care were often seen in the population. An atypical presentation of diabetic ketoacidosis was observed and extensively studied. A structured diabetes care delivery program was implemented more than three decades ago. A better understanding of how to provide simpler but effective dietary education and factors that affect lipid levels were elucidated. The phenomenon of clinical inertia was described, and methods were developed to facilitate the intensification of diabetes therapy and improve glycemic control.
Conclusions
Structured diabetes care can be successfully introduced into a public health system and effective diabetes management can be provided to an under-served population that can result in improved metabolic outcomes. Lessons learned on diabetes management in this population can be extended to similar clinical settings.
PMCID: PMC3688048  PMID: 18785449
African Americans; Diabetes Mellitus; Urban Health Services
16.  Age, BMI, and Race Are Less Important Than Random Plasma Glucose in Identifying Risk of Glucose Intolerance 
Diabetes care  2008;31(5):884-886.
OBJECTIVE
Age, BMI, and race/ethnicity are used in National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and American Diabetes Association (ADA) guidelines to prompt screening for pre-diabetes and diabetes, but cutoffs have not been evaluated rigorously.
RESEARCH DESIGN AND METHODS
Random plasma glucose (RPG) was measured and 75-g oral glucose tolerance tests were performed in 1,139 individuals without known diabetes. Screening performance was assessed by logistic regression and area under the receiver operating characteristic curve (AROC).
RESULTS
NIDDK/ADA indicators age >45 years and BMI >25 kg/m2 provided significant detection of both diabetes and dysglycemia (both AROCs 0.63), but screening was better with continuous-variable models of age, BMI, and race and better still with models of age, BMI, race, sex, and family history (AROC 0.78 and 0.72). However, screening was even better with RPG alone (AROCs 0.81 and 0.72). RPG >125 mg/dl could be used to prompt further evaluation with an OGTT.
CONCLUSIONS
Use of age, BMI, and race/ethnicity in guidelines for screening to detect diabetes and pre-diabetes may be less important than evaluation of RPG. RPG should be investigated further as a convenient, inexpensive screen with good predictive utility.
doi:10.2337/dc07-2282
PMCID: PMC3685424  PMID: 18310308
18.  Education, Income, and Incident Heart Failure in Post Menopausal Women: The Women’s Health Initiative Hormone Therapy trials 
Objective
To estimate the effect of education and income on incident heart failure (HF) hospitalization among post-menopausal women.
Background
Investigations of socioeconomic status (SES) have focused on outcomes after HF diagnosis, not associations with incident HF. We used data from the Women’s Health Initiative Hormone Trials to examine the association between SES levels and incident HF hospitalization.
Methods
We included 26,160 healthy, post-menopausal women. Education and income were self-reported. ANOVA, Chi-square tests, and proportional hazards models were used for statistical analysis, with adjustment for demographics, co-morbid conditions, behavioral factors, and hormone and dietary modification assignments.
Results
Women with household incomes <$20,000/year had higher HF hospitalization incidence (57.3/10,000 person-years) than women with household incomes >$50,000/year (16.7/10,000 person-years; p<0.01). Women with less than a high school education had higher HF hospitalization incidence (51.2/10,000 person-years) than college graduates and above (25.5/10,000 person-years; p<0.01). In multivariable analyses, women with the lowest income levels had 56% higher risk (HR 1.56, 95% CI 1.19 to 2.04) than the highest income women; women with the least amount of education had 21% higher risk for incident HF hospitalization (HR 1.21, 95% CI 0.90 to 1.62) than the most educated women.
Conclusions
Lower income is associated with an increased incidence of HF hospitalization among healthy, post-menopausal women, whereas multivariable adjustment attenuated the association of education with incident HF.
doi:10.1016/j.jacc.2011.07.006
PMCID: PMC3635103  PMID: 21939829
heart failure; socioeconomic status; women
19.  Serum 25-Hydroxyvitamin D and Physical Performance in Postmenopausal Women 
Journal of Women's Health  2011;20(11):1603-1608.
Abstract
Background
Impairments in physical performance increase sharply with age. Low serum 25-hydroxyvitamin D (25-OHD) levels may be a modifiable risk factor for physical performance decline.
Methods
Five hundred thirty-two participants in the Women's Health Initiative Clinical Trial (WHI CT) were among a 25% randomly selected subsample of women who participated in performance-based measures of physical performance at baseline, year 1, year 3, and year 6. A physical performance summary score was derived from three tests: timed walk, chair-stand, and grip strength. Levels of 25-OHD were measured at baseline. We used the generalized estimating equations (GEE) method to examine repeated measures of physical performance as a function of follow-up time since baseline according to 25-OHD concentration.
Results
In 6 years of follow-up, participants with serum 25OHD ≥75 nmol/L had significantly higher scores for physical performance (β=2.64, 95% confidence interval [CI] 0.90-4.39) compared with the reference category (<35 nmol/L) after adjustment for age, chronic conditions, body mass index (BMI), race/ethnicity, time spent walking outside, trial arm, clinic latitude, and season of blood draw. However, the rate of decline in physical performance did not differ by level of 25OHD.
Conclusions
Higher baseline serum 25-OHD was associated with better physical performance but did not reduce decline in physical performance over the 6-year period.
doi:10.1089/jwh.2010.2606
PMCID: PMC3216069  PMID: 21923280
20.  Perceptual Adaptation to Sinewave-vocoded Speech Across Languages 
Listeners rapidly adapt to many forms of degraded speech. What level of information drives this adaptation, however, remains unresolved. The current study exposed listeners to sinewave-vocoded speech in one of three languages, which manipulated the type of information shared between the training languages (German, Mandarin, or English) and the testing language (English) in an audio-visual (AV) or an audio plus still frames modality (A+Stills). Three control groups were included to assess procedural learning effects. After training, listeners’ perception of novel sinewave-vocoded English sentences was tested. Listeners exposed to German-AV materials performed equivalently to listeners exposed to English AV or A+Stills materials and significantly better than two control groups. The Mandarin groups and German-A+Stills group showed an intermediate level of performance. These results suggest that full lexical access is not absolutely necessary for adaptation to degraded speech, but providing AV-training in a language that is similar phonetically to the testing language can facilitate adaptation.
doi:10.1037/a0024281
PMCID: PMC3179795  PMID: 21688936
perceptual adaptation; vocoded speech; cross-language; degraded speech; speech perception
21.  Weight Change and Cognitive Function: Findings from the Women's Health Initiative Study of Cognitive Aging 
Obesity (Silver Spring, Md.)  2011;19(8):1595-1600.
Although studies exploring relationships between obesity and cognitive impairment in the elderly are conflicting, literature suggests that overweight and obesity may be protective against cognitive impairment and dementia in older women. We examine the associations between changes in weight and waist circumference with global and domain-specific cognitive function in a large, well-defined cohort of 2283 older, post-menopausal women (age 65-79) prospectively followed through the Women's Health Initiative (WHI) Study of Cognitive Aging (WHISCA). We assessed the associations between changes in weight and waist circumference collected up to 5 years prior to WHISCA enrollment and mean levels of global and domain-specific cognitive performance across an average of 5.4 years of subsequent follow-up. There was a lack of associations between weight and cognition in women who remained stable or gained weight. The only significant relationships observed were in association with weight loss (p≤0.05), most likely signaling incipient disease. Moreover, cognition was not related to changes in waist circumference. Relationships were largely independent of initial BMI, self-reported caloric intake or dieting. The lack of associations between weight gain and cognition in women is consistent with the existent literature.
doi:10.1038/oby.2011.23
PMCID: PMC3175491  PMID: 21394095
22.  Resting Heart Rate and Coronary Artery Calcium in Postmenopausal Women 
Journal of Women's Health  2011;20(5):661-669.
Abstract
Objective
To test the hypothesis of a significant association between resting heart rate (RHR) and coronary artery calcium (CAC).
Methods
This is a cross-sectional study of a subset of women enrolled in the estrogen-alone clinical trial of the Women's Health Initiative (WHI). We used a longitudinal study that enrolled 998 postmenopausal women with a history of hysterectomy between the ages of 50 and 59 at enrollment at 40 different clinical centers. RHR was measured at enrollment and throughout the study, and CAC was determined approximately 7 years after the baseline clinic visit.
Results
The mean (standard deviation [SD]) age was 55 (2.8) years. With adjustment for age and ethnicity, a 10-unit increment in RHR was significantly associated with CAC (SD 1.18, 95% confidence interval [CI] 1.01-1.38), but this was no longer significant after adjustment for body mass index (BMI), income, education, dyslipidemia, diabetes, smoking, and hypertension (SD 1.06, 95% CI 0.90-1.25). In a fully adjusted multivariable model, however, there was a significant interaction (p=0.03) between baseline RHR and systolic blood pressure (SBP) for the presence of any CAC. Compared to women with an RHR < 80 beats per minute (BPM) and an SBP < 140 mm Hg, those who had an RHR ≥ 80 BPM and an SBP ≥ 140 mm Hg had 2.66-fold higher odds (1.08-6.57) for the presence of any CAC.
Conclusions
Compared to those with normal BP and RHR, postmenopausal, hysterectomized women with an elevated SBP and RHR have a significantly higher odds for the presence of calcified coronary artery disease.
doi:10.1089/jwh.2010.2475
PMCID: PMC3096501  PMID: 21438696
23.  Lack of Association Between 25(OH)D Levels and Incident Type 2 Diabetes in Older Women 
Diabetes Care  2011;34(3):628-634.
OBJECTIVE
To examine whether lower serum levels of serum 25-hydroxyvitamin (OH) D [25(OH)D] are associated with increased risk of developing type 2 diabetes.
RESEARCH DESIGN AND METHODS
A post hoc analysis of three nested case-control studies of fractures, colon cancer, and breast cancer that measured serum 25(OH)D levels in women participating in the Women’s Health Initiative (WHI) Clinical Trials and Observational Study who were free of prevalent diabetes at baseline. Diabetes was defined as self-report of physician diagnosis or receiving insulin or oral hypoglycemic medication. We used inverse probability weighting to make the study population representative of the WHI population as a whole. Weighted logistic regression models compared 25(OH)D levels (divided into quartiles, clinical cut points [<50, 50–<75, ≥75 nmol/L], or as a continuous variable) using the distribution of control subjects and adjusted for multiple confounding factors.
RESULTS
Of 5,140 women (mean age 66 years) followed for an average of 7.3 years, 317 (6.2%) developed diabetes. Regardless of the cut points used or as a continuous variable, 25(OH)D levels were not associated with diabetes incidence in either age or fully adjusted models. Nor was any relationship found between 25(OH)D and incident diabetes when evaluated by strata of BMI, race/ethnicity, or randomization status in the Calcium Vitamin D trial.
CONCLUSIONS
Lower serum 25(OH)D levels were not associated with increased risk of developing type 2 diabetes in this racially and ethnically diverse population of postmenopausal women.
doi:10.2337/dc10-1632
PMCID: PMC3041195  PMID: 21289227
24.  VASOMOTOR SYMPTOMS AND CORONARY ARTERY CALCIUM IN POSTMENOPAUSAL WOMEN 
Menopause (New York, N.Y.)  2010;17(6):1136-1145.
Objective
We assessed whether vasomotor symptoms (VMS) were associated with coronary artery calcium (CAC) and how hormone therapy may influence this association.
Methods
Subjects were a subset of women aged 50 to 59 and a history of hysterectomy that enrolled in the Women’s Health Initiative (WHI) clinical trial of estrogen alone and underwent a computed tomography scan of the chest at the end of the trial to determine CAC. Participants provided information about VMS (hot flashes and/or night sweats), as well as HT use, on self-administered questionnaires at trial baseline.
Results
The sample consisted of 918 women with a mean (SD) age of 55.1 (2.8) years at WHI randomization and 64.8 (2.9) years at CAC ascertainment. The prevalence of a CAC score > 0 was 46%, while the prevalence of a CAC score ≥ 10 and > 100 was 39 and 19%, respectively. At randomization, 77% reported a history of any VMS at any time prior to or at enrollment in the WHI while 20% reported any VMS only present at enrollment. Compared to those without a history of any VMS and after adjustment for potential confounders, a history of any VMS at any time up to and including WHI enrollment was associated with a significantly reduced odds for CAC > 0 (Odds Ratio 0.66, 95% CI 0.45 – 0.98). Moreover, as duration of HT increased the inverse association between any VMS and CAC moved toward the null.
Conclusion
A history of any VMS was significantly associated with a reduced odds for CAC independent of traditional CVD risk factors and other relevant covariates. This association appears to be influenced by duration of hormone therapy.
doi:10.1097/gme.0b013e3181e664dc
PMCID: PMC3037019  PMID: 20651617
calcium; coronary; vasomotor symptoms; women; menopause; atherosclerosis
25.  Screening for Diabetes and Pre-Diabetes With Proposed A1C-Based Diagnostic Criteria 
Diabetes Care  2010;33(10):2184-2189.
OBJECTIVE
An International Expert Committee (IEC) and the American Diabetes Association (ADA) proposed diagnostic criteria for diabetes and pre-diabetes based on A1C levels. We hypothesized that screening for diabetes and pre-diabetes with A1C measurements would differ from using oral glucose tolerance tests (OGTT).
RESEARCH DESIGN AND METHODS
We compared pre-diabetes, dysglycemia (diabetes or pre-diabetes), and diabetes identified by the proposed criteria (A1C ≥6.5% for diabetes and 6.0–6.4% [IEC] or 5.7–6.4% [ADA] for high risk/pre-diabetes) with standard OGTT diagnoses in three datasets. Non-Hispanic white or black adults without known diabetes who had A1C and 75-g OGTT measurements were included from the prospective Screening for Impaired Glucose Tolerance study (n = 1,581), and from the National Health and Nutrition Examination Survey (NHANES) III (n = 2014), and NHANES 2005–2006 (n = 1,111).
RESULTS
OGTTs revealed pre-diabetes in 35.8% and diabetes in 5.2% of combined study subjects. A1C provided receiver operating characteristic (ROC) curve areas for diabetes of 0.79–0.83, but ROC curve areas were ≤0.70 for dysglycemia or pre-diabetes. The proposed criteria missed 70% of individuals with diabetes, 71–84% with dysglycemia, and 82–94% with pre-diabetes. Compared with the IEC criteria, the ADA criteria for pre-diabetes resulted in fewer false-negative and more false-positive result. There were also racial differences, with false-positive results being more common in black subjects and false-negative results being more common in white subjects. With use of NHANES 2005–2006 data, ∼5.9 million non-Hispanic U.S. adults with unrecognized diabetes and 43–52 million with pre-diabetes would be missed by screening with A1C.
CONCLUSIONS
The proposed A1C diagnostic criteria are insensitive and racially discrepant for screening, missing most Americans with undiagnosed diabetes and pre-diabetes.
doi:10.2337/dc10-0433
PMCID: PMC2945158  PMID: 20639452

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