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1.  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.
PMCID: PMC3954506  PMID: 23963599
Myocardial perfusion imaging; ischemia; coronary artery disease; clinical trials
2.  Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium 
Cancer causes & control : CCC  2012;24(1):13-25.
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).
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.
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).
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.
PMCID: PMC3529822  PMID: 23112111
Diabetes; Risk factor; Cohort consortium; Pancreatic cancer
3.  Determinants of Racial/Ethnic Disparities in Incidence of Diabetes in Postmenopausal Women in the U.S. 
Diabetes Care  2012;35(11):2226-2234.
To examine determinants of racial/ethnic differences in diabetes incidence among postmenopausal women participating in the Women’s Health Initiative.
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.
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.
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.
PMCID: PMC3476929  PMID: 22833490
4.  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.
PMCID: PMC3478524  PMID: 22829448
5.  Ethnic heterogeneity in glucoregulatory function during treatment with atypical antipsychotics in patients with schizophrenia✩  
Journal of psychiatric research  2008;42(13):1076-1085.
Atypical antipsychotics induce weight gain and are linked to increased diabetes risk, but their relative impact on factors that elevate disease risk are unknown.
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.
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.
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.
PMCID: PMC3769976  PMID: 18295798
Risperidone; Olanzapine; Schizophrenia; Diabetes; Minorities
6.  Sagittal Abdominal Diameter and Visceral Adiposity 
Obesity surgery  2013;23(7):874-881.
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.
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.
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.
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.
PMCID: PMC3750719  PMID: 23408092
Obesity; Type 2 diabetes; Waist circumference; Anthropometry; Intra-abdominal fat; Insulin resistance; Sagittal abdominal diameter
7.  Diabetes, Metformin, and Breast Cancer in Postmenopausal Women 
Journal of Clinical Oncology  2012;30(23):2844-2852.
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.
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.
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.
PMCID: PMC3826090  PMID: 22689798
8.  Diabetes Management in Urban African Americans: Review of a Public Hospital Experience 
Ethnicity & disease  2008;18(3):336-341.
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.
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.
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
9.  Age, BMI, and Race Are Less Important Than Random Plasma Glucose in Identifying Risk of Glucose Intolerance 
Diabetes care  2008;31(5):884-886.
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.
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).
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.
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.
PMCID: PMC3685424  PMID: 18310308
11.  Education, Income, and Incident Heart Failure in Post Menopausal Women: The Women’s Health Initiative Hormone Therapy trials 
To estimate the effect of education and income on incident heart failure (HF) hospitalization among post-menopausal women.
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.
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.
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.
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.
PMCID: PMC3635103  PMID: 21939829
heart failure; socioeconomic status; women
12.  Serum 25-Hydroxyvitamin D and Physical Performance in Postmenopausal Women 
Journal of Women's Health  2011;20(11):1603-1608.
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.
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.
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.
Higher baseline serum 25-OHD was associated with better physical performance but did not reduce decline in physical performance over the 6-year period.
PMCID: PMC3216069  PMID: 21923280
13.  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.
PMCID: PMC3179795  PMID: 21688936
perceptual adaptation; vocoded speech; cross-language; degraded speech; speech perception
14.  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.
PMCID: PMC3175491  PMID: 21394095
15.  Resting Heart Rate and Coronary Artery Calcium in Postmenopausal Women 
Journal of Women's Health  2011;20(5):661-669.
To test the hypothesis of a significant association between resting heart rate (RHR) and coronary artery calcium (CAC).
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.
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.
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.
PMCID: PMC3096501  PMID: 21438696
16.  Lack of Association Between 25(OH)D Levels and Incident Type 2 Diabetes in Older Women 
Diabetes Care  2011;34(3):628-634.
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.
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.
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.
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.
PMCID: PMC3041195  PMID: 21289227
Menopause (New York, N.Y.)  2010;17(6):1136-1145.
We assessed whether vasomotor symptoms (VMS) were associated with coronary artery calcium (CAC) and how hormone therapy may influence this association.
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.
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.
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.
PMCID: PMC3037019  PMID: 20651617
calcium; coronary; vasomotor symptoms; women; menopause; atherosclerosis
18.  Screening for Diabetes and Pre-Diabetes With Proposed A1C-Based Diagnostic Criteria 
Diabetes Care  2010;33(10):2184-2189.
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).
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).
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.
The proposed A1C diagnostic criteria are insensitive and racially discrepant for screening, missing most Americans with undiagnosed diabetes and pre-diabetes.
PMCID: PMC2945158  PMID: 20639452
19.  The Lack of Utility of Circulating Biomarkers of Inflammation and Endothelial Dysfunction for Type 2 Diabetes Risk Prediction Among Postmenopausal Women 
Archives of internal medicine  2010;170(17):1557-1565.
Recent studies have linked plasma markers of inflammation and endothelial dysfunction to type 2 diabetes mellitus (DM) development. However, the utility of these novel biomarkers for type 2 DM risk prediction remains uncertain.
The Women’s Health Initiative Observational Study (WHIOS), a prospective cohort, and a nested case-control study within the WHIOS of 1584 incident type 2 DM cases and 2198 matched controls were used to evaluate the utility of plasma markers of inflammation and endothelial dysfunction for type 2 DM risk prediction. Between September 1994 and December 1998, 93 676 women aged 50 to 79 years were enrolled in the WHIOS. Fasting plasma levels of glucose, insulin, white blood cells, tumor necrosis factor receptor 2, interleukin 6, high-sensitivity C-reactive protein, E-selectin, soluble intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 were measured using blood samples collected at baseline. A series of prediction models including traditional risk factors and novel plasma markers were evaluated on the basis of global model fit, model discrimination, net reclassification improvement, and positive and negative predictive values.
Although white blood cell count and levels of interleukin 6, high-sensitivity C-reactive protein, and soluble intercellular adhesion molecule 1 significantly enhanced model fit, none of the inflammatory and endothelial dysfunction markers improved the ability of model discrimination (area under the receiver operating characteristic curve, 0.93 vs 0.93), net reclassification, or predictive values (positive, 0.22 vs 0.24; negative, 0.99 vs 0.99 [using 15% 6-year type 2 DM risk as the cutoff]) compared with traditional risk factors. Similar results were obtained in ethnic-specific analyses.
Beyond traditional risk factors, measurement of plasma markers of systemic inflammation and endothelial dysfunction contribute relatively little additional value in clinical type 2 DM risk prediction in a multiethnic cohort of postmenopausal women.
PMCID: PMC3127580  PMID: 20876407
20.  On-site Basic Health Screening and Brief Health Counseling of Chronic Medical Conditions for Veterans in Methadone Maintenance Treatment 
Journal of addiction medicine  2010;4(3):160-166.
In order to improve the delivery of health services for chronic medical conditions in our methadone clinic, we added an onsite health screening and brief health counseling to the treatment plans for patients receiving methadone maintenance treatment at the Atlanta Veterans Affairs Medical Center (VAMC). We then conducted a follow up retrospective chart review to assess whether this intervention improved health outcome for those patients.
We reviewed the charts of one hundred and two patients who received treatment at Atlanta VAMC methadone clinic between 2002 and 2008. We sought to determine whether our increased health education and screening intervention was associated with improved: 1) Improved drug addiction outcome (as measured by comparing percentage of opiate and cocaine positive drug screens from admission to most recent). 2) Basic health screening, (as measured by the patient's compliance with primary care physicians (PCP) appointments and current smoking status). 3) Management of co-occurring medical conditions (as measured by levels of LDL cholesterol, hemoglobin A1c, and systolic blood pressure (SBP). 4) Presence of QTc prolongation (difference in QTc between baseline and most recent EKG).
Illicit drug use (opiate and cocaine) markedly decreased in patients overall. The effect was more robust for those successfully “retained” (n=55, p<0.0001) in treatment, compared to those who “dropped out” (n=40, p=0.05) of treatment. Compliance with PCP appointments was high (82% and 88% before and after the onsite intervention, respectively) for “retained” patients. LDL cholesterol level was within normal range for all patients. A1c improved by 40% after the onsite intervention as reflected by the decreased percentage of patients with A1c > 7 % from before to after the intervention (90% vs. 50%, p=0.05). However, the prevalence of uncontrolled hypertension did not significantly improve after the onsite intervention (38% vs. 28%, p=0.34). As might be expected with MMT, the prevalence of QTc prolongation actually increased from 399 m sec. (+/- 92) to 439 msec. (+/- 22) after the onsite intervention (p=0.003).
Our retrospective study supports the previous literature that methadone maintenance therapy is effective in reducing illicit drug use. Although patients with history of heroin dependence and in methadone maintenance treatment are at increased risk for chronic medical conditions like hepatitis C and diabetes, there are minimal federal guidelines for medical care, except than a physical exam upon admission, and basic screening for some infectious diseases e.g. HIV and Hepatitis C for those patients. Our study demonstrated the need for and potential benefit of enhancing the delivery of health promotion services for chronic medical conditions in methadone maintained patients. Improving management of hepatitis C, diabetes, hypertension, and other related conditions, in this high risk, difficult-to-treat, and underserved population may reduce their morbidity and premature mortality.
PMCID: PMC2930493  PMID: 20823944
mass screening; health education; health promotion; methadone; diabetes mellitus
21.  Screening Adults for Pre-Diabetes and Diabetes May Be Cost-Saving 
Diabetes Care  2010;33(7):1484-1490.
The economic costs of hyperglycemia are substantial. Early detection would allow management to prevent or delay development of diabetes and diabetes-related complications. We investigated the economic justification for screening for pre-diabetes/diabetes.
We projected health system and societal costs over 3 years for 1,259 adults, comparing costs associated with five opportunistic screening tests. All subjects had measurements taken of random plasma and capillary glucose (RPG and RCG), A1C, and plasma and capillary glucose 1 h after a 50 g oral glucose challenge test without prior fasting (GCT-pl and GCT-cap), and a subsequent diagnostic 75 g oral glucose tolerance test (OGTT).
Assuming 70% specificity screening cutoffs, Medicare costs for testing, retail costs for generic metformin, and costs for false negatives as 10% of reported costs associated with pre-diabetes/diabetes, health system costs over 3 years for the different screening tests would be GCT-pl $180,635; GCT-cap $182,980; RPG $182,780; RCG $186,090; and A1C $192,261; all lower than costs for no screening, which would be $205,966. Under varying assumptions, projected health system costs for screening and treatment with metformin or lifestyle modification would be less than costs for no screening as long as disease prevalence is at least 70% of that of our population and false-negative costs are at least 10% of disease costs. Societal costs would equal or exceed costs of no screening depending on treatment type.
Screening appears to be cost-saving compared to no screening from a health system perspective, and potentially cost-neutral from a societal perspective. These data suggest that strong consideration should be given to screening—with preventive management—and that use of GCTs may be cost-effective.
PMCID: PMC2890345  PMID: 20587721
22.  Clinical Evaluation of the Appropriateness Use Criteria for Single-Photon Emission-Computed Tomography: Differences by Patient Population, Physician Specialty, and Patient Outcomes 
ISRN Cardiology  2011;2011:798318.
Objectives. Determine outcome of the 2005 appropriateness use criteria (AUC) for SPECT in a diverse population of patients and physicians. Background. AUC for SPECT were the first cardiology document to identify 52 clinical indications for imaging, 49 of them for stress SPECT. AUC have been proposed as cornerstone of responsible use of perfusion imaging. Methods. 585 consecutive patients undergoing SPECT were evaluated prospectively. Appropriateness was examined for demographic variables, clinical variables, and for physician and patient subgroups. Combined end-point of total mortality, cardiac revascularization, and cardiac admissions at 1 year post SPECT was evaluated. Results. SPECT indications were: appropriate, 63%; uncertain, 20%; inappropriate, 14%; not assigned, 3%. Most appropriate SPECT were observed in patients with known coronary disease (72%), chest pain syndrome (89%), high pre-test likelihood of disease (100%), men (70%), inpatients (72%), and cardiovascular physicians' referrals (69%). End-point was reached in 53 patients (97.4% follow up). Unadjusted event rates were: appropriate (12%), uncertain (7.1%), inappropriate (2.4%) SPECT (P = .01). Conclusion. Appropriateness of SPECT differs in subgroups of patients and physicians. Clinically significant outcomes occur more frequently in the appropriate stress SPECT group. Focused efforts are need for outpatients, asymptomatic patients, women, and non-cardiovascular physicians.
PMCID: PMC3262510  PMID: 22347656
23.  Association of glycemic load with cardiovascular disease risk factors: the Women's Health Initiative Observational Study 
Associations between dietary glycemic load (GL) and cardiovascular disease (CVD) risk factors, including plasma lipoprotein/lipid levels, blood pressure (BP), and glucose metabolism factors, in the Women's Health Initiative Observational Study were examined.
A random sample of 878 Observational Study participants (postmenopausal women age 50 to 79 years) with baseline blood measures (647 White, 104 Black, 127 Hispanic) was included. Dietary GL was estimated from baseline food frequency questionnaires, which assessed dietary intake over the previous three months. At the baseline visit, participants completed demographic and health habit questionnaires, fasting blood samples were collected, anthropometric measurements were completed, and BP was assessed.
In all participants combined, GL was inversely associated with high-density lipoprotein (HDL) cholesterol (P for trend = 0.004) and positively associated with log10-transformed triglycerides (P = 0.008). While there were no statistically significant interactions of race/ethnicity with associations between GL and CVD risk factors, stratified results were suggestive, showing that GL was positively associated with total cholesterol (P = 0.018) and low-density lipoprotein (LDL) cholesterol (P = 0.038) in Hispanics. In Whites, there was a trend of reduced HDL cholesterol with higher GL (P = 0.003), while GL was positively associated with log10-transformed triglycerides (P = 0.015). Associations between GL and HDL cholesterol and GL and triglycerides also varied by BMI, although the interactions were not statistically significant.
Among these generally healthy postmenopausal women, GL was associated with HDL cholesterol and triglycerides. Suggestive effects of race/ethnicity and BMI on these associations need to be confirmed in larger studies.
PMCID: PMC2866821  PMID: 20053533
Glycemic load; Glycemic index; Carbohydrate; Cardiovascular disease; Women's Health Initiative
24.  Diabetes Care in Black and White Veterans in the Southeastern U.S. 
Diabetes Care  2010;33(5):958-963.
Eliminating health disparities is a national priority, but progress has been difficult because of racial/ethnic differences in insurance coverage and access to health care. We investigated whether there were differences in diabetes care in the Veterans Administration (VA), where health care access should be relatively uniform.
A1C and plasma glucose were compared before/after diagnosis of diabetes.
Data were available for 1,456 black and 2,624 white veterans who met criteria for consistent primary care. Over 4–5 years before and after diagnosis, blacks had similar glucose and ∼0.2% higher A1C levels than whites, and A1C differences could be attributed to glucose-independent associations between race and A1C. Blacks and whites also had comparable intervals between diagnostic-level hyperglycemia and diagnosis and between diagnosis and drug initiation. However, A1C was higher in blacks at the time of diagnosis (7.8 vs. 7.1%) and at initiation of pharmacotherapy (8.5 vs. 7.8%) (both P < 0.001). Differences in A1C at diagnosis and drug initiation were too large to be explained by differences in age, sex, BMI, and glucose-independent associations between race and A1C.
In the VA, glucose levels are generally comparable in blacks and whites except at the times of diagnosis and initiation of pharmacotherapy, when glucose levels are higher in blacks. While understanding the basis for such residual disparities may be important to improve the health of racial/ethnic minorities in the U.S., a health care system with structure and organization similar to that in the VA may also contribute importantly to relieving disparities in health.
PMCID: PMC2858198  PMID: 20103548
25.  Dual Mechanism for Type-2 Diabetes Resolution after Roux-en-Y Gastric Bypass 
The American surgeon  2009;75(6):498-503.
Resolution of Type-2 diabetes mellitus (DM) after weight loss surgery is well documented, but the mechanism is elusive. We evaluated the glucose-insulin metabolism of patients undergoing a Roux-en-Y gastric bypass (RYGB) using the intravenous glucose tolerance test (IVGTT) and compared it with patients who underwent laparoscopic adjustable gastric band (AB) placement. Thirty-one female patients (age range, 20 to 50 years; body mass index, 47.2 kg/m2) underwent RYGB. Nine female patients underwent AB placement and served as control subjects. All patients underwent IVGTT at baseline and 1 month and 6 months after surgery. Thirteen patients undergoing RYGB and one patient undergoing AB exhibited impaired glucose tolerance defined by the American Diabetes Association. By 6 months post surgery, diabetes was resolved in all but one patient undergoing RYGB and none of the patients undergoing AB. Patients with diabetes undergoing demonstrated increased insulin secretion and β-cell responsiveness 1 month after surgery and continued this trend up to 6 months, whereas none of the patients undergoing AB had changes in β-cell function. Both patients undergoing RYGB and those undergoing AB demonstrated significant weight loss (34.6 and 35.0 kg/m2, respectively) and improved insulin sensitivity at 6 months. RYGB ameliorates DM resolution in two phases: 1) early augmentation of beta cell function at 1 month; and 2) attenuation of peripheral insulin resistance at 6 months. Patients undergoing AB only exhibited reduction in peripheral insulin resistance at 6 months but no changes in insulin secretion.
PMCID: PMC3068861  PMID: 19545098

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