Person:

Cook, Nancy

OBJECTIVE—Subclinical inflammation is linked with the development of type 2 diabetes, and epidemiologic data suggest that this association may be stronger in women. Although small clinical studies have shown a prominent hypoglycemic effect of short-term high-dose aspirin, no randomized trials have directly evaluated the efficacy of aspirin in diabetes prevention at doses acceptable for use in routine clinical practice. We evaluated whether chronic low-dose aspirin prevents the development of clinical diabetes among initially healthy American women. RESEARCH DESIGN AND METHODS—Subjects were enrolled in the Women's Health Study, a 10-year randomized double-blind, placebo-controlled trial of aspirin and vitamin E for primary prevention of cardiovascular disease and cancer. Between 1992 and 1995, 38,716 women aged ≥45 years and free of clinical diabetes were randomly assigned to either low-dose aspirin or placebo (median follow-up 10.2 years). Documented clinical type 2 diabetes was prospectively evaluated throughout the trial. RESULTS—Among women randomly assigned to receive aspirin (n = 19,326) or placebo (n = 19,390), there was no statistically significant difference in the incidence of type 2 diabetes. There were 849 cases of diabetes in the aspirin group and 847 in the placebo group (rate ratio 1.01 [95% CI 0.91–1.11]). Stratification by diabetes risk factors including age, BMI, family history of diabetes, physical activity, A1C, and high-sensitivity C-reactive protein did not support a modulating effect of these variables. Analyses accounting for treatment duration and adherence similarly found no beneficial effects. CONCLUSIONS—These data suggest that long-term low-dose aspirin does not prevent the development of clinical type 2 diabetes in initially healthy women.

Objective: To evaluate the association of kidney function with cardiovascular disease and mortality among apparently healthy women. Design: Prospective cohort study. Setting: Women’s Health Study, United States. Participants: 27 939 female health professionals aged ≥45 who were free of cardiovascular disease and other major disease and who provided a blood sample at study entry. Main outcome measures: Time to cardiovascular disease (non-fatal stroke, non-fatal myocardial infarction, coronary revascularisation procedures, or death from cardiovascular cause), specific cardiovascular disease events, and all-cause mortality. End points were confirmed after review of medical records and death certificates. Results: Glomerular filtration rate (GFR) was estimated with the abbreviated Modification of Diet in Renal Disease Study equation. At baseline, 1315 (4.7%) women had GFR <60 ml/min/1.73 m2. During 12 years of follow-up, 1199 incident cardiovascular disease events and 856 deaths (179 from cardiovascular disease) occurred. Compared with women with GFR ≥90 ml/min/1.73 m2, the multivariable adjusted hazard ratios for any first cardiovascular disease were 0.95 (95% CI 0.83 to 1.08), 0.84 (0.70 to 1.00), and 1.00 (0.79 to 1.27) among women with GFR of 75-89.9, 60-74.9, and <60 ml/min/1.73 m2, respectively; the equivalent hazard ratios for all cause mortality were 0.93 (0.79 to 1.09), 1.03 (0.85 to 1.26), and 1.09 (0.83 to 1.45). Similar null findings were observed for myocardial infarction, stroke, coronary revascularisation, and non-cardiovascular death. However, an increased risk of death from cardiovascular disease was found among women with GFR <60 ml/min/1.73 m2 (hazard ratio 1.68 (1.02 to 2.79)). Conclusions: In this large cohort of women, a glomerular filtration rate <60 ml/min/1.73 m2 was associated with increased risk of cardiovascular disease death but not other cardiovascular disease events or non-cardiovascular disease mortality. We observed no increase in risk of any of the outcomes among women with less severe impairment of kidney function.

Background: Estrogen and androgen have been linked to the regulation of circulating hepatocyte growth factor (HGF), an adipose tissue-derived cytokine. It is possible that the CYP19A1 gene which alters sex hormones production may influence HGF levels. We examined the association between the CYP19A1 gene variants and plasma HGF concentrations. Design We evaluated 45 common and putative functional variants of CYP19A1 and circulating levels of HGF among 260 postmenopausal women who later developed colorectal cancer from the Women's Health Initiative Observational Cohort. As the distribution of HGF levels was highly skewed, we transformed HGF concentrations for all women into a log-, ranked-, or normal score-scale value. Multiple linear regression with adjustment for age was used to evaluate the associations. Results: We observed an association between the rs7172156, rs1008805, rs6493494, rs749292, and rs11636639 variants and HGF levels in ranked and normal score scales (corrected p values ≤0.02), although the association of these 5 SNPs with log-scale HGF was not significant (corrected p values ≥0.16). The associations remained unchanged after additional adjustment for hormone therapy use and estradiol levels. These 5 SNPs, which were in linkage disequilibrium (pairwise D′≥97%, r2≥56%), constituted a block with 2 common haplotypes accounting for 82% frequency. The most common haplotype, TCCCA, was associated with lower ranked- or normal score-transformed HGF levels (corrected p values ≤0.001), whereas the second most common haplotype, CTTCA, was associated with higher ranked- or normal score-transformed HGF levels (corrected p values ≤0.02). Conclusion: Our findings of a potential association between the CYP19A1 variants and circulating HGF levels warrant confirmation in studies with larger sample size.

OBJECTIVE: Homocysteinemia may play an etiologic role in the pathogenesis of type 2 diabetes by promoting oxidative stress, systemic inflammation, and endothelial dysfunction. We investigated whether homocysteine-lowering treatment by B vitamin supplementation prevents the risk of type 2 diabetes. RESEARCH DESIGN AND METHODS: The Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a randomized, double-blind, placebo-controlled trial of 5,442 female health professionals aged ≥40 years with a history of cardiovascular disease (CVD) or three or more CVD risk factors, included 4,252 women free of diabetes at baseline. Participants were randomly assigned to either an active treatment group (daily intake of a combination pill of 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12) or to the placebo group. RESULTS: During a median follow-up of 7.3 years, 504 women had an incident diagnosis of type 2 diabetes. Overall, there was no significant difference between the active treatment group and the placebo group in diabetes risk (relative risk 0.94 [95% CI 0.79–1.11]; P = 0.46), despite significant lowering of homocysteine levels. Also, there was no evidence for effect modifications by baseline intakes of dietary folate, vitamin B6, and vitamin B12. In a sensitivity analysis, the null result remained for women compliant with their study pills (0.92 [0.76–1.10]; P = 0.36). CONCLUSIONS: Lowering homocysteine levels by daily supplementation with folic acid and vitamins B6 and B12 did not reduce the risk of developing type 2 diabetes among women at high risk for CVD.

Aims Atrial fibrillation (AF) is associated with adverse outcome. Whether recently discovered genetic risk markers improve AF risk prediction is unknown. Methods and results We derived and validated a novel AF risk prediction model from 32 possible predictors in the Women's Health Study (WHS), a cohort of 20 822 women without cardiovascular disease (CVD) at baseline followed prospectively for incident AF (median: 14.5 years). We then created a genetic risk score (GRS) comprised of 12 risk alleles in nine loci and assessed model performance in the validation cohort with and without the GRS. The newly derived WHS AF risk algorithm included terms for age, weight, height, systolic blood pressure, alcohol use, and smoking (current and past). In the validation cohort, this model was well calibrated with good discrimination [C-index (95% CI) = 0.718 (0.684–0.753)] and improved all reclassification indices when compared with age alone. The addition of the genetic score to the WHS AF risk algorithm model improved the C-index [0.741 (0.709–0.774); P = 0.001], the category-less net reclassification [0.490 (0.301–0.670); P < 0.0001], and the integrated discrimination improvement [0.00526 (0.0033–0.0076); P < 0.0001]. However, there was no improvement in net reclassification into 10-year risk categories of <1, 1–5, and 5+% [0.041 (−0.044–0.12); P = 0.33]. Conclusion: Among women without CVD, a simple risk prediction model utilizing readily available risk markers identified women at higher risk for AF. The addition of genetic information resulted in modest improvements in predictive accuracy that did not translate into improved reclassification into discrete AF risk categories.

Background: Self-reported physical activity measures continue to be validated against accelerometers; however, the absence of standardized, accelerometer moderate-to-vigorous physical activity (MVPA) definitions has made comparisons across studies difficult. Furthermore, recent accelerometer models assess accelerations in three axes, instead of only the vertical axis, but validation studies have yet to take incorporate triaxial data. Methods: Participants (n = 10 115) from the Women’s Health Study wore a hip-worn accelerometer (ActiGraph GT3X+) for seven days during waking hours (2011–2014). Women then completed a physical activity questionnaire. We compared self-reported with accelerometer-assessed MVPA, using four established cutpoints for MVPA: three using only vertical axis data (760, 1041 and 1952 counts per minute (cpm)) and one using triaxial data (2690 cpm). Results: According to self-reported physical activity, 66.6% of women met the US federal physical activity guidelines, engaging in ≥150 minutes per week of MVPA. The percent of women who met guidelines varied widely depending on the accelerometer MVPA definition (760 cpm: 50.0%, 1041 cpm: 33.0%, 1952 cpm: 13.4%, and 2690 cpm: 19.3%). Conclusions: Triaxial count data do not substantially reduce the difference between self-reported and accelerometer-assessed MVPA.

Background: Clinical practice focuses on the primary prevention of cardiovascular (CV) disease (CVD) through the modification and pharmacological treatment of elevated risk factors. Prediction models based on established risk factors are available for use in the primary prevention setting. However, the prevention of risk factor development through healthy lifestyle behaviors, or primordial prevention, is of paramount importance to achieve optimal population‐wide CV health and minimize long‐term CVD risk. Methods and Results: We developed a lifestyle‐based CVD prediction model among 61 025 women in the Nurses’ Health Study and 34 478 men in the Health Professionals Follow‐up Study, who were free of chronic disease in 1986 and followed for ≤24 years. Lifestyle factors were assessed by questionnaires in 1986. In the derivation step, we used the Bayes Information Criterion to create parsimonious 20‐year risk prediction models among a random two thirds of participants in each cohort separately. The scores were validated in the remaining one third of participants in each cohort. Over 24 years, there were 3775 cases of CVD in women and 3506 cases in men. The Healthy Heart Score included age, smoking, body mass index, exercise, alcohol, and a composite diet score. In the validation cohort, the risk score demonstrated good discrimination (Harrell's C‐index, 0.72; 95% confidence interval [CI], 0.71, 0.74 [women]; 0.77; 95% CI, 0.76, 0.79 [men]), fit, and calibration, particularly among individuals without baseline hypertension or hypercholesterolemia. Conclusions: The Healthy Heart Score accurately identifies individuals at elevated risk for CVD and may serve as an important clinical and public health screening tool for the primordial prevention of CVD.

Background: Investigators measuring exposure biomarkers in urine typically adjust for creatinine to account for dilution-dependent sample variation in urine concentrations. Similarly, it is standard to adjust for serum lipids when measuring lipophilic chemicals in serum. However, there is controversy regarding the best approach, and existing methods may not effectively correct for measurement error. Objectives: We compared adjustment methods, including novel approaches, using simulated case–control data. Methods: Using a directed acyclic graph framework, we defined six causal scenarios for epidemiologic studies of environmental chemicals measured in urine or serum. The scenarios include variables known to influence creatinine (e.g., age and hydration) or serum lipid levels (e.g., body mass index and recent fat intake). Over a range of true effect sizes, we analyzed each scenario using seven adjustment approaches and estimated the corresponding bias and confidence interval coverage across 1,000 simulated studies. Results: For urinary biomarker measurements, our novel method, which incorporates both covariate-adjusted standardization and the inclusion of creatinine as a covariate in the regression model, had low bias and possessed 95% confidence interval coverage of nearly 95% for most simulated scenarios. For serum biomarker measurements, a similar approach involving standardization plus serum lipid level adjustment generally performed well. Conclusions: To control measurement error bias caused by variations in serum lipids or by urinary diluteness, we recommend improved methods for standardizing exposure concentrations across individuals. Citation O’Brien KM, Upson K, Cook NR, Weinberg CR. 2016. Environmental chemicals in urine and blood: improving methods for creatinine and lipid adjustment. Environ Health Perspect 124:220–227; http://dx.doi.org/10.1289/ehp.1509693

Context: Whether subclinical hypothyroidism (SCH) is associated with cardiometabolic abnormalities is uncertain. Objective: To examine diverse cardiometabolic biomarkers across euthyroid, SCH, and overt hypothyroidism (HT) in women free of cardiovascular disease. Design: Cross-sectional adjusted associations for lipids, lipoprotein subclasses, lipoprotein insulin resistance score, inflammatory, coagulation, and glycemic biomarkers by analysis of covariance for thyroid categories or thyroid stimulating hormone (TSH) quintiles on a Women’s Health Study subcohort. Setting: Outpatient. Patients or Other Participants: Randomly sampled 3914 middle-aged and older women for thyroid function analysis (TSH, free T4), of whom 3321 were not on lipid-lowering therapy. Intervention: None. Main Outcome Measure: Associations of SCH and HT with cardiometabolic markers. Results: Going from euthyroid to HT, the lipoprotein subclass profiles were indicative of insulin resistance (respective values and P for trend): larger very-low-density lipoprotein size (nm) (51.5 [95% confidence interval (CI), 51.2, 51.8] to 52.9 [51.8, 54.1], P = 0.001); higher low-density lipoprotein (LDL) particle concentration (nmol/L) [1283 (95% CI, 1267, 1299) to 1358 (1298, 1418), P = 0.004], and smaller LDL size. There was worsening lipoprotein insulin resistance score from euthyroid (49.2; 95% CI, 48.3, 50.2) to SCH (52.1; 95% CI, 50.1, 54.0) and HT (52.1; 95% CI, 48.6, 55.6); P for trend of 0.008. Of the other biomarkers, SCH and HT were associated with higher high-sensitivity C-reactive protein and hemoglobin A1c. For increasing TSH quintiles, results were overall similar. Conclusions: In apparently healthy women, SCH cardiometabolic profiles indicated worsening insulin resistance and higher cardiovascular disease risk markers compared with euthyroid individuals, despite similar LDL and total cholesterol. These findings suggest that cardiometabolic risk may increase early in the progression toward SCH and overt HT.

Background: Subclinical myocardial injury, as measured by high‐sensitivity cardiac troponin T (hsTnT), and myocardial stress, as measured by N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), are related to glycemic control in patients with type 2 diabetes mellitus, and are strong predictors of adverse cardiovascular outcomes. We sought to determine whether antihyperglycemic therapy improves measures of myocardial injury and myocardial stress in patients with type 2 diabetes mellitus. Methods and Results: We randomized, in a 2×2 factorial fashion, 438 patients with type 2 diabetes mellitus to insulin glargine, metformin, the combination, or placebo and measured changes in NT‐proBNP and hsTnT after 12 weeks of therapy. At baseline, the median (Q1–Q3) plasma concentration was 35.4 (15.7–86.3) ng/L for NT‐proBNP and 6.7 (4.6–10.1) ng/L for hsTnT. The adjusted (95% confidence interval) change in NT‐proBNP concentration was 20.7% (7.9–35.0) in the insulin arm compared with 0.13% (−10.8 to 12.5) in the no‐insulin arm (P=0.03 for comparison). These changes were not related to changes in fasting or postprandial glucose, glycated hemoglobin, weight, blood pressure, or inflammation. In the metformin arm, the adjusted change in NT‐proBNP was 7.8% (−3.7 to 20.7) compared with 13.0% (0.72–26.8) in the no‐metformin arm (P=0.58). No significant changes in hsTnT concentrations were observed for any of the treatment arms. Conclusions: Insulin glargine was associated with a significant 20.7% increase in NT‐proBNP, a marker of myocardial stress, after 12 weeks of therapy. No change in hsTnT, a marker of myocardial injury, was observed. The changes were independent of substantial improvements in glucose control. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00366301.