Faculty Bibliography

BACKGROUND: Among individuals without diabetes, elevated hemoglobin A1c (HbA1c) has been associated with increased morbidity and mortality, but the literature is sparse regarding the prognostic importance of low HbA1c. METHODS AND RESULTS: National Health and Nutrition Examination Survey III (NHANES III) participants, 20 years and older, were followed up to 12 years (median follow-up, 8.8 years) for all-cause mortality. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the association between HbA1c levels and all-cause mortality for 14 099 participants without diabetes. There were 1825 deaths during the follow-up period. Participants with a low HbA1c (<4.0%) had the highest levels of mean red blood cell volume, ferritin, and liver enzymes and the lowest levels of mean total cholesterol and diastolic blood pressure compared with their counterparts with HbA1c levels between 4.0% and 6.4%. An HbA1c <4.0% versus 5.0% to 5.4% was associated with an increased risk of all-cause mortality (HR, 3.73; 95% CI, 1.45 to 9.63) after adjustment for age, race-ethnicity, and sex. This association was attenuated but remained statistically significant after further multivariable adjustment for lifestyle, cardiovascular factors, metabolic factors, red blood cell indices, iron storage indices, and liver function indices (HR, 2.90; 95% CI, 1.25 to 6.76). CONCLUSIONS: In this nationally representative cohort, low HbA1c was associated with increased all-cause mortality among US adults without diabetes. Additional research is needed to confirm these results and identify potential mechanisms that may be underlying this association.

OBJECTIVE: New clinical practice recommendations include A1C as an alternative to fasting glucose as a diagnostic test for identifying pre-diabetes. The impact of these new recommendations on the diagnosis of pre-diabetes is unknown. RESEARCH DESIGN AND METHODS: Data from the National Health and Nutrition Examination Survey 1999-2006 (n = 7,029) were analyzed to determine the percentage and number of U.S. adults without diabetes classified as having pre-diabetes by the elevated A1C (5.7-6.4%) and by the impaired fasting glucose (IFG) (fasting glucose 100-125 mg/dl) criterion separately. Test characteristics (sensitivity, specificity, and positive and negative predictive values) using IFG as the reference standard were calculated. RESULTS: The prevalence of pre-diabetes among U.S. adults was 12.6% by the A1C criterion and 28.2% by the fasting glucose criterion. Only 7.7% of U.S. adults, reflecting 61 and 27% of those with pre-diabetes by A1C and fasting glucose, respectively, had pre-diabetes according to both definitions. A1C used alone would reclassify 37.6 million Americans with IFG to not having pre-diabetes and 8.9 million without IFG to having pre-diabetes (46.5 million reclassified). Using IFG as the reference standard, pre-diabetes by the A1C criterion has 27% sensitivity, 93% specificity, 61% positive predictive value, and 77% negative predictive value. CONCLUSIONS: Using A1C as the pre-diabetes criterion would reclassify the pre-diabetes diagnosis of nearly 50 million Americans. It is imperative that clinicians and health systems understand the differences and similarities in using A1C or IFG in diagnosis of pre-diabetes.

BACKGROUND: Nonadherence to statins limits the benefits of this common drug class. Individual studies assessing predictors of nonadherence have produced inconsistent results. OBJECTIVE: To identify reliable predictors of nonadherence to statins through systematic review and meta-analysis. METHODS: Multiple databases, including MEDLINE, EMBASE, and PsycINFO, were searched (from inception through February 2009) to identify studies that evaluated predictors of nonadherence to statins. Studies were selected using a priori defined criteria, and each study was reviewed by 2 authors who abstracted data on study characteristics and outcomes. Relative risks were then pooled, using an inverse-variance weighted random-effects model. RESULTS: Twenty-two cohort studies met inclusion criteria. Age had a U-shaped association with adherence; the oldest (>/=70 years) and youngest (<50 years) subjects had lower adherence than the middle-aged (50-69 years) subjects. Women and patients with lower incomes were more likely to be nonadherent than were men (odds of nonadherence 1.07; 95% CI 1.04 to 1.11) and those with higher incomes (odds of nonadherence 1.18; 95% CI 1.10 to 1.28), respectively. A history of cardiovascular disease predicted better adherence to statins (odds of nonadherence 0.68; 95% CI 0.66 to 0.78). Similarly, a diagnosis of hypertension or diabetes was associated with better adherence. Although there were too few studies for quantitative pooling, increased testing of lipid levels and lower out-of-pocket costs appeared to be associated with better adherence. There was substantial (I(2) range 68.7-96.3%) heterogeneity between studies across factors. CONCLUSIONS: Several sociodemographic, medical, and health-care utilization characteristics are associated with statin nonadherence. These factors may be useful guides for targeting statin adherence interventions.

OBJECTIVE: To assess the impact of a decision aid on perceived risk of heart attacks and medication adherence among urban primary care patients with diabetes. METHODS: We randomly allocated 150 patients with diabetes to participate in a usual primary care visit either with or without the Statin Choice tool. Participants completed a questionnaire at baseline and telephone follow-up at 3 and 6 months. RESULTS: Intervention patients were more likely to accurately perceive their underlying risk for a heart attack without taking a statin (OR: 1.9, CI: 1.0-3.8) and with taking a statin (OR: 1.4, CI: 0.7-2.8); a decline in risk overestimation among patients receiving the decision aid accounts for this finding. There was no difference in statin adherence at 3 or 6 months. CONCLUSION: A decision aid about using statins to reduce coronary risk among patients with diabetes improved risk communication, beliefs, and decisional conflict, but did not improve adherence to statins. PRACTICE IMPLICATIONS: Decision aid enhanced communication about the risks and benefits of statins improved patient risk perceptions but did not alter adherence among patients with diabetes.

A prediction model, developed in the Framingham Heart Study (FHS), has been proposed for use in estimating a given individual's risk of hypertension. We compared this model with systolic blood pressure (SBP) alone and age-specific diastolic blood pressure categories for the prediction of hypertension. Participants in the Multi-Ethnic Study of Atherosclerosis, without hypertension or diabetes mellitus (n=3013), were followed for the incidence of hypertension (SBP > or =140 mm Hg and/or diastolic blood pressure > or =90 mm Hg and/or the initiation of antihypertensive medication). The predicted probability of developing hypertension among 4 adjacent study examinations, with a median of 1.6 years between examinations, was determined. The mean (SD) age of participants was 58.5 (9.7) years, and 53% were women. During follow-up, 849 incident cases of hypertension occurred. The c statistic for the FHS model was 0.788 (95% CI: 0.773 to 0.804) compared with 0.768 (95% CI: 0.751 to 0.785; P=0.096 compared with the FHS model) for SBP alone and 0.699 (95% CI: 0.681 to 0.717; P<0.001 compared with the FHS model) for age-specific diastolic blood pressure categories. The relative integrated discrimination improvement index for the FHS model versus SBP alone was 10.0% (95% CI: -1.7% to 22.7%) and versus age-specific diastolic blood pressure categories was 146.0% (95% CI: 116.0% to 181.0%). Using the FHS model, there were significant differences between observed and predicted hypertension risks (Hosmer-Lemeshow goodness of fit: P<0.001); recalibrated and best-fit models produced a better model fit (P=0.064 and 0.245, respectively). In this multiethnic cohort of US adults, the FHS model was not substantially better than SBP alone for predicting hypertension.

Several models for estimating risk of incident diabetes in US adults are available. The authors aimed to determine the discriminative ability and calibration of published diabetes risk prediction models in a contemporary multiethnic cohort. Participants in the Multi-Ethnic Study of Atherosclerosis without diabetes at baseline (2000-2002; n = 5,329) were followed for a median of 4.75 years. The predicted risk of diabetes was calculated using published models from the Framingham Offspring Study, the Atherosclerosis Risk in Communities (ARIC) Study, and the San Antonio Heart Study. The mean age of participants was 61.6 years (standard deviation, 10.2); 29.3% were obese, 53.1% had hypertension, 34.9% had a family history of diabetes, 27.5% had high triglyceride levels, 33.8% had low high density lipoprotein cholesterol levels, and 15.3% had impaired fasting glucose. There were 446 incident cases of diabetes (fasting glucose level >or=126 mg/dL or initiation of antidiabetes medication use) diagnosed during follow-up. C statistics were 0.78, 0.84, and 0.83 for the Framingham, ARIC, and San Antonio risk prediction models, respectively. There were significant differences between observed and predicted diabetes risks (Hosmer-Lemeshow goodness-of-fit chi-squared test for each model: P < 0.001). The recalibrated and best-fit models achieved sufficient goodness of fit (each P > 0.10). The Framingham, ARIC, and San Antonio models maintained high discriminative ability but required recalibration in a modern, multiethnic US cohort.

Hypertension is associated with impaired endothelial function in cross-sectional studies. However, few longitudinal data exist on whether endothelial dysfunction precedes the development of hypertension. We examined the cross-sectional and longitudinal relationships between endothelial-dependent brachial artery flow-mediated dilation (FMD) and hypertension prevalence and incidence in 3500 participants from the Multi-Ethnic Study of Atherosclerosis, an ethnically diverse, community-based cohort study. At baseline, the prevalence ratios (95% CI) of hypertension from the highest to the lowest quartile of FMD were 1.00 (referent), 1.26 (1.12 to 1.40), 1.35 (1.21 to 1.52), and 1.68 (1.50 to 1.87; linear trend P<0.001). This association remained (P=0.017) after adjustment for demographics (age, sex, and ethnicity), Multi-Ethnic Study of Atherosclerosis site, and other risk factors. Of the 1869 participants without hypertension at baseline, 584 (31.3%) developed hypertension over a median follow-up of 4.8 years. The unadjusted relative risks (95% CI) of incident hypertension from the highest to the lowest quartile of FMD were 1.00 (referent), 1.38 (1.14 to 1.67), 1.44 (1.19 to 1.74), and 1.64 (1.36 to 1.97; linear trend P<0.001). However, after adjustment for demographics and Multi-Ethnic Study of Atherosclerosis site, the relationship between FMD and incident hypertension was attenuated and not statistically significant: 1.00 (referent), 1.26 (1.04 to 1.52), 1.19 (0.98 to 1.44), and 1.18 (0.97 to 1.44). The longitudinal results also did not appreciably change after adjustment for additional risk factors and baseline blood pressure levels. In this sample, reduced FMD was not an independent predictor of hypertension incidence, suggesting that impaired endothelial function does not play a major role in the development of hypertension.

Chronic kidney disease (CKD), defined by either microalbuminuria (MA) or a reduced estimated glomerular filtration rate (eGFR), is associated with an increased risk of peripheral arterial disease (PAD). The presence of both abnormalities might identify a subgroup of adults at particularly high risk of PAD. Accordingly, we sought to evaluate the combined effect of a reduced eGFR and MA on the prevalence of PAD among United States adults. United States adults >or=40 years old (n = 6,951) participating in the 1999 to 2004 National Health and Nutrition Examination Survey were cross-classified into 4 groups according to the presence or absence of MA (urinary albumin/creatinine ratio >or=30 mg/g) and reduced eGFR (<60 mL/min/1.73 m(2)). PAD was defined as an ankle-brachial index of <0.9. The prevalence of PAD among adults without MA or a reduced eGFR was 3.6% compared to 9.7%, 14.8%, and 25.4% among adults with MA alone, reduced eGFR alone, and both reduced eGFR and MA, respectively. After multivariate adjustment, the odds ratio for prevalent PAD associated with MA alone, reduced eGFR alone, and both reduced eGFR and MA compared to those without MA or reduced eGFR was 1.72 (95% confidence interval 1.16 to 2.55), 1.58 (95% confidence interval 1.09 to 2.29), and 2.26 (95% confidence interval 1.30 to 3.94), respectively. In conclusion, the coexistence of MA and reduced eGFR was associated with a high prevalence of PAD and might be useful in identifying patients with vascular disease.