Aaron M. Secrest

Improvements in the life expectancy of type 1 diabetes: The Pittsburgh Epidemiology of Diabetes Complications Study cohort

Survival in type 1 diabetes has improved, but the impact on life expectancy in the U.S. type 1 diabetes population is not well established. Our objective was to estimate the life expectancy of the Pittsburgh Epidemiology of Diabetes Complications (EDC) study cohort and quantify improvements by comparing two subcohorts based on year of diabetes diagnosis (1950–1964 [n = 390] vs. 1965–1980 [n = 543]). The EDC study is a prospective cohort study of 933 participants with childhood-onset (aged <17 years) type 1 diabetes diagnosed at Children’s Hospital of Pittsburgh from 1950 to 1980. Mortality ascertainment was censored 31 December 2009. Abridged cohort life tables were constructed to calculate life expectancy. Death occurred in 237 (60.8%) of the 1950–1964 subcohort compared with 88 (16.2%) of the 1965–1980 subcohort. The life expectancy at birth for those diagnosed 1965–1980 was ∼15 years greater than participants diagnosed 1950–1964 (68.8 [95% CI 64.7–72.8] vs. 53.4 [50.8–56.0] years, respectively) (P < 0.0001); this difference persisted regardless of sex or pubertal status at diagnosis. This improvement in life expectancy emphasizes the need for insurance companies to update analysis of the life expectancy of those with childhood-onset type 1 diabetes because weighting of insurance premiums is based on outdated estimates.

All-cause mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes: the Allegheny County type 1 diabetes registry.

OBJECTIVE Although management of type 1 diabetes improved dramatically in the 1980s, the effect on mortality is not clear. RESEARCH DESIGN AND METHODS We report trends in 30-year mortality using the Allegheny County (Pennsylvania) childhood-onset (age <18 years) type 1 diabetes registry (n = 1,075) with diagnosis from 1965–1979, by dividing the cohort into three diagnosis year cohorts (1965–1969, 1970–1974, and 1975–1979). Local (Allegheny County) mortality data were used to calculate standardized mortality ratios (SMRs). RESULTS As of 1 January 2008, vital status was ascertained for 97.0% of participants (n = 1,043) when mean age ± SD and duration of diabetes were 42.8 ± 8.0 and 32.0 ± 7.6 years, respectively. The 279 deaths (26.0%) observed were 7 times higher than expected (SMR 6.9 [95% CI 6.1–7.7]). An improving trend in SMR was seen by diagnosis cohort at 30 years of diabetes duration (9.3 [7.2–11.3], 7.5 [5.8–9.2], and 5.6 [4.0–7.2] for 1965–1969, 1970–1974, and 1975–1979, respectively). Although no sex difference in survival was observed (P = 0.27), female diabetic patients were 13 times more likely to die than age-matched women in the general population (SMR 13.2 [10.7–15.7]), much higher than the SMR for men (5.0 [4.0–6.0]). Conversely, whereas 30-year survival was significantly lower in African Americans than in Caucasians (57.2 vs. 82.7%, respectively; P < 0.001), no differences in SMR were seen by race. CONCLUSIONS Although survival has clearly improved, those with diabetes diagnosed most recently (1975–1979) still had a mortality rate 5.6 times higher than that seen in the general population, revealing a continuing need for improvements in treatment and care, particularly for women and African Americans with type 1 diabetes.

Cardiovascular Autonomic Neuropathy, HDL Cholesterol, and Smoking Correlate With Arterial Stiffness Markers Determined 18 Years Later in Type 1 Diabetes

OBJECTIVE To examine the relationship between cardiovascular autonomic neuropathy and pulse waveform analysis (PWA) measures of arterial stiffness in a childhood-onset type 1 diabetes population. RESEARCH DESIGN AND METHODS Cardiac autonomic nerve function was measured in the baseline examination of the Pittsburgh Epidemiology of Diabetes Complications Study of childhood-onset type 1 diabetes by heart rate variability (R-R interval) during deep breathing and expressed as expiration-to-inspiration (E/I) ratio. Other cardiovascular and diabetes factors were also assessed. PWA was performed using SphgymoCor Px on 144 participants at the 18-year follow-up examination. Univariate and multivariate analyses for associations between baseline nerve function and other cardiovascular and diabetes-related factors were performed for augmentation index (AIx), augmentation pressure (AP), and subendocardial viability ratio (SEVR), a surrogate marker of myocardial perfusion. RESULTS E/I ratio correlated negatively with both AIx (r = −0.18, P = 0.03) and AP (r = −0.32, P < 0.001) and positively with SEVR (r = 0.47, P < 0.001) univariately. Lower baseline E/I ratio, HDL cholesterol, and a history of smoking were associated with higher follow-up (18 years later) AIx and AP and lower SEVR in multivariate analyses. Higher baseline HbA1 was also associated with higher AP and lower SEVR multivariately. CONCLUSIONS Cardiovascular autonomic neuropathy is associated with increased arterial stiffness measures and decreased estimated myocardial perfusion in those with type 1 diabetes some 18 years later. This association persists after adjustment for potential confounders as well as for baseline HbA1, HDL cholesterol, and smoking history, which were also associated with these PWA measures.

Characterizing sudden death and dead-in-bed syndrome in Type 1 diabetes: analysis from two childhood-onset Type 1 diabetes registries

Diabet. Med. 28, 293–300 (2011)

Changing Impact of Modifiable Risk Factors on the Incidence of Major Outcomes of Type 1 Diabetes: The Pittsburgh Epidemiology of Diabetes Complications Study

OBJECTIVE The incidence of type 1 diabetes complications appears to be decreasing, but relative contributions of risk factors are unclear. We thus estimated the effect of modifiable risk factors on the incidence of a composite end point, major outcomes of diabetes (MOD). RESEARCH DESIGN AND METHODS The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study was used to derive two cohorts based on diabetes diagnosis year (1960–1969 and 1970–1980). Baseline exam data in the current analysis for the 1960s group were collected in 1986–1988 and for the 1970s in 1996–1998. Each group was followed for 8 years for MOD incidence (diabetes-related death, myocardial infarction, revascularization procedure/blockage ≥50%, stroke, end-stage renal disease, blindness, and amputation). Assessed risk factors include the following: HbA1c, hypertension, microalbuminuria, BMI, hypercholesterolemia, and smoking. Accelerated failure time models were used to estimate the acceleration factor. RESULTS MOD incidence decreased in the 1970s cohort (15.8% [95% CI 11.6–21.4]) compared with the 1960s (22.6% [17.0–29.1]) over the 8-year follow-up (P = 0.06). Hypertension and microalbuminuria were associated with significantly accelerated MOD incidence in both cohorts (P < 0.01 for both). High HbA1c (P = 0.0005), hypercholesterolemia (P = 0.01), and current smoking (P = 0.003) significantly accelerated the incidence of MOD in the 1960s but not 1970s cohort. BMI was not associated with MOD in either cohort. CONCLUSIONS These results suggest that hypertension and microalbuminuria remain important predictors of complications that are not being adequately addressed.

Augmentation pressure and subendocardial viability ratio are associated with microalbuminuria and with poor renal function in type 1 diabetes

In this report we explore the hypothesis that arterial stiffness indices, which predict cardiovascular disease, might also correlate with microalbuminuria (MA) in type 1 diabetes (T1D), and thus have potential for risk assessment. Three pulse wave analysis (PWA) indices, measured using the SphygmoCor device, were evaluated on 144 participants with childhood-onset T1D. These variables, augmentation index (AIx), augmentation pressure (AP) and subendocardial viability ratio (SEVR, an estimate of myocardial perfusion) (an estimate of myocardial perfusion), were each analysed cross-sectionally in relation to both prevalent MA (defined as albuminuria excretion rate (AER) = 20—199 μg/min) and renal function (assessed by both eGFR and serum cystatin C). AP and SEVR were each univariately associated with AER, estimated glomerular filtration rate (eGFR) and cystatin C. Lower SEVR was also independently related to the presence of MA and degree of albuminuria within normo- and microalbuminuric participants. SEVR, not AP, was independently and negatively associated with both measures of renal function. SEVR is a better predictor of AER than brachial blood pressure measures in those without clinical proteinuria, indicating a potential use for PWA in the early detection of individuals at risk for cardiovascular and renal complications of T1D.

Association of Socioeconomic Status with Mortality in Type 1 Diabetes: The Pittsburgh Epidemiology of Diabetes Complications Study

PURPOSE Socioeconomic status (SES) as a risk factor for mortality in type 1 diabetes (T1D) has not been adequately studied prospectively. METHODS Complete clinical and SES (income, education, occupation) data were available for 317 T1D participants in the Pittsburgh Epidemiology of Diabetes Complications Study within 4 years of age 28 (chosen to maximize income, education, and occupational potential, and to minimize the SES effect of advanced diabetes complications). Vital status was determined as of 1/1/2008. RESULTS Over a median 16 years of follow-up, 34 (10.7%) deaths occurred (standardized mortality ratios [SMRs] = 4.1, 95% confidence interval [CI]: 2.7-5.5). SMRs did not differ from the general population for those in the highest education and income groups, whereas in those with low SES, SMRs were increased. Mortality rates were three times lower for individuals with a college degree versus without a college degree (p = 0.004) and nearly four times lower for the highest income versus lower income groups (p = 0.04). In Cox models adjusting for diabetes duration and sex, education was the only SES measure predictive of mortality (hazard ratio [HR] = 3.0, 95% CI: 1.2-7.8), but lost significance after adjusting for HbA(1c), non-HDL cholesterol, hypertension, and microalbuminuria (HR = 2.1, 95% CI: 0.8-5.6). CONCLUSIONS The strong association of education with mortality in T1D is partially mediated by better glycemic, lipid, and blood pressure control.

Pulse wave analysis and prevalent cardiovascular disease in type 1 diabetes

OBJECTIVE Type 1 diabetes (T1D) is associated with a high risk for and mortality from premature coronary artery disease (CAD), including coronary artery calcification (CAC), a subclinical marker, and lower extremity arterial disease (LEAD). Pulse wave analysis (PWA) arterial stiffness indices have been associated with cardiovascular disease (CVD) risk factors and outcomes in various populations, but little is known regarding these relationships in T1D. METHODS PWA was performed using the SphygmoCor Px device on 144 participants in the Pittsburgh EDC Study of childhood-onset T1D. The cross-sectional associations between arterial stiffness indices, augmentation index (AIx) and augmentation pressure (AP), and subendocardial viability ratio (SEVR), an estimate of myocardial perfusion, with prevalent CAD, electron beam computed tomography-measured CAC and low (<0.90) ankle-brachial index (ABI) were examined. RESULTS Higher AP (but not AIx) and lower SEVR were univariately associated with prevalent CAD, high CAC score, and low ABI. AP and SEVRs association with CAD and CAC did not, however, remain significant after adjustment for age. In individuals not using nitrates, which profoundly affect PWA measures, AP was significantly higher in those with CAD events and explained more of the variance than either age or brachial blood pressure measures. SEVR was associated with low ABI in multivariable models. CONCLUSIONS Greater augmentation pressure is independently associated with prevalent CAD and estimated myocardial perfusion with low ABI in type 1 diabetes. These measures may thus help to better characterize CVD risk in type 1 diabetes and need to be examined prospectively.

Surveillance of Patients for Early Detection of Melanoma Patterns in Dermatologist vs Patient Discovery

OBJECTIVE To determine which groups of patients are most and least likely to detect their own melanomas independent of dermatologist evaluation. DESIGN Retrospective analysis. SETTING Academic dermatology department from January 1, 2003, through December 31, 2008. PATIENTS One hundred sixty-seven consecutive patients with incident biopsy-confirmed melanomas. MAIN OUTCOME MEASURES Proportion of melanomas found on dermatologist examination vs those brought to the attention of the examining dermatologist by the patient. Secondary analysis examined associations between who detected the melanoma (dermatologist vs patient) and patient age, personal history of skin cancer, family history of melanoma, and depth of lesion. RESULTS Of the 167 melanomas, 101 (60.5%) were brought to the attention of the dermatologist by the patient. Detection by a dermatologist was significantly associated with patient age of 50 years or older (P = .002), personal skin cancer history (P < .001), and a lesion depth of less than 0.75 mm at the time of detection (P = .03). Only 3.0% of all melanomas in this study were detected by dermatologists in patients who had a low baseline risk of melanoma (age <50 years, no personal history of skin cancer, and no family history of melanoma). These patients were much more likely to detect their own melanoma (odds ratio, 7.32 [95% confidence interval, 2.69-19.90]). CONCLUSIONS Screening for melanoma in asymptomatic patients younger than 50 years with no medical history of skin cancer or family history of melanoma yields few physician-detected melanomas because these patients are most likely to detect their melanomas themselves. Screening and surveillance efforts should focus on patients 50 years or older and those with a personal history of skin cancer or a family history of melanoma.

Bisphosphonate inhibitors of ATP-mediated HIV-1 reverse transcriptase catalyzed excision of chain-terminating 3'-azido, 3'-deoxythymidine: a QSAR investigation.

We report the results of an investigation of the inhibition of the ATP-mediated HIV-1 reverse transcriptase catalyzed phosphorolysis in vitro of AZT from AZT-terminated DNA primers by a series of 42 bisphosphonates. The four most active compounds possess neutral, halogen-substituted phenyl or biphenyl sidechains and have IC(50) values < 1 microM in excision inhibition assays. Use of two comparative molecular similarity analysis methods to analyze these inhibition results yielded a classification model with an overall accuracy of 94%, and a regression model having good accord with experiment (q(2)=0.63, r(2)=0.91), with the experimental activities being predicted within, on average, a factor of 2. The most active species had little or no toxicity against three human cell lines (IC(50)(avg) > 200 microM). These results are of general interest since they suggest that it may be possible to develop potent bisphosphonate-based AZT-excision inhibitors with little cellular toxicity, opening up a new route to restoring AZT sensitivity in otherwise resistant HIV-1 strains.