Epidemiology Of Diabetes Complications Study Research Articles

1461-P: HbA1c-Independent Association between DNA Methylation (DNAm) and 28-Year Risk of Microvascular Complications in Type 1 Diabetes (T1D)

DNAm has been associated with microvascular disease but the few epigenome-wide association studies (EWAS) of complications in T1D were largely cross-sectional with limited data on glycemic exposure. We thus performed separate EWAS of 28-yr overt nephropathy (ON) and proliferative retinopathy (PR) risk to determine whether DNAm associations are independent of concurrent HbA1c or differ by long-term HbA1c trajectory in the Pittsburgh Epidemiology of Diabetes Complications study of childhood onset (<17 yrs) T1D (baseline mean age 29, T1D duration 21 yrs). After quality control, baseline whole blood DNAm (Illumina EPIC array) at 683,597 CpGs was analyzed in Cox models for time-to-ON (albumin excretion rate >200µg/min in ≥2 of 3 timed urines, n=306 free of ON at baseline) and PR (ETDRS grade≥60 or laser photocoagulation, n=265 free of PR), adjusting for T1D duration, sex, smoking pack-years, est. blood cell composition, and technical covariates. Additional EWAS further adjusted for baseline HbA1c. CpGs with false discovery rate (FDR) <0.20 were examined by previously derived latent HbA1c trajectory (Low: stable 7-8%, Improved: 10% decreasing to 7%, Intermediate-High: stable 9%-11%). Over 28 yrs, 65 (21.2%) developed ON; 139 (52.5%) PR. For ON, DNAm at cg19693031 (TXNIP) was associated (β per 5% DNAm=−0.43±0.09, p=2.84E-07, FDR=0.19) but attenuated in a baseline HbA1c-adjusted EWAS (β=−0.32±0.08, p=7.76E-05, FDR=0.98). For PR, 3 CpGs (cg27512687 [KIF16B]; cg04202206 [ISCA1]; cg14678509 [intergenic]) had FDR<0.20; only cg27512687 remained so after HbA1c adjustment (β=−2.6±0.49, p=8.46E-08, FDR=0.06). There was no interaction with baseline HbA1c (p=0.49); the magnitude of the cg27512687-PR association was similar regardless of HbA1c trajectory. Thus, further study of cg27512687 in KIF16B, a locus encoding a kinesin involved in receptor recycling/degradation, is warranted as it may make an HbA1c-independent contribution to PR risk T1D. Disclosure R.G.Miller: None. J.Mychaleckyj: None. S.Onengut-gumuscu: None. T.J.Orchard: None. T.Costacou: None. Funding American Diabetes Association (1-19-JDF-109 to R.G.M.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK034818)

TXNIP DNA methylation is associated with glycemic control over 28 years in type 1 diabetes: findings from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study

IntroductionDNA methylation (DNAme) has been cross-sectionally associated with type 2 diabetes and hemoglobin A1c (HbA1c) in the general population. However, longitudinal data and data in type 1 diabetes are currently...

Long term risk of heart failure in individuals with childhood-onset type 1 diabetes

BackgroundWe aimed to evaluate the risk of heart failure in young adults with childhood-onset type 1 diabetes from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. We also examined risk factors and microvascular disease burden associated with the incidence of heart failure. MethodsParticipants in the EDC study without known baseline heart failure (n = 655) were enrolled and then followed for 25 years. “Any” heart failure comprised the underlying cause of death, primary reason for hospitalization, EDC clinic examination findings or self-report of a physician diagnosis. “Hard” heart failure was determined only by the underlying cause of death or primary reason for hospitalization. Incidence rates for heart failure were estimated using Poisson models. Cox models were constructed to examine the associations between risk factors and microvascular disease burden with incident heart failure. ResultsThe mean baseline age and diabetes duration were 27(8) years and 19 (8) years. Incidence for any and hard heart failure were 3.4 and 1.8/1000 person-years. Diabetes duration, ever smoking and triglycerides were significant risk factors of any heart failure; longer diabetes duration, lower estimated glomerular filtration rate and higher white blood cell count significantly predicted hard heart failure. A gradient association was observed between the number of microvascular disease (from 0 to 3) and “hard” heart failure endpoint but not “any” clinically defined heart failure. ConclusionYoung adults with long-duration type 1 diabetes had a high risk of heart failure. As microvascular disease burden increases so does the risk of heart failure independently of diabetes duration, A1c and coronary artery disease.

Abstract 551: HDL Particle Concentration And Incident Ischemic Stroke In Type 1 Diabetes

Recently, we showed that HDL particle concentration (HDL-P) and cholesterol efflux capacity (CEC) predict coronary artery disease (CAD) better than HDL-C in people with type 1 diabetes (T1D). Cardiovascular risk factors have been shown to associate with different cardiovascular outcomes differently. We therefore investigated the association of HDL-P and CEC with ischemic stroke (IS) incidence in people with T1D. We quantified HDL-P using calibrated differential ion mobility and total and ABCA1-specific HDL CEC in 549 participants with childhood-onset (<17 years) T1D from the Epidemiology of Diabetes Complications study using the first available blood sample. The participants were free of cerebrovascular disease at baseline (mean age 27.8 years, T1D duration 19.6 years, 49% women). Stroke incidence/type was determined by self-report of physician diagnosis and confirmed by medical record review. During the follow-up (median 25 years), there were 35 (6.5%) incident IS events. Participants with IS were more likely to be older, have a longer T1D duration, have hypertension, a history of smoking, and a worse lipid, inflammatory and renal markers’ profile at baseline; HDL-C, HDL-P, and CEC did not differ between participants with and without IS. While HDL-C, total HDL-P, and CEC were not associated with IS risk, extra-small HDL-P (xsHDL-P, ~7.8nm) subspecies were strongly associated with incident IS (HR=4.49, 95% CI: 1.72-11.74), even after adjustment for IS risk factors (including smoking, diabetes duration, hypertension as well as HDL-C), in multivariable Cox proportional hazards regression analyses. When all stroke events including hemorrhagic stroke were considered the association was weaker (n=47 events, HR=2.5, 95% CI: 0.97-6.47) suggesting specificity in the association of xsHDL-P with ischemic stroke.In contrast to a strong protective association of total HDL-P and CEC against CAD in the same T1D population, these HDL metrics were not associated with IS. However, the xsHDL-P subspecies were specifically associated with increased IS risk. These striking findings require further investigation and suggest a differential association of HDL particle metrics with CAD and IS.

Joint 30-year HbA1c and lipid trajectories and mortality in type 1 diabetes

AimsHigher HbA1c has been associated with dyslipidemia in type 1 diabetes, but it is unknown whether there is heterogeneity in this association. Thus we assessed the longitudinal association between HbA1c and lipids over 30 years in a type 1 diabetes cohort and examined whether variation in such longitudinal patterns was associated with total and cause-specific mortality. MethodsData were from the Pittsburgh Epidemiology of Diabetes Complications study (n = 581 with ≥2 visits, 51% male, baseline mean age 27, diabetes duration 19 years). Longitudinal associations between HbA1c and lipids were assessed in mixed models. Group-based multi-trajectory models identified simultaneous trajectories of HbA1c and lipids. ResultsLongitudinal HbA1c was associated with Non-HDLc (p < 0.0001) and triglycerides (p < 0.0001), but not HDLc (men: p = 0.72, women: p = 0.76). There was heterogeneity in the HbA1c-Non-HDLc association only, with five HbA1c-Non-HDLc groups identified. One group (20%) had an unexpected combination of high HbA1c but normal Non-HDLc and had only moderately increased cardiovascular mortality (rate ratio [RR] = 2.80, 95% CI 1.31–6.00) and kidney disease mortality (RR = 2.30, 95% CI 0.97–5.50) compared to Low HbA1c-Normal Non-HDLc. ConclusionsThese results suggest there is a subgroup with type 1 diabetes who, despite poor glycemic control, has a relatively good prognosis, perhaps related to good Non-HDLc.

Predictors of the age at which natural menopause occurs in women with type 1 diabetes: the Pittsburgh Epidemiology of Diabetes Complications (EDC) study.

Women with type 1 diabetes (T1D) are thought to experience menopause earlier than women without diabetes, although not all studies agree. We assessed metabolic predictors of the age at which natural menopause occurs among women with T1D participating in the Epidemiology of Diabetes Complications study. Women with childhood-onset (<17 y) of T1D who underwent natural menopause without use of hormone therapy during their menopausal transition were included in the analysis (n = 105; mean baseline age, 29.5 and diabetes duration, 20.2 y). Self-reported reproductive history and the Women's Ischemia Syndrome Evaluation hormonal algorithms were used to determine menopause status. Linear regression was used to ascertain whether time-weighted metabolic factors (eg, BMI, lipids, HbA1c, insulin dose, albumin excretion rate [AER]) were associated with age at natural menopause. Univariately, only insulin dose (β = -4.87, P = 0.04) and log (AER) (β = -0.62, P = 0.02) were associated (negatively) with age at natural menopause. Adjusting for BMI, smoking status, lipids, HbA1c, number of pregnancies, and oral contraceptive use, each 0.1 unit increase in the daily dose of insulin per kilogram body weight was associated with 0.64 years younger age at natural menopause (P = 0.01), while for every 30% increase in AER, age at natural menopause decreased by 0.18 years (P = 0.03). Higher average levels of insulin dose and AER over time were significantly associated with a younger age at which natural menopause occurred among women with T1D. The biologic mechanisms underlying the observed associations between exogenous insulin dose and AER on reproductive health should be investigated among women with T1D.

Heterogeneous long-term trajectories of glycaemic control in type 1 diabetes.

We aimed to identify long-term HbA1c trajectories and examine associated characteristics in an observational, childhood-onset (<17years) type 1 diabetes cohort. Data are from the Epidemiology of Diabetes Complications study, comprising 405 participants with ≥2 of seven possible HbA1c measurements over follow-up (1988-2013) and available DNA (baseline mean diabetes duration 21years, 53% men). HbA1c trajectories were estimated using latent class growth models. Baseline and change in participant characteristics were compared across trajectories. Five HbA1c trajectories were identified: low (51%), intermediate stable (22%), improved (19%), high stable (6%), and worsened (2%; not included in analyses). Age, diabetes duration, diabetes onset age, and sex did not differ across trajectories. Characteristics did not differ significantly between intermediate stable and low trajectories at baseline, though albumin excretion rate (AER, p=0.0002) and estimated glomerular filtration rate (eGFR, p=0.001) worsened slightly more in intermediate stable over time. Improved and high stable trajectories had higher baseline LDL-c (p=0.002 and 0.003, respectively). Improved trajectory increased median self-monitoring of blood glucose from <1 to 3.5 times/day (p<0.0001) and had larger LDL-c improvement (p=0.004) but greater worsening of AER (p<0.0001) and eGFR (p<0.0001) than low. The A allele of rs12970134 (near MC4R) was associated with improved (p=0.0003) or high stable (p=0.001) HbA1c trajectory, both patterns with high baseline HbA1c. Long-term HbA1c trajectories were primarily associated with modifiable factors in this type 1 diabetes cohort. The intermediate stable pattern had a risk factor profile that suggests some protection against adverse metabolic effects of chronic hyperglycaemia, warranting further study.

Association of age at diabetes complication diagnosis with age at natural menopause in women with type 1 diabetes: The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study.

Vascular damage is thought to have a role in premature ovarian aging. We thus assessed the association between the presence, and age at onset of, vascular diabetes complications and age at natural menopause in women with type 1 diabetes. Female participants of the Epidemiology of Diabetes Complications study with type 1 diabetes who experienced natural menopause and who never received hormone therapy during their menopausal transition were included in the analysis (n=105). Microalbuminuria (MA), overt nephropathy, proliferative retinopathy, confirmed distal symmetric polyneuropathy, and coronary artery disease, were assessed during biennial clinical exanimations for the first 10 years of follow-up and at year 18, 25 and 30. Menopausal status was determined via self-report and sex hormone data. For each complication, separate linear regression models were used to assess whether, compared with women without the complication of interest, an earlier age at complication development (i.e., <30 years of age) was associated with an earlier age at natural menopause. Although results from multivariable linear regression models suggested a similar age at menopause between women with normo-albuminuria and those diagnosed with MA after 30 years of age, menopause occurred 2.06 years earlier (β±SE=-2.06±1.08) among women diagnosed with MA before age 30 (p=0.06). No significant association was observed for other complications. Among women with type 1 diabetes, menopause appears to occur earlier in those diagnosed with MA before age 30 compared to those with normo-albuminuria, suggesting that vascular dysfunction associated with early microvascular disease may affect ovarian aging.

Cardiovascular health in early adulthood predicts the development of coronary heart disease in individuals with type 1 diabetes: 25year follow-up from the Pittsburgh Epidemiology of Diabetes Complications study.

Type 1 diabetes increases CHD risk. We examined the use of the American Heart Association's cardiovascular health metrics (blood pressure, total cholesterol, glucose/HbA1c, BMI, physical activity, diet, smoking) to predict incidence of CHD among individuals with type 1 diabetes, with the hypothesis that a better American Heart Association health metric profile would be associated with lower incident CHD. Prevalence of the seven cardiovascular health metrics was determined using first and second visits from adult participants (mean age 28.6years) in the Epidemiology of Diabetes Complications prospective cohort study of childhood-onset type 1 diabetes. An ideal metric score (0-7) was defined as the sum of all metrics within the ideal range, and a total metric score (0-14) was calculated based on poor, intermediate and ideal categories for each metric. Incident CHD development (medical record-confirmed CHD death, myocardial infarction, revascularisation, ischaemic electrocardiogram changes or Epidemiology of Diabetes Complications physician-determined angina) over 25years of follow-up was examined by metric scores. Among 435 participants, BMI, blood pressure, total cholesterol and smoking demonstrated the highest prevalence within the ideal range, while diet and HbA1c demonstrated the lowest. During 25years of follow-up, 177 participants developed CHD. In Cox models, each additional metric within the ideal range was associated with a 19% lower risk (p = 0.01), and each unit increase in total metric score was associated with a 17% lower risk (p < 0.01) of CHD, adjusting for diabetes duration, estimated glomerular filtration rate, albumin excretion rate, triacylglycerols, depression and white blood cell count. Among individuals with type 1 diabetes, higher cardiovascular health metric scores were associated with lower risk of incident CHD. The American Heart Association-defined cardiovascular health metrics provide straightforward goals for health promotion that may reduce CHD risk in the type 1 diabetes population. Graphical abstract.

Skin intrinsic fluorescence scores are a predictor of all-cause mortality risk in type 1 diabetes: The Epidemiology of Diabetes Complications study.

We assessed the association of skin intrinsic fluorescence (SIF) scores, as a measure of advanced glycation end-products (AGE), with all-cause mortality in type 1 diabetes (T1D). This is an observational retrospective study of a convenience sample from the Epidemiology of Diabetes Complications (EDC) study. AGEs were measured with a SIF score between 2007 and 2014; vital status was assessed in 2020. Among 245 participants, mean age was 48.6 ± 7.4 years, median diabetes duration was 39.5 years (IQR: 34.2, 44.9), and 53.5% were female. Compared to survivors, the deceased (n = 20) were older, with higher SIF scores, longer diabetes duration, lower body mass index (BMI), and an adverse risk factor profile (all p≤0.05). Univariate Cox regression showed a marginal association between SIF score and mortality (HR: 1.1, 95% CI 0.9-1.2, p = 0.06), which persisted after adjustment for multiple daily insulin shots/pump (MDI) use (HR: 1.1, 95% CI 1.0-1.2, p = 0.04). This association was attenuated after adjustment for T1D duration, A1c months, or estimated glomerular filtration rate (eGFR). In individuals with long duration T1D, SIF scores adjusted for MDI predicted all-cause mortality, although this association was attenuated after adjustments. Given the nature of sampling and small number of events, our findings require replication.

Utility of Insulin Resistance in Estimating Cardiovascular Risk in Subjects with Type 1 Diabetes According to the Scores of the Steno Type 1 Risk Engine.

Background: We sought to assess the potential of insulin resistance (IR) for estimating cardiovascular disease (CVD) risk in adults with type 1 diabetes (T1DM) according to the scores of the Steno Type 1 Risk Engine (ST1RE). Methods: A total of 179 adults with T1DM (50.8% men, age 41.2 ± 13.1 years, duration of T1DM 16 (12–23) years) without established CVD were evaluated. IR was assessed by the estimation of insulin sensitivity (eIS) using two validated prediction equations: the estimated insulin sensitivity developed from the Pittsburgh Epidemiology of Diabetes Complications Study (eIS-EDC) and the estimated insulin sensitivity developed from Coronary Artery Calcification in T1DM Study (eIS-CACTI) ST1RE was used to estimate 10-year CVD risk and to classify subjects into three groups according to their risk: low (<10%; n = 105), moderate (10–20%; n = 53), and high (≥20%; n = 21). Results: Both eIS-EDC and eIS-CACTI correlated negatively with ST1RE scores (eIS-EDC: r = −0.636, p < 0.001; eIS-CACTI: r = −0.291, p < 0.001). The C-statistic for predicting moderate/high risk and high risk was 0.816 (95% confidence interval (CI): 0.754–0.878) and 0.843 (95% CI: 0.772–0.913), respectively, for the eIS-EDC equation, and was 0.686 (95% CI: 0.609–0.763) and 0.646 (95% CI: 0.513–0.778), respectively, for the eIS-CACTI equation. The eIS-EDC equation had a significantly higher C-statistic both for moderate-/high-risk (p = 0.001) and high-risk (p = 0.007) subjects. Two cut-off points of eIS-EDC were identified for detecting moderate/high risk (8.52 mg·kg−1·min−1; sensitivity 74% and specificity 76%) and high risk (8.08 mg·kg−1·min−1; sensitivity 65% and specificity 95%) with potential applicability in clinical practice. Conclusions: eIS negatively correlates with the score of CVD risk in the ST1RE. Two cut-off points of eIS are reported with potential utility in clinical practice for detecting adults with T1DM with the highest CVD risk.

1633-P: Women with Type 1 Diabetes (T1D) Experience a Shorter Reproductive Period Compared with Nondiabetic Women: The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study and the Study of Women’s Health Across the Nation (SWAN)

Evidence suggests that insulin deficiency and hyperglycemia may disrupt the normal function of the female reproductive system, leading to delayed menarche and premature ovarian aging. We compared the length of the reproductive period of women with T1D and women without diabetes. We assessed age at menarche and natural menopause in women with childhood-onset T1D (diagnosed in 1950-80) who participated in the Pittsburgh EDC study’s 2010-16 follow-up (where reproductive history was assessed) and nondiabetic participants from the Pittsburgh site of the SWAN study. Women who had not yet reached natural menopause, had a hysterectomy/oophorectomy before menopause or received sex hormone therapy during the menopausal transition were excluded from analyses. In EDC, covariate data were selected from the follow-up visit where chronological age was closest to the baseline age in SWAN. Reproductive history was self-reported. The Women’s Ischemia Syndrome Evaluation historical and hormonal algorithms were also used to assess menopause status. Women with T1D (n=105) were younger (42.8 vs. 46.0 yrs, p=.0003), more likely to be white (96.2% vs. 68.3%, p&amp;lt;.0001), never smokers (67.3% vs. 48.1%, p=.002), with lower BMI (25.2 vs. 26.5 kg/m2, p=.002) and higher HDL-C (61.0 vs. 53.0 mg/dl, p&amp;lt;.0001) compared with women without diabetes (n=341). Women with T1D were also older at menarche (13.3 vs. 12.6 yrs, p&amp;lt;.0001) but younger at natural menopause (50.1 vs. 51.9 yrs, p&amp;lt;.0001). Adjusting for age, race, smoking status, BMI, HDL, and number of pregnancies, T1D was associated with 3.3 (95% CI: 2.5-4.0) fewer reproductive years. The length of the reproductive period of women with T1D is shorter, having delayed menarche and earlier natural menopause, compared with women without diabetes. Factors that could be related to a shorter reproductive period in T1D should be investigated. Disclosure Y. Yi: None. S.R. El Khoudary: None. R.G. Miller: None. D. Rubinstein: None. K.A. Matthews: None. T.J. Orchard: None. T. Costacou: None. Funding National Institutes of Health (DK34818); Rossi Memorial Fund; National Institute on Aging; National Institute of Nursing Research; Office of Research on Women’s Health

Costs and outcomes of "intermediate" vs "minimal" care for youth-onset type 1 diabetes in six countries.

Data are needed to demonstrate that providing an "intermediate" level of type 1 diabetes (T1D) care is cost-effective compared to "minimal" care in less-resourced countries. We studied these care scenarios in six countries. We modeled the complications/costs/mortality/healthy life years (HLYs) associated with "intermediate" care including two blood glucose tests/day (mean HbA1c 9.0% [75 mmol/mol]) in three lower-gross domestic product (GDP) countries (Mali, Tanzania, Pakistan), or three tests/day (mean HbA1c 8.5% [69 mmol/mol]) in three higher-GDP countries (Bolivia, Sri Lanka, Azerbaijan); and compared findings to "minimal" care (mean HbA1c 12.5% [113 mmol/mol]). A discrete time Markov illness-death model with age and calendar-year-dependent transition probabilities was developed, with inputs of 30 years of complications and Standardized Mortality Rate data from the youth cohort in the Pittsburgh Epidemiology of Diabetes Complications Study, background mortality, and costs determined from international and local prices. Cumulative 30 years incidences of complications were much lower for "intermediate care" than "minimal care", for example, for renal failure incidence was 68.1% (HbA1c 12.5%) compared to 3.9% (9%) and 2.4% (8.5%). For Mali, Tanzania, Pakistan, Bolivia, Sri Lanka, and Azerbaijan, 30 years survival was 50.1%/52.7%/76.7%/72.5%/82.8%/89.2% for "intermediate" and 8.5%/10.1%/39.4%/25.8%/45.5%/62.1% for "minimal" care, respectively. The cost of a HLY gained as a % GDP/capita was 141.1%/110.0%/52.3%/41.8%/17.0%/15.6%, respectively. Marked reductions in complications rates and mortality are achievable with "intermediate" T1D care achieving mean clinic HbA1c of 8.5% to 9% (69-75 mmol/mol). This is also "very cost-effective" in four of six countries according to the WHO "Fair Choices" approach which costs HLYs gained against GDP/capita.

Older age of childhood type 1 diabetes onset is associated with islet autoantibody positivity >30 years later: the Pittsburgh Epidemiology of Diabetes Complications Study.

To examine the association between islet autoantibody positivity and clinical characteristics, residual β-cell function (C-peptide) and prevalence of complications in a childhood-onset (age <17 years), long-duration (≥32 years) type 1 diabetes cohort. Islet autoantibodies (glutamic acid decarboxylase, insulinoma-associated protein 2 and zinc transporter-8 antibodies) were measured in the serum of participants who attended the 2011-2013 Pittsburgh Epidemiology of Diabetes Complications study follow-up examination (n=177, mean age 51 years, diabetes duration 43 years). Prevalences of islet autoantibodies were: glutamic acid decarboxylase, 32%; insulinoma-associated protein 2, 22%; and zinc transporter-8, 4%. Positivity for each islet autoantibody was associated with older age at diabetes onset (glutamic acid decarboxylase antibodies, P=0.03; insulinoma-associated protein 2 antibodies, P=0.001; zinc transporter-8 antibodies, P<0.0001). Older age at onset was also associated with an increasing number of autoantibodies (P = 0.001). Glutamic acid decarboxylase antibody positivity was also associated with lower HbA1c (P = 0.02), insulinoma-associated protein 2 antibody positivity was associated with lower prevalence of severe hypoglycaemic episodes (P=0.02) and both distal and autonomic neuropathy (P=0.04 for both), and zinc transporter-8 antibody positivity was associated with higher total and LDL cholesterol (P=0.01). No association between autoantibody positivity and C-peptide was observed. The strong association between islet autoantibody positivity and older age at type 1 diabetes onset supports the hypothesis of a less aggressive, and thus more persistent, immune process in those with older age at onset. This observation suggests that there may be long-term persistence of heterogeneity in the underlying autoimmune process.

Mediation analysis for estimating cardioprotection of longitudinal RAS inhibition beyond lowering blood pressure and albuminuria in type 1 diabetes

PurposeWe assessed the extent of cardiovascular benefit of renin–angiotensin system (RAS) inhibition beyond lowering blood pressure (BP) and albuminuria in type 1 diabetes (T1D). MethodsThis cohort study included 605 T1D participants from the Pittsburgh Epidemiology of Diabetes Complications study without baseline coronary artery disease (CAD). Participant follow-up extended through 25 years. We implemented marginal structural models to estimate total effect of and controlled direct effect by isolating the role of BP or albuminuria in mediating the relation between RAS inhibitors and CAD. ResultsTotal effect of longitudinal RAS inhibition treatment was associated with 38% decreased CAD risk (HR [95% CI]: 0.62 [0.23, 1.77]). The controlled direct effect of RAS inhibition was a 27% risk reduction (HR: 0.73 [0.20, 2.59]) when isolating the role of BP and 26% risk reduction (HR: 0.74 [0.16, 3.35]) when isolating the role of albuminuria. The mediation proportion for each 10 mm Hg systolic BP and each 1 log unit of albumin excretion rate were 34% and 37%, respectively. ConclusionOur findings suggest that BP regulation and albuminuria reduction can only partially explain cardiovascular benefit of RAS inhibition on CAD in T1D, supporting the assertion that RAS inhibitors provide additional cardioprotection beyond lowering BP and albuminuria.

Periodontal disease, smoking, cardiovascular complications and mortality in type 1 diabetes

AimTo assess the role of periodontal disease (PD) as a predictor of coronary artery disease (CAD) and mortality in a prospective type 1 diabetes (T1D) cohort and to evaluate the role of smoking in this relationship. MethodsData were based on 320 participants of the Pittsburgh Epidemiology of Diabetes Complications study of T1D who, during 1992–94, received a partial mouth periodontal exam, and who were followed for up to 19 years to ascertain complication incidence. PD was defined as clinical attachment loss of ≥4 mm for at least 10% of the examined sites. Predictors of all-cause mortality; Hard CAD (CAD death, myocardial infarction or revascularization), and Total CAD (Hard CAD, angina, ischemic ECG) were assessed using Cox models. ResultsDuring 19 years of follow-up, 33.7% (97/288) developed CAD, 27.3% (83/304) developed Hard CAD, and 16.9% (54/320) died. Among current smokers, 46.4% (26/56) developed CAD, 42.7% (24/56) developed Hard CAD and 29.5% (18/61) died. PD was not associated with all-cause mortality, although it was a significant predictor of both CAD (HR = 1.12, CI = 1.01–1.23) and Hard CAD (HR = 1.30, CI = 1.11–1.51). As smoking modified the PD-CAD and PD-Hard CAD associations, analyses were stratified by smoking status. PD was associated with an increased risk of CAD (HR = 1.25, CI = 1.03–1.50) and Hard CAD (HR = 1.85, CI = 1.17–2.93) only among smokers. ConclusionPD was a significant predictor of CAD and Hard CAD among current smokers with T1D.

1691-P: A Variant in the Melanocortin-4 Receptor (MC4R) Locus Is Associated with Glycemic Control and Insulin Resistance (IR) in Type 1 Diabetes (T1D)

The MC4R gene (18q21.32) plays a role in regulating appetite and energy homeostasis and is consistently linked with obesity. A variant near MC4R (rs12970134) has also been associated with IR and type 2 diabetes, independent of BMI. We examined the association of rs12970134 with HbA1c, IR, and BMI in the Pittsburgh Epidemiology of Diabetes Complications study, a prospective T1D cohort (mean age 27, T1D duration 18 years at baseline, 1986-88). In 422 EDC participants of European ancestry with available DNA, we assessed associations between 16 published IR SNPs, including rs12970134, and longitudinal measures of HbA1c, estimated glucose disposal rate (eGDR, an inverse measure of IR), and BMI over 18 years of follow-up (1986-88 to 2004-06). General additive mixed models were adjusted for sex, T1D duration, and principal components of ancestry. The rs12970134 SNP was associated with longitudinal HbA1c (β=0.33, p=5x10-5, see Figure) and eGDR (β=-0.31, p=0.008) trajectories, but not BMI (β=0.21, p=0.38). The associations remained significant after adjusting for BMI and insulin dose. There was no evidence for a SNP x time interaction (p&amp;gt;0.25 for both); all groups showed a similar fall in HbA1c after publication of the DCCT results. Thus, the rs12970134 SNP near MC4R is associated with glycemic control and insulin resistance, despite no association with BMI, in this T1D cohort. Disclosure R.G. Miller: None. T. Costacou: None. S. Onengut-Gumuscu: None. W. Chen: None. S.S. Rich: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH. Funding National Institutes of Health; Rossi Memorial Fund; JDRF

428-P: Heart Failure (HF) and Its Risk Factors in Long-Duration Type 1 Diabetes (T1D)

To assess HF incidence in childhood onset, T1D, and its risk factors, we used 25 year follow-up data from the Epidemiology of Diabetes Complications Study (n=644, baseline age and T1D duration 27 and 19 years respectively). HF was determined by clinic exams, hospitalization, and/or self-reports. In a separate analysis, serum NT-proBNP (electrochemiluminescence immunoassay) was measured in the earliest available sample (n=572; HF diagnostic cutoff of 450 pg/mL). Hazard ratios (HR) per 1 s.d. increase in risk factor levels were estimated with Cox models. Forty-one (6.3%) HF cases (3 baseline prevalent and 38 incident) were identified during follow-up. The 5.9% (38/642) cumulative incidence of HF yielded an incidence density of 2.97/1000 person-years. In the overall population (and not including NT-proBNP), allowing for a wide range of potential baseline confounders (sex, T1D duration, smoke, BMI, hypertension, HbA1c, lipids, WBC, eGFR and albumin excretion), T1D duration (HR=1.7, p=0.003), ever smoking (HR=2.4, p=0.02) and non-HDLc (HR=1.4, p=0.04) were strongly associated with incident HF after backward elimination. In the sub analysis of 572 participants with NT-proBNP, 21 had values &amp;gt;450 pg/mL, 85.6% (18) of whom had end stage renal disease (ESRD) including 3 with concurrent HF. In those without ESRD at the time of NT-proBNP testing (n=551), NT-proBNP significantly predicted incident HF (32 clinically defined events, HR=1.7, p=0.03). Although in a backward elimination model (removal criterion: p≥ 0.2), allowing for other risk factors, NT-proBNP (HR=1.5, p=0.09) became marginal, it was retained in this final model along with T1D duration (HR=1.8, p=0.003), ever smoking (HR=2.6, p=0.01) and non-HDLc (HR=1.4, p=0.05). HF incidence in this long-duration T1D cohort is increased compared to the general population with similar age (e.g., incidence=0.97/1000 pyrs). Diabetes duration, smoking and non-HDLc are strong risk factors of HF; while in those without ESRD, NT-proBNP is a moderate predictor. Disclosure J. Guo: None. T. Costacou: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH. Funding National Institutes of Health

Abstract MP45: Cardiovascular Health in Early Adulthood Predicts the Development of Coronary Artery Disease: 25 Year Follow Up in Individuals With Type 1 Diabetes From the Pittsburgh Epidemiology of Diabetes Complications Study

Introduction: Coronary artery disease (CAD) is especially burdensome among individuals with type 1 diabetes (TID). The AHA created metrics to monitor cardiovascular health (CVH) to promote primordial prevention. CVH metrics define 3 health behaviors (diet, physical activity, and smoking), and 4 health factors (BMI, total cholesterol, blood pressure and fasting glucose) as ideal, intermediate or poor based on set criteria. These CVH metrics have been shown to be related to cardiovascular outcomes in the general population. The purpose of this research is to describe the prevalence of CVH metrics in young adults with T1D, a group at particularly high risk for CAD , and assess the hypothesis that more favorable metrics protect against future hard CAD outcomes. Methods: Data are from the longitudinal Pittsburgh Epidemiology of Diabetes Complications (EDC) study. CVH metrics are defined by an average of measures taken at first visit and first follow up visit (1986-1990, “baseline”) for participants age ≥20 at study entry without prevalent CAD. CVH metrics were scored according to AHA criteria, with HbA1c in place of fasting glucose. Total CVH score (possible range 0-14) is the sum of subscores for each metric where poor=0, intermediate=1 and ideal=2. Cox proportional hazards models were used to assess the association between baseline CVH and CAD incidence during 25 years of follow-up. Results: Characteristics of the 463 individuals analyzed after exclusions (179 age &lt;20 or prevalent CAD, 15 missing data) are shown in Table 1. No participants achieved ideal status for all 7 CVH metrics. Each unit increase in ideal CVH score was associated with 28% lower risk (95% CI: 0.63-0.82, p&lt;0.01), while each unit increase in total CVH score was associated with 23% lower risk of CAD (95% CI: 0.71-0.84, p&lt;0.01), adjusting for baseline diabetes duration, sex, race, albumin excretion rate, and triglycerides. Conclusions: CVH metric scores appear to be predictive of CAD in adults with T1D, demonstrating the value of promoting ideal CVH for CAD prevention.

Recent trends over time in vascular disease in type 1 diabetes: insights from the Pittsburgh Epidemiology of Diabetes Complications study.

To evaluate recent trends, by diagnosis year, in the cumulative incidence of vascular type 1 diabetes (T1D) complications and their risk factors up to 35 years duration. Participants from the Epidemiology of Diabetes Complications study of childhood-onset T1D were categorized into three calendar year onset cohorts: 1965-69, 1970-74, and 1975-80. All-cause, cardiovascular and renal mortality were determined both on the complete cohort (n=440) as well as in the subset with clinical examinations (n=363). Coronary artery disease (CAD, CAD death, myocardial infarction, revascularization, angina and ischemic ECG abnormalities); lower extremity arterial disease (LEAD, abnormal Ankle Brachial Index/amputation/intermittent claudication); distal symmetric polyneuropathy (DSP, clinical exam); cardiac autonomic neuropathy (CAN, abnormal heart rate response to deep breathing); overt nephropathy (ON, albumin excretion rate>200 μg/min) and proliferative retinopathy (PR, fundus photography) were assessed on the subset with clinical examinations. While all-cause, cardiovascular and renal mortality improved with a more recent diagnosis in the overall cohort, no univariate differences were observed for complications requiring examination (CAD, DSP, CAN, ON), although a borderline trend toward improved complication-free survival with a more recent onset was observed for PR (p=0.06). LEAD incidence showed an anomalous pattern, being highest in the 1975-80 and lowest in the 1970-74 cohort (p=0.009). Allowing for risk factors over time did not materially change these results. Despite declines in all-cause, cardiovascular and renal mortality in the total cohort, no improvements were observed in either mortality or complication incidence with a more recent onset in the examined cohort.