Epidemiology Of Diabetes Complications Research Articles

An Epigenome-Wide Association Study of DNA Methylation and Proliferative Retinopathy over 28 Years in Type 1 Diabetes

To perform a prospective epigenome-wide association study of DNA methylation (DNAm) and 28-year proliferative diabetic retinopathy (PDR) incidence in type 1 diabetes (T1D). Prospective observational cohort study. The Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset (< 17 years) T1D. Stereoscopic fundus photographs were taken in fields 1, 2, and 4 at baseline, 2, 4, 6, 8, 16, 23, and 28 years after DNAm measurements. The photos were graded using the modified Airlie House System. In those free of PDR at baseline (n=265; mean T1D duration of 18 years at baseline), whole blood DNAm (EPIC array) at 683 597 CpGs was analyzed in Cox models for time to event. Associations between significant CpGs and clinical risk factors were assessed; genetic variants associated with DNAm were identified (methylation quantitative trait loci [meQTLs]). Mendelian randomization was used to examine evidence of causal associations between DNAm and PDR. Post hoc regional and functional analyses were performed. Proliferative diabetic retinopathy was defined as the first instance of a grade of ≥ 60 in at least 1 eye or pan-retinal photocoagulation for PDR. Follow-up time was calculated from the study visit at which DNAm data were available (baseline) until PDR incidence or censoring (December 31, 2018 or last follow-up). PDR incidence was 53% over 28-years' follow-up. Greater DNAm of cg27512687 (KIF16B) was associated with reduced PDR incidence (P=6.3×10-9; false discovery rate [FDR]: < 0.01); 113 cis-meQTLs (P<5×10-8) were identified. Mendelianrandomization analysis using the sentinel meQTL as the instrumental variable supported a potentially causal association between cg27512687 and PDR. Cg27512687 was also associated with lower pulse rate and albumin excretion rate and higher estimated glomerular filtration rate, but its association with PDR remained independently significant after adjustment for those factors. In regional analyses, DNAm of FUT4, FKBP1A, and RIN2 was also associated with PDR incidence. DNA methylation of KIF16B, FUT4, FKBP1A, and RIN2 was associated with PDR incidence, supporting roles for epigenetic regulation of iron clearance, developmental pathways, and autophagy in PDR pathogenesis. Further study of those loci may provide insight into novel targets for interventions to prevent or delay PDR in T1D. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

DNA methylation and 28-year cardiovascular disease risk in type 1 diabetes: the Epidemiology of Diabetes Complications (EDC) cohort study

BackgroundThe potential for DNA methylation (DNAm) as an early marker for cardiovascular disease (CVD) and how such an association might differ by glycemic exposure has not been examined in type 1 diabetes, a population at increased CVD risk. We thus performed a prospective epigenome-wide association study of blood leukocyte DNAm (EPIC array) and time to CVD incidence over 28 years in a childhood-onset (< 17 years) type 1 diabetes cohort, the Pittsburgh Epidemiology of Diabetes Complications (EDC) study (n = 368 with DNA and no CVD at baseline), both overall and separately by glycemic exposure, as measured by HbA1c at baseline (split at the median: < 8.9% and ≥ 8.9%). We also assessed whether DNAm-CVD associations were independent of established cardiometabolic risk factors, including body mass index, estimated glucose disposal rate, cholesterol, triglycerides, blood pressure, pulse rate, albumin excretion rate, and estimated glomerular filtration rate.ResultsCVD (first instance of CVD death, myocardial infarction, coronary revascularization, ischemic ECG, angina, or stroke) developed in 172 participants (46.7%) over 28 years. Overall, in Cox regression models for time to CVD, none of the 683,597 CpGs examined reached significance at a false discovery rate (FDR) ≤ 0.05. In participants with HbA1c < 8.9% (n = 180), again none reached FDR ≤ 0.05, but three were associated at the a priori nominal significance level FDR ≤ 0.10: cg07147033 in MIB2, cg12324048 (intergenic, chromosome 3), and cg15883830 (intergenic, chromosome 1). In participants with HbA1c ≥ 8.9% (n = 188), two CpGs in loci involved in calcium channel activity were significantly associated with CVD (FDR ≤ 0.05): cg21823999 in GPM6A and cg23621817 in CHRNA9; four additional CpGs were nominally associated (FDR ≤ 0.10). In participants with HbA1c ≥ 8.9%, DNAm-CVD associations were only modestly attenuated after cardiometabolic risk factor adjustment, while attenuation was greater in those with HbA1c < 8.9%. No pathways were enriched in those with HbA1c < 8.9%, while pathways for calcium channel activity and integral component of synaptic membrane were significantly enriched in those with HbA1c ≥ 8.9%.ConclusionsThese results provide novel evidence that DNAm at loci involved in calcium channel activity and development may contribute to long-term CVD risk beyond known risk factors in type 1 diabetes, particularly in individuals with greater glycemic exposure, warranting further study.

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.

297-OR: TXNIP DNA Methylation (DNAme) and Long-Term HbA1c in Type 1 Diabetes (T1D)

DNAme is associated with past HbA1c in DCCT/EDIC but these associations were examined when there was separation in HbA1c distribution by trial intervention arm. Thus, we performed an epigenome-wide association study (EWAS) of DNAme and HbA1c in a T1D cohort without intervention or risk factor exclusion to identify loci with DNAme associated with concurrent and future HbA1c over 28 years. Whole blood DNAme was assayed via Illumina EPIC beadchip in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood onset (&amp;lt;17 years) T1D (n=411; mean age 29, T1D duration 21 yrs) . After quality control DNAme at 683,597 CpGs were analyzed. We performed cross-sectional EWAS with baseline HbA1c in linear models adjusted for T1D duration, sex, smoking pack-years, estimated blood cell composition, and batch covariates and longitudinal repeated measures analyses of HbA1c (2, 4, 6, 8, 16, 23, and 28 yrs post-baseline) . DNAme was significantly inversely associated with current HbA1c at two CpGs: cg19693031 (Chr 1, TXNIP locus, p=9.5x10-11) and cg21534330 (Chr 17, CSNK1D locus, p=3.3x10-10) . In GWAS, we further identified 34 methylation quantitative trait loci (meQTLs) in the SLC2A1 - SLC2A1-AS1 linkage-disequilibrium block (Chr 1: 43408279-43438299) associated with cg19693031 DNAme. All cg19693031 meQTLs identified were also reported as whole blood expression QTLs (eQTLs) in GTEx. For cg21534330, none of 15 trans meQTLs were eQTLs in GTEx. In repeated measures analysis, cg19693031 DNAme was consistently associated with lower average HbA1c over 28 years (-0.26 per 5% DNAme, p&amp;lt;0.0001, no time interaction) . DNAme at cg21534330 was not associated with HbA1c after baseline. Our results replicate prior findings that DNAme at cg19693031 in TXNIP relates to glycemic control in T1D and extend this association prospectively over 28 years. These findings strengthen the potential for interventions targeting TXNIP to improve glycemic control in T1D through its role in SLC2A1/GLUT1-mediated glucose regulation. Disclosure R.G.Miller: Stock/Shareholder; Becton, Dickinson and Company. J.Mychaleckyj: None. S.Onengut-gumuscu: None. T.J.Orchard: None. T.Costacou: None. Funding American Diabetes Association (1-19-JDF-109) ; NIH/NIDDK (R01-DK034818) , Rossi Memorial Fund

411-P: Potential to Utilize DNA Methylation as a Biomarker to Predict Major Coronary Artery Disease (CAD) Risk in Type 1 Diabetes (T1D)

DNA methylation (DNAme) has been associated with risk of future CAD in the general population and is a potential target for pharmacological intervention. In T1D, DNAme has been associated with microvascular complications but its association with CAD has not been examined in this high risk population. Thus, we performed an epigenome-wide association study (EWAS) of DNAme and 28-year major CAD (CAD death, nonfatal myocardial infarction) incidence in an observational T1D cohort. Whole blood DNAme was assayed via Illumina EPIC beadchip in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood onset (&amp;lt;17 years) T1D (n=400; mean age 29, T1D duration 21 yrs) . After quality control DNAme at 683,597 CpGs was analyzed in Cox models for time-to-CAD, adjusting for T1D duration, sex, smoking pack-years, estimated blood cell composition, and technical/batch covariates. Over 28 years 102 (25%) developed major CAD. DNAme at two CpGs was associated with lower CAD risk: cg06125996 (Chr 5, NLN; log HR per 5% DNAme= -1.10, p=6.0e-11) and cg051638 (Chr 9, CARD9; log HR= -0.97, p=1.2e-08) . Other associations with FDR&amp;lt;5% included CpGs in MRPS21, ZNF428, PCMTD1, and LYRM4. KEGG pathway analysis of all CpGs with FDR&amp;lt;10% (n=44) suggested enrichment for renin-angiotensin-aldosterone system, lipid metabolism, and immune system pathways. In GWAS we identified methylation quantitative trait loci (QTL) associated with DNAme at cg06125996 and cg05163804, three of which were annotated as expression QTLs in GTEx including SNPs in genes involved in insulin receptor signaling (SIK2) and cytokine activity (CMTM2, CMTM4) , and calcium ion binding (EFHB) . DNAme was not correlated with cross-sectional HbA1c at either CpG and adjusting for baseline HbA1c did not alter CpG-CAD associations. Our results demonstrate that DNAme may be an early marker of CAD risk in T1D, but the potential role of glycemic exposure in this association is unclear and warrants further study. Disclosure R.G.Miller: Stock/Shareholder; Becton, Dickinson and Company. J.Mychaleckyj: None. S.Onengut-gumuscu: None. T.J.Orchard: None. T.Costacou: None. Funding American Diabetes Association (1-19-JDF-109) ; NIH/NIDDK R01-DK034818, Rossi Memorial Fund

30-Year Cardiovascular Disease in Type 1 Diabetes: Risk and Risk Factors Differ by Long-term Patterns of Glycemic Control.

We hypothesized that there is heterogeneity in long-term patterns of glycemic control with respect to cardiovascular disease (CVD) development in type 1 diabetes and that risk factors for CVD differ by glycemic control pattern. Thus, we estimated associations between data-derived latent HbA1c trajectories and 30-year CVD risk in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset (<17 years old) type 1 diabetes. Participants (n = 536 with two or more HbA1c measurements [median 6] and CVD-free at baseline; mean age 27 and diabetes duration 18 years) were followed from 1986 to 1988 to 2016 to 2018 to ascertain CVD incidence (CVD death, myocardial infarction, stroke, coronary revascularization or blockage ≥50%, ischemic electrocardiogram, or angina). Latent HbA1c trajectories and their association with time-to-CVD incidence were simultaneously assessed using joint latent class mixed models. Two HbA1c trajectories with respect to differential CVD risk were identified: low (HbA1c ∼8% [64 mmol/mol] and improving over follow-up, 76% of cohort) and high (HbA1c ∼10% [86 mmol/mol] and stable, 24%). Overall, 30-year CVD incidence was 47.4% (n = 253); major adverse cardiovascular event incidence was 31.0% (n = 176). High HbA1c was associated with threefold increased CVD risk versus low HbA1c. Both groups had similar age and diabetes duration. Non-HDL cholesterol and estimated glomerular filtration rate were associated with CVD risk only in low HbA1c; albumin excretion rate was associated with CVD risk only in high HbA1c. These risk factor differences suggest that pathways to CVD may differ by glycemic control, potentially resulting in important implications for prognosis in type 1 diabetes.

Predictors of Change in Skin Intrinsic Fluorescence in Type 1 Diabetes: The Epidemiology of Diabetes Complications Study.

Skin intrinsic fluorescent (SIF) scores are indirect measures of advanced glycation end-products (AGEs). SIF scores are cross-sectionally associated with type 1 diabetes (T1D) complications such as increased albumin excretion rate (AER), coronary artery calcification (CAC) and neuropathy. We assessed predictors of SIF score change in those with T1D. Data from the 30-year longitudinal Epidemiology of Diabetes Complications (EDC) study of childhood-onset T1D were used to assess AGEs measured with a SIF score produced by the SCOUT DS® device. SIF scores were assessed twice in 83 participants: between 2007-08 and again between 2010-14. Regression analyses were used to assess independent predictors of SIF score change. At baseline, mean age was 47.9 ± 6.9 years, diabetes duration was 36.7 ± 6.4 years, and median glycosylated hemoglobin (HbA1c) was 7.1 (interquartile range: 6.5, 8.5). During a mean follow-up of 5.2 ± 0.9 years, mean change in SIF score was 2.9 ± 2.8 arbitrary units. In multivariable linear regression models, log HbA1c (P < 0.001), log estimated glomerular filtration rate (eGFR) (P < 0.001), overt nephropathy (defined as AER ≥ 200 µg/min, P = 0.06), and multiple daily insulin shots/pump use (MDI) exposure years (P = 0.02) were independent predictors of SIF score change. Increases in SIF score over 5 years were related to increased glycemic levels and decreased kidney function (eGFR). MDI and glomerular damage were related to a decreased SIF score. This is one of the first studies with repeated SIF assessments in T1D and provides unique, albeit preliminary, insight about these associations.

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.

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 female reproductive system's normal function, leading to delayed menarche and premature ovarian aging. We thus compared the length of the reproductive period of women with type 1 diabetes (T1D) to women without diabetes. Women with childhood-onset T1D (diagnosed in 1950-80) from the prospective Epidemiology of Diabetes Complications (EDC) study and nondiabetic women from the Pittsburgh site of the Study of Women's Health Across the Nation (SWAN) were studied. Exclusion criteria comprised not having reached natural menopause, hysterectomy/oophorectomy before menopause, and sex hormone therapy during the menopausal transition. Reproductive history was self-reported. The historical and Women's Ischemia Syndrome Evaluation hormonal algorithms were also used to assess menopause status. Women in the T1D cohort (n = 105) were younger, more likely to be White, never smokers, with lower BMI and higher high-density lipoprotein cholesterol levels (all P values < 0.05) compared with women without diabetes (n = 178). After covariate adjustment, T1D women were also older at menarche (0.5-y delay, P = 0.002) but younger at natural menopause (-2.0 y, P < 0.0001). Women with T1D thus experienced 2.5 fewer reproductive years compared to those without diabetes (P < 0.0001). These findings were restricted to the subgroup of women who were diagnosed with T1D before reaching menarche (n = 80). Women with T1D onset before menarche have a shorter reproductive period compared with nondiabetic women, exhibiting delayed menarche and earlier natural menopause. Factors that may be related to a shorter reproductive period in T1D should be investigated.

Insulin resistance-associated genetic variants in type 1 diabetes.

To examine candidate insulin resistance single nucleotide polymorphisms (SNPs) for associations with glycemic control, insulin resistance, BMI, and complications in an observational type 1 diabetes (T1D) cohort: the Pittsburgh Epidemiology of Diabetes Complications (EDC) study. In 422 European-ancestry participants, we assessed associations using additive models between 15 candidate SNPs and 25-year mortality, cardiovascular disease, microalbuminuria, overt nephropathy and proliferative retinopathy, and 25-year mean HbA1c, estimated glucose disposal rate (eGDR, inverse measure of insulin resistance), and BMI. The A allele of rs12970134 was associated with higher mean HbA1c (β = +0.34 ± 0.09, p = 0.00009) and nominally associated with worse eGDR (p = 0.02). Further analyses suggest the HbA1c association may be modified by diabetes therapy regimen: rs12970134 AA genotype was associated with higher HbA1c under non-intensive therapy conditions (<3 insulin injections/day or monitoring blood glucose<3 times/day [p = 0.004]), but not under intensive therapy (≥3 injections/day or insulin pump and monitoring glucose≥3 times/day [p = 0.71]). There were no significant associations between any SNPs and BMI or complications. rs12970134, near MC4R, is strongly associated with HbA1c in this cohort. Further exploration of this genomic region is warranted, as it may hold promise for discovering new therapeutic targets to improve glycemic control in T1D.

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.

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.

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

285-OR: Long-Term HbA1c Trajectories and Mortality and Major Atherosclerotic Cardiovascular Events (MACE) in Type 1 Diabetes (T1D)

While poor glycemic control is a well-established risk factor for mortality and MACE in T1D, specific patterns of control over time have not been well-studied. Thus, we sought to identify long-term trajectories of HbA1c and examine associated participant characteristics, mortality, and MACE incidence in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, a prospective observational cohort with childhood-onset (&amp;lt;17 years) T1D. These data were analyzed as part of a DNA methylation sub-study (currently in progress), where n=422 (baseline mean T1D duration 21 yrs, 53% male) have been followed for outcomes, including 28-year mortality and MACE. Beginning in 1988, HbA1c was measured at baseline, 2, 4, 6, 8, 15, and 22 yrs. HbA1c trajectories were identified using latent class growth modeling. Five HbA1c trajectories were identified (Figure). There were no significant differences in age, T1D duration, age at T1D onset, sex, education, or insulin dose between groups. Both mortality and MACE were significantly increased in IMPROVED (p&amp;lt;0.02) and even more so in HIGH (p&amp;lt;.0001) compared to LOW. MODERATE and WORSENED did not have increased risk of either outcome compared to LOW. These results demonstrate that, despite improvement, past high HbA1c remains associated with increased long-term mortality and MACE risk in this T1D cohort. Disclosure R.G. Miller: None. T. Costacou: None. T.J. Orchard: None. Funding American Diabetes Association (1-19-JDF-109 to R.G.M.)

4-OR: Diabetes Duration and the Relative Importance of Cardiovascular Risk Factors in Type 1 Diabetes

Based on a Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) report and their own findings, Pittsburgh Epidemiology of Diabetes Complications investigators concluded that the relative impact of HbA1c and kidney disease in type 1 diabetes (T1D) on cardiovascular disease (CVD) varies according to T1D duration. We investigate the relative importance of HbA1c and other CVD risk factors during ∼ 30 years of DCCT/EDIC follow-up within the primary (RET-: subjects with a mean T1D duration of 2.6 years and without retinopathy at baseline) and within the secondary DCCT cohort (RET+: subjects with a mean T1D duration of 8.6 years and with mild to moderate retinopathy at baseline). CVD included fatal/nonfatal myocardial infarction (MI) or stroke, silent MI, revascularization, confirmed angina, or congestive heart failure. Cox regression models with robust error variances were used to find the most significant CVD risk factors (p&amp;lt;0.05) within RET- and within RET+. The importance of risk factors was determined by evaluating the z value, a measure of association strength between risk factor and CVD. In case of hazard assumption violation, time by covariate interaction was included in model. DCCT enrolled 1441 subjects (age 13-39); 115 of 715 RET+ subjects and 69 of 726 RET- subjects had a CVD event. For RET+, the most important risk factors were baseline (B) age (z ∼4.2), time dependent (T) mean (M) systolic blood pressure (SBP) (z ∼4.0), any severe hypoglycemia (z ∼3.7), and TM HbA1c (z ∼3.2). Other significant risk factors included B autonomic neuropathy, TM insulin dose, TM LDL, T current (C) ACE inhibitor use, TC insulin regimen and B severity of retinopathy but not T1D duration. For RET-, B age, TM HbA1c, TC triglycerides and TM SBP with an increasing CVD effect over follow-up time were significant. The relative importance of CVD risk factors in a young T1D cohort varies according to microvascular complications, which correlate with T1D duration. Disclosure E.R. Fahrmann: None. H. Driscoll: None.

Risk factors differ by first manifestation of cardiovascular disease in type 1 diabetes

AimsWe compared risk factors for three CVD manifestations and a composite outcome over 25 years’ follow-up in the Pittsburgh Epidemiology of Diabetes Complications (EDC) prospective cohort study of childhood-onset (<17 years) type 1 diabetes (n = 658). MethodsFirst CVD manifestations examined were: (1) major atherosclerotic cardiovascular event (MACE, i.e. CVD death, myocardial infarction, stroke), (2) coronary revascularization, (3) soft coronary artery disease (CAD, i.e. ischemia ECG, angina), and a (4) composite (MACE + revascularization) outcome. Baseline and time-varying mean and current risk factors, including medication use, were assessed, in diabetes duration-adjusted models. ResultsMACE (n = 107) was predicted by ln(albumin excretion rate) (AER, HR = 1.3, p < 0.0001), systolic BP (SBP, HR = 1.03, p < 0.0001), white blood cell count (WBC, HR = 1.2, p < 0.0001), HbA1c (HR = 1.2p = 0.03), LDLc (HR = 1.01, p = 0.03). Soft CAD (n = 91) was predicted by ln(AER) (HR = 1.2, p = 0.004), SBP (HR = 1.03, p = 0.0002), WBC (HR = 1.2, p = 0.0003), HbA1c (HR = 1.2, p = 0.005). Revascularization (n = 38) was predicted by LDLc (HR = 1.03, p < 0.0001), eGFR (HR = 0.98, p = 0.002), HbA1c (HR = 1.3, p = 0.03). Adding revascularization to MACE enhanced the role of LDLc, while diminishing that of HbA1c, compared to MACE alone. ConclusionsImportant risk factor associations may be affected by examining composite CVD outcomes. More research is needed to determine how to best incorporate revascularization into composite CVD definitions.

Understanding Metabolic Memory: A Tale of Two Studies.

The results of the Diabetes Control and Complications Trial (DCCT) have given rise to much encouragement in the battle to stave off the complications of type 1 diabetes, showing dramatic declines in the development of severe retinopathy, nephropathy, and neuropathy in those treated intensively compared with conventional therapy. Particularly encouraging has been the continuing difference between the two groups despite both having similar HbA1c (∼8%) since the end of DCCT, when 96% of participants entered the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. This continuing relative benefit has been termed "metabolic memory," which implies altered metabolic regulation. Based on evidence from both the Epidemiology of Diabetes Complications (EDC) prospective cohort study of childhood-onset type 1 diabetes and DCCT/EDIC, we show that the metabolic memory effect can be largely explained by lower cumulative glycemic exposure in the intensive therapy group, and, on average, the development of complications increases with greater glycemic exposure, irrespective of whether this results from a high exposure for a short time or a lower exposure for a longer time. Thus, there is no need for a concept like "metabolic memory" to explain these observations. Potential mechanisms explaining the cumulative glycemic effect are also briefly discussed.

Optimal Blood Pressure Thresholds for Minimal Coronary Artery Disease Risk in Type 1 Diabetes.

We aimed to determine optimal blood pressure (BP) thresholds for minimizing coronary artery disease (CAD) risk in people with childhood-onset type 1 diabetes. The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study participants without known CAD at baseline (n = 605) were included and followed for 25 years. The associations of time-weighted BP measures (systolic BP [SBP], diastolic BP [DBP], and mean arterial pressure) with incident CAD were examined by using Cox models. Areas under the receiver operating characteristic curve (AUC) were summarized by different cut points of time-weighted BPs. Risk stratification analyses were then performed on the basis of BP (<120/80 vs. ≥120/80 mmHg) and HbA1c (<8% vs. ≥8%). Baseline mean age was 27 years. Half of the cohort were women and 98% were white. A dose-gradient association was observed for categorized time-weighted BPs and CAD. According to AUC, the optimal cut point for SBP was 120 mmHg and for DBP was 80 mmHg. BP ≥120/80 mmHg was associated with a 1.9 times (95% CI 1.4, 2.6) greater risk of developing CAD than that for BP <120/80 mmHg. Participants with good control of both BP and HbA1c had BP <120/80 mmHg and HbA1c <8%. Those with only high BP (hazard ratio [HR] 2.0 [95% CI 1.1, 3.9]) carried a similar risk of developing CAD as those with only high HbA1c (HR 1.6 [95% CI 0.97, 2.8]). The optimal BP threshold associated with minimal CAD risk is 120/80 mmHg in young adults with childhood-onset type 1 diabetes.

1536-P: Parametric Survival Analysis of Complications from Type 1 Diabetes

Aim: To develop novel models of the risk of fatal and non-fatal complications for individuals with type 1 diabetes (T1D). Models used two 30 years’ follow-up studies: Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) and Epidemiology of Diabetes Complications (EDC). Method: Models were developed for: Microalbuminuria, Macroalbuminuria, End-Stage Renal Disease, Impaired Glomerular Filtration Rate, Non-proliferative Diabetic Retinopathy, Proliferative Diabetic Retinopathy, Clinically Significant Macular Edema, Ketoacidosis, Hypoglycemia, Ulcers, Diabetic Peripheral Neuropathy, Amputations, Cardiovascular (CVD) Major Adverse Cardiac Event (MACE), CVD non-MACE, Death after CVD MACE, Death after CVD non-MACE, and Death with no history of CVD. Each model considered 44 risk factors, including demographics, time-varying clinical measures, and other T1D complications. Bivariate associations, followed by stepwise regression, were used for variable selection. Interval-censored Weibull and Gompertz survival models were chosen for non-fatal and fatal complications, respectively. Final models combined optimal statistical prediction and expert knowledge for model interpretability. Results: All models included age, gender, diabetes duration, and HbA1C, with HbA1c significantly increasing the risk of most complications. Across all models, the highest predictor of a complication was history of another complication(s). Blood pressure (e.g., systolic, diastolic), pulse rate, and lipid variables (e.g., triglycerides, LDL, HDL, total cholesterol) were significantly predictive of most complications. Cumulative hazard plots comparing predicted and actual hazards indicated good accuracy of prediction for all models. Conclusion: Our risk equations highlight the importance of accounting for the time-varying nature of many risk factors and the impact that history of diabetes complications has on a different complication. Disclosure C. Barbosa: None. N. Mack: None. G. Bobashev: None. G.A. King: None. Y. Liu: None. R. Hilscher: None. S. Neuwahl: None. T.J. Hoerger: Research Support; Self; Sanofi. Funding Centers for Disease Control and Prevention