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(1) To describe changes in arterial stiffness and heart rate variability (HRV) over a 5-year interval, (2) examine changes by sex and race–ethnicity, and (3) evaluate the risk factors associated with the longitudinal changes in arterial stiffness and HRV. Participants with youth-onset type 2 diabetes enrolled in the observational follow-up phase of the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial had arterial stiffness [(pulse wave velocity, augmentation index, brachial distensibility] and six indices of HRV measured 5 years apart. Multivariable linear regression models assessed risk factors associated with changes in the outcomes over time. At initial vascular assessment, the 304 participants were a mean age of 21 years, 34% male, and had a mean diabetes duration of 8 years. In more than half the cohort pulse wave velocity, augmentation index and HRV increased over 5 years (p

Aims/Introduction Cardiovascular autonomic neuropathy (CAN) is a predictor of cardiovascular disease and mortality. Cardiovascular reflex tests (CARTs) are the gold standard for the diagnosis of CAN, but might not be feasible in large research cohorts or in clinical care. We investigated whether measures of heart rate variability obtained from standard electrocardiogram (ECG) recordings provide a reliable measure of CAN. Materials and Methods Standardized CARTs (R‐R response to paced breathing, Valsalva, postural changes) and digitized 12‐lead resting ECGs were obtained concomitantly in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications participants (n = 311). Standard deviation of normally conducted R‐R intervals (SDNN) and the root mean square of successive differences between normal‐to‐normal R‐R intervals (rMSSD) were measured from ECG. Sensitivity, specificity, probability of correct classification and Kappa statistics evaluated the agreement between ECG‐derived CAN and CARTs‐defined CAN. Results Participants with CARTs‐defined CAN had significantly lower SDNN and rMSSD compared with those without CAN (P, Participants with cardiovascular reflex tests‐defined cardiovascular autonomic neuropathy (CAN) had significantly lower standard deviation of normally conducted R‐R intervals and root mean square of successive differences between normal‐to‐normal R‐R intervals compared to those without CAN (P

In type 2 diabetes, hyperuricemia is associated with cardiovascular disease (CVD) and the metabolic syndrome (MetS), but associations in type 1 diabetes (T1D) have not been well-defined. This study examined the relationships between serum urate (SU) concentrations, clinical and biochemical factors, and subsequent cardiovascular events in a well-characterized cohort of adults with T1D. In 973 participants with T1D in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC), associations were defined between SU, measured once in blood collected 1997–2000, and (a) concurrent MetS and (b) incident ‘any CVD’ and major adverse cardiovascular events (MACE) through 2013. SU was higher in men than women [mean (SD): 4.47 (0.99) vs. 3.39 (0.97) mg/dl, respectively, p Trial registration clinicaltrials.gov NCT00360815 and NCT00360893.

Summary Background With improved treatment, individuals with type 1 diabetes are living longer but there is limited information on the effects of type 1 diabetes on cognitive ability as they become older adults. We followed up individuals with type 1 diabetes to identify independent risk factors for cognitive decline as people age. Methods 1051 participants with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT) and its follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. Participants completed cognitive assessments at baseline (median age 27 years) and 2, 5, 18, and 32 years later (median age 59). HbA1c levels, frequency of severe hypoglycaemia, non-glycemic risk factors such as elevated blood pressure, and microvascular and macrovascular complications were assessed repeatedly. We examined the effects of these on measures of memory and psychomotor and mental efficiency. These studies are registered with clinicaltrials.gov , NCT00360815 (DCCT) and NCT00360893 (EDIC). Findings Over 32 years of follow-up, we found substantive declines in memory and psychomotor and mental efficiency. Between 18 and 32 years of follow-up, the decline in psychomotor and mental efficiency was five times larger than the change from baseline to year 18. Independent of the other risk factors and comorbidities, exposure to higher HbA1c levels, more episodes of severe hypoglycaemia, and elevated systolic blood pressure were associated with greater decrements in psychomotor and mental efficiency that was most notable by year 32 (p Interpretation Cognitive function declines with ageing in type 1 diabetes. The association of glycaemia and blood pressure levels with cognitive decline suggests that better management might preserve cognitive function. Funding United States National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease.

We determined the relationship between plasma kallikrein and cardiovascular disease (CVD) outcomes as well as major adverse cardiovascular events (MACE) in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) cohort of type 1 diabetes (T1D). Plasma kallikrein levels were measured longitudinally in 693 subjects at DCCT baseline (1983–1989), midpoint (1988–1991), and end (1993) and at EDIC years 4–6 (1997–1999), 8–10 (2001–2003), and 11–13 (2004–2006). Cox proportional hazards regression models assessed the association between plasma kallikrein levels and the risk of CVD. In unadjusted models, higher plasma kallikrein levels were associated with higher risk of any CVD during DCCT/EDIC (hazard ratio [HR] = 1.16 per 20 nmol/L higher levels of plasma kallikrein; P = 0.0177) as well as over the EDIC-only period (HR = 1.22; P = 0.0024). The association between plasma kallikrein levels and the risk of any CVD remained significant during the EDIC follow-up after adjustment for age and mean HbA1c (HR = 1.20; P = 0.0082) and in the fully adjusted model for other CVD risk factors (HR = 1.17; P = 0.0330). For MACE, higher plasma kallikrein levels were associated with higher risk in the unadjusted (HR = 1.25; P = 0.0145), minimally adjusted (HR = 1.23; P = 0.0417, and fully adjusted (HR = 1.27; P = 0.0328) models for EDIC only. These novel findings indicate that plasma kallikrein level associates with the risk of any CVD and MACE in T1D individuals.

OBJECTIVE This epidemiological analysis of the pooled Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort describes the equivalence of a 1-percentage point increase in HbA1c (such as from 7% to 8%) and years of additional age or duration of type 1 diabetes (T1D) relative to the risk of complications. RESEARCH DESIGN AND METHODS Separate Cox proportional hazards models determined the number of additional years of age and/or duration of T1D that would result in the same increase in risk of microvascular (retinopathy, nephropathy, and neuropathy) and cardiovascular complications and mortality as a 1-percentage point increase in HbA1c. RESULTS The risk of any cardiovascular disease associated with a 1-percentage point increase in HbA1c was equivalent to the risk associated with 4.3 (95% CI 2.7–5.9) additional years of age or 5.6 (95% CI 2.7–6.5) additional years’ duration of T1D. The risk of estimated glomerular filtration rate CONCLUSIONS Our results help evaluate the impact of glycemia on advanced complications in a way that may be more interpretable to health care providers and individuals with T1D.

OBJECTIVE To evaluate associations between diabetic peripheral neuropathy (DPN) and urological complications in men and women with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS Measurements of DPN at Epidemiology of Diabetes Intervention and Complications (EDIC) years 1, 14, and 17 and urological complications at EDIC year 17 were examined in 635 men (mean age 51.6 years, diabetes duration 29.5 years) and 371 women (mean age 50.6 years, diabetes duration 29.8 years) enrolled in the Diabetes Control and Complications Trial (DCCT)/EDIC study. DPN was defined by symptoms, signs, and abnormal electrophysiology or by abnormal Michigan Neuropathy Screening Instrument (MNSI) examination or questionnaire scores. RESULTS Erectile dysfunction (ED) in combination with lower urinary tract symptoms (LUTS) was reported in 15% of men and female sexual dysfunction (FSD), LUTS, and urinary incontinence (UI) in 16% of women. Adjusted for age, drinking status, BMI, depression, DCCT/EDIC time-weighted mean HbA1c, microalbuminuria, hypertension, triglycerides, and statin medication use, the odds of reporting ED and LUTS versus no ED or LUTS at EDIC year 17 were 3.52 (95% CI 1.69, 7.31) times greater in men with confirmed DPN at EDIC year 13/14 compared to men without confirmed DPN. Compared to men without DPN, men with DPN based on abnormal MNSI examination or questionnaire scores had significantly higher odds of reporting ED and LUTS versus no ED or LUTS at EDIC year 17. There were no significant differences in DPN between women reporting both FSD and LUTS/UI compared with those without FSD or LUTS/UI at EDIC year 17. CONCLUSIONS In long-standing T1D, DPN is associated with the later development of urological complications in men.

Aims Urinary incontinence (UI) in women is a dynamic condition with numerous risk factors yet most studies have focused on examining its prevalence at a single time. The objective of this study was to describe the long-term time course of UI in women with type 1 diabetes (T1D). Methods Longitudinal data in women with T1D were collected from 568 women in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the observational follow-up of the Diabetes Control and Complications Trial (DCCT) cohort. Over a 12-year period, participants annually responded to whether they had experienced UI in the past year. Results We identified four categories of UI in this population over time: 205 (36.1%) women never reported UI (no UI), 70 (12.3%) reported it one or two consecutive years only (isolated UI), 247 (43.5%) periodically changed status between UI and no UI (intermittent UI), and 46 (8.1%) reported UI continuously after the first report (persistent UI). Compared to women reporting no/isolated UI, women displaying the intermittent phenotype were significantly more likely to be obese (OR: 1.86, 95% CI 1.15, 3.00) and report prior hysterectomy (OR: 2.57, 95% CI: 1.39, 4.77); whereas women with persistent UI were significantly more likely to have abnormal autonomic function (OR: 2.36, 95% CI: 1.16-4.80). Conclusions UI is a dynamic condition in women with T1D. Varying risk factors observed for the different phenotypes of UI suggest distinctive pathophysiological mechanisms. These findings have the potential to be used to guide individualized interventions for UI in women with diabetes.

Background: The aim of this systematic review was to evaluate medical conditions and modifiable risk factors for myelodysplastic syndromes (MDS) using the 2001 or 2008 World Health Organization (WHO) diagnostic criteria. Methods: PubMed, MEDLINE, and Scopus databases were searched for studies published between January 2001 and August 2017. Study characteristics and findings were abstracted for each article. Results: Thirteen articles (4 cohort, 9 case–control) met the inclusion criteria. Smoking and alcohol use were each evaluated as potential MDS risk factors in four studies. Body mass index and anemia were each evaluated in two studies. Other potential risk factors evaluated in single studies included physical activity, dietary intake (tea, isoflavones, meat, fruit, or vegetables), history of allergies, autoimmune disorders and community-acquired infections, and use of antituberculosis drugs, traditional Chinese medicines, or hair dyes. Conclusions: Higher BMI, smoking, a history of autoimmune disorders, community-acquired infections, history of anemia, and use of antituberculosis drugs were associated with higher risk of MDS. Vigorous physical activity and tea and dietary isoflavone intake were associated with lower MDS risk. These findings suggest no association between the other factors and risk of MDS. Impact: Research on risk factors for MDS is limited, and further research in larger studies is needed.

OBJECTIVE The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study has demonstrated the major role of hyperglycemia as a risk factor for clinical cardiovascular outcomes in type 1 diabetes (T1D). We assessed whether and to what extent the effect of glycemia is mediated by other established cardiovascular disease (CVD) risk factors. RESEARCH DESIGN AND METHODS In the DCCT, 1,441 participants were randomized to receive either intensive or conventional diabetes therapy. The EDIC observational follow-up study enrolled 96% of the surviving DCCT cohort with 94% of the survivors still actively participating after more than 27 years of follow-up. Mediation of the effect of glycemia, as captured by HbA1c, on the subsequent CVD risk was quantified using the relative change in the CVD risk associated with HbA1c between models without and with the potential mediator. RESULTS Adjusted for age, only a few factors (e.g., pulse, triglycerides, albumin excretion rate) explained more than 10% of the effect of glycemia on CVD risk when considered individually. In multivariable models, these traditional risk factors together mediated up to ∼50% of the effect of glycemia on the risk of CVD. However, the association between HbA1c and the risk of CVD remained highly significant even after adjustment for these risk factors. CONCLUSIONS While HbA1c is associated with many traditional CVD risk factors, its association with these factors alone cannot explain its effects on risk of CVD. Consequently, aggressive management of traditional nonglycemic CVD risk factors, coupled with aggressive glycemic management, is indicated for individuals with type 1 diabetes.

OBJECTIVE To determine whether self-monitoring of blood glucose (SMBG) is associated with lower HbA1c in youth with type 2 diabetes taking oral medications only or after starting insulin for persistently elevated HbA1c. RESEARCH DESIGN AND METHODS Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study participants (n = 699) taking oral medications were asked to perform SMBG twice daily. After reaching primary outcome (PO) (HbA1c ≥8% [64 mmol/mol]) over 6 months or an inability to wean from temporary insulin because of metabolic decompensation), insulin glargine was started. HbA1c and percent of SMBG (SMBG%) (percent days when the meter was used one or more times) before and after PO were analyzed. RESULTS SMBG declined over time and was inversely related to HbA1c (P < 0.0001). Of 298 youth who reached PO and started insulin, 282 had SMBG data. At PO, mean ± SD age was 15.8 ± 2.3 years, BMI 35.5 ± 7.9 kg/m2, and HbA1c 9.6 ± 2.0% (81 ± 21.9 mmol/mol); 65.3% were female. Median SMBG% was 40% at PO, which increased to 49% after 6 months and fell to 41% after 1 year on insulin. At PO, 22% of youth checked ≥80% of days, which increased to 25% and fell to 19% after 6 and 12 months using insulin, respectively. At PO, compared with those who checked CONCLUSIONS Low SMBG adherence was common and associated with higher HbA1c. Optimal SMBG frequency in youth using or not using insulin, and whether less frequent SMBG is a marker for overall worse self-care, require further study.

OBJECTIVE The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study demonstrated the beneficial effects of intensive therapy on atherosclerosis and clinical cardiovascular disease (CVD) outcomes. The current analyses evaluated the relationship between longitudinal changes in insulin dose and CVD risk factors and outcomes. RESEARCH DESIGN AND METHODS A total of 1,441 participants were randomly assigned to intensive or conventional diabetes therapy during the DCCT. After an average of 6.5 years of follow-up, 96% of the surviving cohort enrolled in the EDIC observational study, which included annual visits with detailed medical history, physical examination, and laboratory testing. CVD events were adjudicated by a review committee. Generalized linear mixed models and Cox proportional hazards regression models were used to assess the association between insulin dose and cardiometabolic risk factors and CVD risk, respectively, over a total of 30 years. RESULTS Higher insulin doses were significantly associated with a less favorable cardiometabolic risk profile (higher BMI, pulse rate, and triglycerides and lower HDL cholesterol) with the exception of lower diastolic blood pressure and lower LDL cholesterol. In a minimally adjusted model, a 0.1 unit/kg body wt/day increase in insulin dose was associated with a 6% increased risk of any CVD (95% CI 3, 9). However, the association with insulin dose was no longer significant after adjustment for other CVD risk factors. CONCLUSIONS During DCCT/EDIC, higher insulin doses were associated with adverse trends in several cardiometabolic risk factors, even after multivariable adjustment, but not with incident CVD outcomes.

Little is known about how arterial stiffness and HRV progress in young adults with youth-onset T2D. We examined changes in pulse wave velocity (PWV), augmentation index (AIx), brachial distensibility and HRV over 5-years in young adults with T2D (n=304, 34% male, first assessment at mean age 21 years, mean diabetes duration 8 years) who participated in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) trial. Changes by sex, race/ethnicity, and the risk factors associated with the changes in arterial stiffness and HRV were assessed. PWV carotid-femoral, AIx and HRV worsened over 5-years (p Disclosure A. S. Shah: None. S. A. Arslanian: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk, Other Relationship; Self; AstraZeneca, Research Support; Self; Eli Lilly and Company, Novo Nordisk. E. M. Urbina: None. L. El ghormli: None. S. Gidding: None. K. S. Hughan: None. L. E. Katz: None. D. Koren: None. J. B. Tryggestad: None. F. Bacha: None. B. H. Braffett: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK61212, U01DK61230, U01DK61239, U01DK61242, U01DK61254)

Background: Young adults with diabetes face transitions in health care (provider, insurance, costs) and commonly have suboptimal glycemic control. We explored healthcare coverage and access to care and their associations with HbA1c, by diabetes type. Methods: In the SEARCH (T1D and T2D) and TODAY (T2D) studies, interviewer-administered surveys collected data on health care coverage at study visits (2017-2019). The associations between healthcare coverage or access and HbA1c were examined separately in T1D and T2D. Results: A total of 1374 participants, mean age 25 years, completed the survey. Mean HbA1c was similar in T1D and T2D for those with public insurance, but higher in T1D with no insurance. Having health insurance and a usual place for diabetes care were associated with lower HbA1c for T1D participants but not for those with T2D (Table). Participants from states with Medicaid eligibility expansion were more likely to have health insurance for T1D: 99% with vs. 91% without expansion; and T2D: 93% with vs. 75% without expansion. Conclusion: Having healthcare coverage and access was associated with better glycemic control for young adults with T1D, but not T2D. Medicaid eligibility expansion was associated with having health insurance. Examining how healthcare access factors affect self-care differently in T1D and T2D is essential. Disclosure C. Pihoker: None. J. Divers: None. P. Zhang: None. D. M. Nathan: None. K. Drews: None. D. Dabelea: None. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly and Company, Janssen Research & Development, LLC, Merck & Co., Inc. B. H. Braffett: None. T. Songer: Employee; Spouse/Partner; Boehringer Ingelheim Pharmaceuticals, Inc. W. H. Herman: Advisory Panel; Spouse/Partner; Rhythm Pharmaceuticals, Inc., Consultant; Self; RTI International, Other Relationship; Self; American Diabetes Association, American Diabetes Association, American Diabetes Association, International Diabetes Federation, Merck Sharp & Dohme Corp., National Committee for Quality Assurance, National Institute of Diabetes and Digestive and Kidney Diseases, Special Government Employee, Research Support; Spouse/Partner; Nestle. M. Tung: None. S. Kuo: None. A. Bellatorre: None. E. M. Isganaitis: None. E. T. Jensen: None.

Background: Onset of type 2 diabetes (T2D) in youth confers a high risk of early adverse cardiovascular outcomes. We describe the cumulative incidence of hypertension, LDL-cholesterol dyslipidemia, hypertriglyceridemia, and prevalence of smoking over time, and examine the relationships with body mass index and measures of glycemia, insulin sensitivity, and beta-cell function in an adolescent cohort with T2D enrolled in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. Methods: Longitudinal data from the TODAY clinical trial and TODAY2 observational follow-up study were used to evaluate the relationships between hypertension, LDL-C dyslipidemia, hypertriglyceridemia, and smoking with risk factors using time-to-event models and generalized estimating equation models. Findings: Data were available on 677 participants. Mean age at baseline was 14±2 years and mean follow-up 10·2±4·5 years. The 14-year cumulative incidence of hypertension, LDL-C dyslipidemia, and hypertriglyceridemia was 59%, 33%, and 37% respectively, and the average prevalence of reported smoking was 23%. Male sex, non-Hispanic white race/ethnicity, obesity, poor glycemic control, lower insulin sensitivity, and reduced beta-cell function were significantly associated with an unfavorable cardiovascular risk profile. After an average of 10·2 years of follow-up, 54% of the cohort had ≥2 cardiovascular risk factors in addition to T2D. Interpretation: Cardiovascular risk factor incidence and prevalence was high over a decade of follow-up in young adults with youth-onset T2D. Addressing glucose control and insulin sensitivity, as well as medical management of cardiovascular risk factors will be critical in youth with T2D for prevention of cardiovascular morbidity and mortality. Trial Registration: Clinicaltrials.gov NCT00081328. Funding: United States National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease. Declaration of Interest: None of the authors reported a conflict of interest. Ethical Approval: The TODAY and TODAY2 studies were approved by institutional review boards at all 15 centers and all participants and guardians provided written informed assent and/or consent as appropriate for age.

OBJECTIVE During the Diabetes Control and Complications Trial (DCCT), intensive diabetes therapy achieving a mean HbA1c of ∼7% was associated with a threefold increase in the rate of severe hypoglycemia (defined as requiring assistance) compared with conventional diabetes therapy with a mean HbA1c of 9% (61.2 vs. 18.7 per 100 patient-years). After ∼30 years of follow-up, we investigated the rates of severe hypoglycemia in the DCCT/Epidemiology of Diabetes Inverventions and Complications (EDIC) cohort. RESEARCH DESIGN AND METHODS Rates of severe hypoglycemia were reported quarterly during DCCT and annually during EDIC (i.e., patient recall of episodes in the preceding 3 months). Risk factors influencing the rate of severe hypoglycemia over time were investigated. RESULTS One-half of the DCCT/EDIC cohort reported episodes of severe hypoglycemia. During EDIC, rates of severe hypoglycemia fell in the former DCCT intensive treatment group but rose in the former conventional treatment group, resulting in similar rates (36.6 vs. 40.8 episodes per 100 patient-years, respectively) with a relative risk of 1.12 (95% CI 0.91–1.37). A preceding episode of severe hypoglycemia was the most powerful predictor of subsequent episodes. Entry into the DCCT study as an adolescent was associated with an increased risk of severe hypoglycemia, whereas insulin pump use was associated with a lower risk. Severe hypoglycemia rates increased with lower HbA1c similarly among participants in both treatment groups. CONCLUSIONS Rates of severe hypoglycemia have equilibrated over time between the two DCCT/EDIC treatment groups in association with advancing duration of diabetes and similar HbA1c levels. Severe hypoglycemia persists and remains a challenge for patients with type 1 diabetes across their life span.

OBJECTIVE Individuals with diabetes have higher resting heart rate compared with those without, which may be predictive of long-term cardiovascular disease (CVD) risk. Using data from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, we evaluated whether the beneficial effect of intensive versus conventional diabetes therapy on heart rate persisted, the factors mediating the differences in heart rate between treatment groups, and the effects of heart rate on future CVD risk. RESEARCH DESIGN AND METHODS Longitudinal changes in heart rate, from annual electrocardiograms over 22 years of EDIC follow-up, were evaluated in 1,402 participants with type 1 diabetes. Linear mixed models were used to assess the effect of DCCT treatment group on mean heart rate over time, and Cox proportional hazards models were used to estimate the effect of heart rate on CVD risk during DCCT/EDIC. RESULTS At DCCT closeout, 52% of participants were male and mean ± SD age was 33 ± 7 years, diabetes duration 12 ± 5 years, and HbA1c 7.4 ± 1.2% (intensive) and 9.1 ± 1.6% (conventional). Through EDIC, participants in the intensive group had significantly lower heart rate in comparison with the conventional group. While significant group differences in heart rate were fully attenuated by DCCT/EDIC mean HbA1c, higher heart rate predicted CVD and major adverse cardiovascular events independent of other risk factors. CONCLUSIONS After 22 years of follow-up, former intensive versus conventional therapy remained significantly associated with lower heart rate, consistent with the long-term beneficial effects of intensive therapy on CVD. DCCT treatment group effects on heart rate were explained by differences in DCCT/EDIC mean HbA1c.

OBJECTIVE The role of genetic factors in the risk of cardiovascular disease (CVD) for patients with type 1 diabetes (T1D) remains unknown. We therefore examined whether previously identified genetic factors for coronary artery disease (CAD) are associated with the risk of CVD above and beyond established demographic and clinical factors in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. RESEARCH DESIGN AND METHODS Polygenic risk scores (PRS) and individual genetic variants identified in previous studies were obtained from genome-wide genotyping performed in 1,371 DCCT/EDIC participants. Two composite CVD outcomes were considered: major adverse cardiovascular events (MACE) (CVD death or nonfatal myocardial infarction [MI] or stroke) and any CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure). Cox proportional hazards models assessed the association between the genetic factors and the risk of CVD with adjustment for other factors (including age, lipids, blood pressure, and glycemia). RESULTS CAD PRS was strongly associated with the subsequent risk of any CVD (42% and 38% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; P < 0.0001) and with the risk of MACE (50% and 40% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; P < 0.0001). Several individual single nucleotide polymorphisms were also nominally associated with the risk of any CVD and MACE. CONCLUSIONS Genetic factors are associated with the risk of subsequent CVD in individuals with T1D above and beyond the effect of established risk factors such as age, lipids, blood pressure, and glycemia.

Background: Heart failure is a prominent complication of type 2 diabetes mellitus (T2D). The goal of this study was to provide longitudinal data on cardiac structure and function (and cross-sectional comparison to normal-weight and obese controls without T2D) in individuals followed from adolescence with youth-onset T2D. Methods: In the TODAY study (Treatment Options for Type 2 Diabetes Mellitus in Adolescents and Youth), echocardiograms were performed at study years 4 to 5 and 9 to 10. Echocardiograms were also obtained at years 8 to 9 in a control population of age, race/ethnicity, and sex-matched normal-weight and obese individuals without diabetes mellitus. Study outcomes were measures of left ventricular structure and function. The cohort included 411 participants with T2D, 194 obese controls, and 51 normal-weight controls. Results: At follow-up, mean participant age was 23 years, 65% women, 20% non-Hispanic white, 35% non-Hispanic black, and 39% Hispanic. Ejection fraction was P P Conclusions: Adverse changes in cardiac structure and function changed significantly from adolescence to early adulthood in participants with youth-onset T2D. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00081328.

Type 1 diabetes (T1D) is associated with lower bone mineral density (BMD) and elevated fracture risk. In this study, we examined risk factors for lower BMD in the DCCT/EDIC study, a well-characterized cohort of older adults with T1D. Dual x-ray absorptiometry (DXA) scans were obtained in 1,058 study participants who had been followed for > 30 years. Cumulative glycemic control was defined as the time-weighted mean HbA1c from DCCT baseline (1983-1989) to the DXA visit. Levels of advanced glycation endproducts (AGE) were assessed by skin intrinsic fluorescence (SIF) in 2010-2011. Kidney disease (sustained eGFR Mean age at DXA was 59±7 years; 48% of participants were female. Mean BMD for total hip and femoral neck was 0.921±0.149 and 0.757±0.129 g/cm2, respectively; 6% were osteoporotic, and 45% were osteopenic. Higher mean HbA1c, higher SIF, and kidney disease, but not retinopathy or neuropathy, were independently associated with lower BMD at the total hip in univariate and multivariable analyses, with similar results for femoral neck (Table). In conclusion, poorer glycemic control, AGE accumulation, and kidney disease are independent risk factors for lower hip BMD in older adults with T1D. Disclosure A.V. Schwartz: None. J.C. Backlund: None. I. deBoer: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Consultant; Self; George Clinical, Goldfinch Bio, Ironwood Pharmaceuticals. M. Rubin: Research Support; Self; Amgen, Ascendis Pharma, Takeda Pharmaceutical Company Limited. A.R. Barnie: None. K. Farrell: Stock/Shareholder; Spouse/Partner; Dexcom, Inc., Tandem Diabetes Care. V.R. Trapani: None. N.S. Gregory: None. A. Wallia: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc., UnitedHealth Group. J.M. Lachin: Board Member; Self; Tolerion, Inc. B.H. Braffett: None. R. Gubitosi-Klug: None. Funding National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Disease (5U01DK094157, RES514948)

DCCT/EDIC participants have been followed for an average of 32 years (N=1,054; mean age 60±7 years; duration T1DM 38±5 years). To evaluate cognitive function in T1DM, mental efficiency and memory were assessed five times during the study. Standardized z-scores were calculated relative to the DCCT baseline evaluation and averaged to obtain three summary domain scores (immediate recall, delayed recall, mental efficiency). Generalized linear mixed models were used. In 2018, mean HbA1c levels were 7.9±0.9% and 46% of participants had experienced ≥1 hypoglycemic coma/seizure. Adjusted for age, sex, and education, cognition declined over time (p Disclosure A.M. Jacobson: None. C.M. Ryan: None. B.H. Braffett: None. R. Gubitosi-Klug: None. G.M. Lorenzi: None. J.A. Luchsinger: Consultant; Self; vTv Therapeutics. V.R. Trapani: None. I. Bebu: None. N. Chaytor: Consultant; Self; Eli Lilly and Company. S.M. Hitt: None. K. Farrell: Stock/Shareholder; Spouse/Partner; Dexcom, Inc., Tandem Diabetes Care. J.M. Lachin: Board Member; Self; Tolerion, Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases

In this study, we sought to determine the burden and characteristics of orgasmic dysfunction (OD) and concomitant erectile dysfunction (ED) in men with type 1 diabetes (T1D) enrolled in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. In 2010, we assessed orgasmic and erectile function using the International Index of Erectile Function (IIEF). Sociodemographic, clinical, and diabetes characteristics were compared by OD status (OD only, OD and ED, no ED or OD). Age-adjusted associations between risk factors and OD status were examined. OD and ED information was available from 563 men. Eighty-three men (14.7%) reported OD of whom 21 reported OD only and 62 reported OD and ED. Age-adjusted odds ratios demonstrated that men who reported OD only had higher odds of depression, low sexual desire, and decreased alcohol use compared with men reporting no dysfunction. Men with OD concomitant with ED had greater odds of elevated hemoglobin A1C, peripheral and autonomic neuropathy, and nephropathy. Men reporting both dysfunctions were also more likely to report smoking, lower urinary tract symptoms, and had greater odds of androgen deficiency than men with no sexual dysfunction. Men with longstanding T1D suffer from an increased burden of OD. Psychogenic factors predominate in men reporting OD only while men who present with concomitant ED report increased burden of diabetes severity, characteristics previously observed with incident ED. ED may be the central impediment to sexual function in men with OD and ED. Longitudinal studies to characterize OD and ED experience over time are warranted.

BACKGROUND: The Treatment Options for type 2 Diabetes in Adolescent and Youth study, a randomized clinical trial of three treatments for type 2 diabetes (T2DM) in youth, demonstrated treatment failure (defined as sustained HbA1c ≥8%, or inability to wean insulin after 3 months after acute metabolic decomposition) in over half of the participants. Given that binding of mononuclear cells to vascular endothelium, initiated by cellular adhesion molecules and chemokines, is an early step in vascular injury, we sought to evaluate (a) changes in cellular adhesion molecule levels during the trial; (b) effect of diabetes treatment; and (c) association of markers with HbA1c, hypertension, hypercholesterolemia, nephropathy, and retinopathy. METHODS: Participants (n = 515 of 699) that had baseline assessment of adhesion molecules (monocyte chemoattractant protein-1 [MCP-1], vascular cell adhesion marker [VCAM], intercellular adhesion marker [ICAM], and E-Selectin) and at least one other assessment, measured at month 12, 24, or 36, were included. RESULTS: Over 1 to 3 years, significant increases in MCP-1 and decreases in VCAM (both P < .0001) concentrations were found; however, no significant interactions were identified with treatment group for any molecule. For every 1% increase in HbA1c, ICAM increased by 1.8%, VCAM by 1.5%, and E-selectin by 6.8% (all P < .0001). E-selectin increased by 3.7% and 4.2% for every 10 mm Hg increase in systolic and diastolic blood pressure, respectively (both P < .0001). ICAM was 10.2% higher and E-selectin was 15.5% higher in participants with microalbuminuria (both P < .01). There was no significant association of adhesion molecule levels with retinopathy. CONCLUSION: Concentrations of cellular adhesion molecules rise with increasing HbA1c in youth with T2DM, and are associated with blood pressure and microalbuminuria, markers of vascular injury.

OBJECTIVE Type 1 diabetes has been associated with high rates of urinary and sexual problems, but the cumulative burden and overlap of these complications are unknown. We sought to determine prevalence of urological complications in persons with type 1 diabetes, associations with clinical and diabetes-related factors, and rates of emergence, persistence, and remission. RESEARCH DESIGN AND METHODS This ancillary longitudinal study among participants in the Diabetes Control and Complications Trial (DCCT) and observational follow-up study Epidemiology of Diabetes Interventions and Complications (EDIC) (652 women and 713 men) was conducted in 2003 and 2010/2011. Urinary incontinence (UI), lower urinary tract symptoms, urinary tract infection, female sexual dysfunction, erectile dysfunction, low male sexual desire, and orgasmic dysfunction were measured with validated instruments. Logistic regression determined association of complications with demographics and clinical characteristics. RESULTS Of sexually active women completing the 2010/2011 survey, 35% reported no complications, 39% had one, 19% two, 5% three, and 2% four. In men, 31% had no complications, 36% had one, 22% two, 9% three, and 3% four. Sexual dysfunction was most prevalent (42% women and 45% men) followed by UI in women (31%) and low sexual desire in men (40%). Urological complications were associated with age, BMI, and HbA1c. Remission rates ranged from 4 to 12% over the 7-year interval between surveys. CONCLUSIONS Urological complications are prevalent and frequently co-occur in persons with type 1 diabetes. Remission rates in a minority subset indicate a rationale for future studies to mitigate the onset or impact of urological complications of diabetes.

OBJECTIVE Intensive treatment (INT) of type 1 diabetes reduces the incidence of cardiovascular disease (CVD) events compared with conventional treatment (CONV), but it also results in more weight gain. Our objective was to examine whether excessive weight gain from INT of type 1 diabetes is independently associated with subsequent CVD events. RESEARCH DESIGN AND METHODS Quartiles (Q) of weight gain in 1,213 participants aged 18 years and older at enrollment in the Diabetes Control and Complications Trial (DCCT) were determined within randomized treatment groups (INT vs. CONV) using change in BMI from baseline to the closeout DCCT visits. Effects of this weight gain on CVD risk factors and outcomes during an additional 20 years of observational follow-up were then determined. RESULTS The Q4 INT group experienced greater proportional weight gain (median change in BMI, 6.08 kg/m2), increases in CVD risk factors, and need for medications for hypertension and lipids compared with the Q1–3 INT and comparable CONV groups. Over a mean of 26 years of follow-up, the numbers of major and total CVD events were not statistically different in Q4 compared with Q1–3 of either the INT or CONV group. By year 14, however, the incident CVD event curve became significantly higher in the Q4 INT group than in the Q1–3 INT groups (P = 0.024) and was similar to that for the CONV group. CONCLUSIONS For the first 13 years after DCCT, INT for type 1 diabetes reduced macrovascular events compared with CONV, even when excessive weight gain occurred. After this, total CVD events significantly increased in the Q4 INT group, becoming equivalent to those in the CONV group. Longer follow-up is needed to determine whether this trend continues and results in more major CVD events.

Reproductive age may be a risk factor for vascular disease. Anti-Mullerian hormone (AMH) is produced by viable ovarian follicles and reflects reproductive age. We examined whether AMH concentrations were associated with markers of subclinical cardiovascular disease (CVD) and kidney disease among women with type 1 diabetes. We performed a cross-sectional analysis of the Epidemiology of Diabetes Interventions and Complications Study. Participants included women with type 1 diabetes and ≥1 AMH measurement (n = 390). In multivariable regression models which adjusted for repeated measures, we examined the associations between AMH with CVD risk factors, estimated glomerular filtration rate, and albumin excretion ratio. We also examined whether initial AMH concentrations were associated with the presence of any coronary artery calcification (CAC) or carotid intima media thickness (cIMT). After adjustment for age, AMH was not associated with waist circumference, blood pressure, lipid profiles, or renal function. Higher initial AMH concentrations had borderline but non-significant associations with the presence of CAC after adjustment for age (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.00, 1.16) which were minimally altered by addition of other CVD risk factors, although women in the 3rd quartile of AMH had lower odds of CAC than women in the lowest quartile (OR 0.40, 95% CI 0.17, 0.94). After adjustment for age, higher AMH was associated with statistically significant but only slightly higher cIMT (0.005 mm, p = 0.0087) which was minimally altered by addition of other CVD risk factors. Among midlife women with type 1 diabetes, AMH has slight but significant associations with subclinical measures of atherosclerosis. Future studies should examine whether these associations are clinically significant. NCT00360815 and NCT00360893 Study Start Date April 1994.

OBJECTIVE During the Diabetes Control and Complications Trial (DCCT), intensive diabetes therapy achieving a mean HbA1c of ∼7% was associated with a threefold increase in the rate of severe hypoglycemia (defined as requiring assistance) compared with conventional diabetes therapy with a mean HbA1c of 9% (61.2 vs. 18.7 per 100 patient-years). After ∼30 years of follow-up, we investigated the rates of severe hypoglycemia in the DCCT/Epidemiology of Diabetes Inverventions and Complications (EDIC) cohort. RESEARCH DESIGN AND METHODS Rates of severe hypoglycemia were reported quarterly during DCCT and annually during EDIC (i.e., patient recall of episodes in the preceding 3 months). Risk factors influencing the rate of severe hypoglycemia over time were investigated. RESULTS One-half of the DCCT/EDIC cohort reported episodes of severe hypoglycemia. During EDIC, rates of severe hypoglycemia fell in the former DCCT intensive treatment group but rose in the former conventional treatment group, resulting in similar rates (40.8 vs. 36.6 episodes per 100 patient-years, respectively) with a relative risk of 1.12 (95% CI 0.91–1.37). A preceding episode of severe hypoglycemia was the most powerful predictor of subsequent episodes. Entry into the DCCT study as an adolescent was associated with an increased risk of severe hypoglycemia, whereas insulin pump use was associated with a lower risk. Severe hypoglycemia rates increased with lower HbA1c similarly among participants in both treatment groups. CONCLUSIONS Rates of severe hypoglycemia have equilibrated over time between the two DCCT/EDIC treatment groups in association with advancing duration of diabetes and similar HbA1c levels. Severe hypoglycemia persists and remains a challenge for patients with type 1 diabetes across their life span.

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

OBJECTIVE The Diabetes Control and Complications Trial (DCCT) and its observational follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) demonstrated the dominant role of glycemia, second only to age, as a risk factor for a first cardiovascular event in type 1 diabetes (T1D). We now investigate the association between established risk factors and the total cardiovascular disease (CVD) burden, including subsequent (i.e., recurrent) events. RESEARCH DESIGN AND METHODS CVD events in the 1,441 DCCT/EDIC participants were analyzed separately by type (CVD death, acute myocardial infarction [MI], stroke, silent MI, angina, percutaneous transluminal coronary angioplasty/coronary artery bypass graft [PTCA/CABG], and congestive heart failure [CHF]) or as composite outcomes (CVD or major adverse cardiovascular events [MACE]). Proportional rate models and conditional models assessed associations between risk factors and CVD outcomes. RESULTS Over a median follow-up of 29 years, 239 participants had 421 CVD events, and 120 individuals had 149 MACE. Age was the strongest risk factor for acute MI, silent MI, stroke, and PTCA/CABG, while glycemia was the strongest risk factor for CVD death, CHF, and angina, second strongest for acute MI and PTCA/CABG, third strongest for stroke, and not associated with silent MI. HbA1c was the strongest modifiable risk factor for a first CVD event (CVD: HR 1.38 [95% CI 1.21, 1.56] per 1% higher HbA1c; MACE: HR 1.54 [1.30, 1.82]) and also for subsequent CVD events (CVD: incidence ratio [IR] 1.28 [95% CI 1.09, 1.51]; MACE: IR 1.89 [1.36, 2.61]). CONCLUSIONS Intensive glycemic management is recommended to lower the risk of initial CVD events in T1D. After a first event, optimal glycemic control may reduce the risk of recurrent CVD events and should be maintained.

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study demonstrated that intensive glucose control reduced the risk of developing diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN). We evaluated multiple risk factors and phenotypes associated with DPN and CAN in this large, well-characterized cohort of participants with type 1 diabetes, followed for >23 years. DPN was defined by symptoms, signs, and nerve conduction study abnormalities in ≥2 nerves; CAN was assessed using standardized cardiovascular reflex tests. Generalized estimating equation models assessed the association of DPN and CAN with individual risk factors measured repeatedly. During DCCT/EDIC, 33% of participants developed DPN and 44% CAN. Higher mean HbA1c was the most significant risk factor for DPN, followed by older age, longer duration, greater height, macroalbuminuria, higher mean pulse rate, β-blocker use, and sustained albuminuria. The most significant risk factor for CAN was older age, followed by higher mean HbA1c, sustained albuminuria, longer duration of type 1 diabetes, higher mean pulse rate, higher mean systolic blood pressure, β-blocker use, estimated glomerular filtration rate

Objective: Studies have demonstrated that glycated hemoglobin (HbA1c) is a significant predictor of hearing impairment in type 1 diabetes. We identified additional factors associated with hearing impairment in participants with type 1 diabetes from the Diabetes Control and Complications Trial and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Methods: A total of 1,150 DCCT/EDIC participants were recruited for the Hearing Study. A medical history, physical measurements, and a self-administered hearing questionnaire were obtained. Audiometry was performed by study-certified personnel and assessed centrally. Logistic regression models assessed the association of risk factors and comorbidities with speech- and high-frequency hearing impairment. Results: Mean age was 55 ± 7 years, duration of diabetes 34 ± 5 years, and DCCT/EDIC HbA1c 7.9 ± 0.9% (63 mmol/mol). In multivariable models, higher odds of speech-frequency impairment were significantly associated with older age, higher HbA1c, history of noise exposure, male sex, and higher triglycerides. Higher odds of high-frequency impairment were associated with older age, male sex, history of noise exposure, higher skin intrinsic florescence (SIF) as a marker of tissue glycation, higher HbA1c, nonprofessional/nontechnical occupations, sedentary activity, and lower low-density-lipoprotein cholesterol. Among participants who previously completed computed tomography and carotid ultrasonography, coronary artery calcification (CAC) >0 and carotid intima-medial thickness were significantly associated with high-but not speech-frequency impairment. Conclusion: Consistent with previous reports, male sex, age, several metabolic factors, and noise exposure are independently associated with hearing impairment. The association with SIF further emphasizes the importance of glycemia-as a modifiable risk factor-over time. In addition, the macrovascular contribution of CAC is novel and important. Abbreviations: AER = albumin excretion rate; CAC = coronary artery calcification; CVD = cardiovascular disease; DCCT/EDIC = Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications; eGFR = estimated glomerular filtration rate; ETDRS = Early Treatment Diabetic Retinopathy Study; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; IMT = intima-media thickness; LDL = low-density lipoprotein; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio; SIF = skin intrinsic fluorescence; T1D = type 1 diabetes.

Snaith et al. (1) suggest that the relationship between insulin dose and adverse cardiometabolic profile might be mediated by insulin resistance and cite data linking clamp-derived measurement of insulin resistance and coronary artery calcification (2). We do not have any direct assessment of insulin resistance in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study; however, the association among weight gain, insulin resistance, and adverse …

Atherosclerosis begins in childhood, accelerating in those with obesity, hypertension and type 2 diabetes (T2DM). Binding of mononuclear cells to vascular endothelium, initiated by cellular adhesion molecules and chemokines, is an early step in this process. The TODAY study, a clinical trial of adolescents with T2DM, included three treatment arms. The primary end-point was treatment failure defined as A1c persistently >=8% over 6 months period or metabolic decompensation. The aims of the present analysis are to evaluate: 1) changes in ICAM, VCAM, E-Selectin and MCP-1 over time 2) whether treatment group influences levels of these biomarkers and 3) the association of these markers with macrovascular and microvascular outcomes. Participants from the TODAY cohort (n=515) with at least two of the four annual assessments of adhesion molecules at baseline, 12, 24, 36 months were included. Over the study period, there were significant increases in ICAM (p=0.002) and MCP-1 (p Disclosure J.B. Tryggestad: None. R. Shah: None. B. Braffett: None. F. Bacha: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, Pediatric Diabetes Consortium. Other Relationship; Self; AstraZeneca, Jaeb Center for Health Research. S. Gidding: Research Support; Self; Color Genomics. R. Gubitosi-Klug: None. E.M. Urbina: None. L.E. Katz: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study reported that intensive glucose control as assessed by hemoglobin A1c (HbA1c) reduced the risk of diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) in type 1 diabetes (T1D), with long lasting benefits. We evaluated additional clinical parameters and risk factors that could contribute to the development of DPN and CAN in this cohort. DPN was assessed at three different times and defined as a composite of symptoms, signs, and abnormal nerve conduction studies in ≥2 nerves; CAN was assessed seven different times and defined based on R-R variation, Valsalva maneuver, and postural changes in blood pressure. Generalized estimating equation models were used to evaluate the association of DPN and CAN with individual risk factors over repeated time points spanning 30 years. Among 1,441 DCCT/EDIC participants, 32% developed DPN and 44% developed CAN. Higher mean HbA1c was the most significant risk factor for DPN (OR=1.56 per 1%, 95% CI 1.41,1.72). DPN was also associated with older age (1.43 per 5 years, 95% CI 1.31,1.55), longer duration of T1D, higher albuminuria, β-blocker use, higher mean diastolic blood pressure, and higher HbA1c at DCCT eligibility. CAN was associated (in order) with older age (1.51 per 5 years, 95% CI 1.40,1.63), longer duration of T1D (1.07 per 1 year, 95% CI 1.05,1.10), any sustained microalbuminuria (AER ≥30 mg/24 hour on two consecutive visits), higher mean HbA1c, higher mean and current pulse rate (likely as an indirect measure of CAN), higher mean systolic blood pressure, β-blocker use, any eGFR Disclosure B. Braffett: None. R. Gubitosi-Klug: None. J.W. Albers: Consultant; Self; Eli Lilly and Company. E.L. Feldman: None. C. Martin: None. N.H. White: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH. M.F. Lopes-Virella: None. P. Raskin: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Gan & Lee Pharmaceuticals, Novo Nordisk A/S. R. Pop-Busui: Consultant; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Other Relationship; Self; American Diabetes Association. Funding Division of Diabetes Endocrinology & Metabolic Diseases (U01DK094176, U01DK094157); National Eye Institute; National Institute of Neurologic Disorders and Stroke; General Clinical Research Centers Program; Clinical Translational Science Center

We have previously shown that high levels of oxidized LDL and AGE-LDL in circulating IC are strong predictors of atherosclerosis progression in 518 subjects with type 1 diabetes from the DCCT/EDIC cohort. In this study we investigated whether oxLDL, MDA-LDL and AGE-LDL in circulating IC measured in the same subjects at DCCT baseline were associated with acute CVD events. Three overlapping CVD outcomes were considered: any CVD events, major adverse cardiac and cerebrovascular events (MACE) and myocardial infarction (MI). Cox proportional hazards models assessed the association between IC biomarker values and the subsequent risk of CVD, using inverse probability weighting to obtain results representative of the full DCCT/EDIC cohort. Results: Levels of AGE-LDL, oxLDL and MDA-LDL in circulating IC, measured at baseline (Table) were significantly associated with the 3 CVD outcomes in unadjusted models and were minimally attenuated after adjustment for age and mean HbA1c. After adjustments for conventional CVD risk factors, including LDL-Chol, high levels of oxLDL-IC and MDA-LDL-IC remained independently associated with increased subsequent risk of any CVD, and higher oxLDL-IC with increased risk of MACE and MI events. Conclusions: High levels of oxLDL-IC measured more than one decade prior to the occurrence of CVD events identified patients at high risk, even after adjustment by LDL-C and conventional CVD risk factors. Disclosure M.F. Lopes-Virella: None. I. Bebu: None. K.J. Hunt: None. G. Virella: None. N.L. Baker: None. B. Braffett: None. J. Lachin: Board Member; Self; Tolerion, Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases

Objective To gain insight into the effect of blood pressure on the pathophysiology of diabetic erectile dysfunction, we determined the onset, severity and treatment of hypertension and risk of incident erectile dysfunction in men with type I diabetes. Methods This prospective cohort study included 692 men without prevalent erectile dysfunction in the Epidemiology of Diabetes Interventions and Complications study. Erectile dysfunction was assessed yearly for 16 years with a single question querying presence of impotence. Multivariable cox proportional hazards models examined associations of hypertension variables with risk for incident erectile dysfunction. Results Over 7762 person-years of follow-up, 337 of 692 men reported incident erectile dysfunction representing an unadjusted rate of 43.4 cases per 1000 person-years. Risk of erectile dysfunction significantly increased with each 10 mmHg of SBP elevation for those not taking antihypertensive medications, after adjustment for age, cigarette smoking and HbA1c levels [relative risk (RR) = 1.21, 95% CI = 1.04-1.41]. This relationship disappeared among those reporting antihypertensive medication use (RR = 0.96, 95% CI = 0.84-1.10) and the interaction between SBP and medication use was statistically significant (P = 0.02). Antihypertensive medication did not confer any reduction of erectile dysfunction risk, with similar rates across all measures of blood pressure and hypertension. Conclusion Among men with type 1 diabetes not using antihypertensive medications, higher SBP is associated with increased risk of developing erectile dysfunction. These findings provide evidence to support further investigation into the potential benefit of early blood pressure control on risk of erectile dysfunction in men with diabetes regardless of age, blood pressure level, or glycemic control.

We investigated whether the composition of modified forms of LDL in circulating immune complexes (LDL-ICs) was associated with cardiovascular disease (CVD) outcomes, including any CVD, major adverse cardiac and cerebrovascular events (MACCE), myocardial infarction (MI), and coronary artery disease, in type 1 diabetes (T1D). Our results demonstrate that the baseline levels of oxidized LDL (oxLDL), MDA-modified LDL (MDA-LDL), and advanced glycosylation–modified LDL (AGE-LDL) in circulating ICs were associated with the four CVD outcomes in unadjusted models, and adjustment by age and mean HbA1c only resulted in minimal reduction of these associations. After adjustments were made for other cardiovascular risk factors, particularly LDL cholesterol, oxLDL-IC and MDA-LDL-IC remained independently associated with the risk of CVD, and oxLDL-IC was independently associated with the risk of MACCE and MI. In the majority of cases, the baseline levels of modified LDL-IC (measured many years before the occurrence of any CVD event) were associated with the risk of CVD over a 25-year period even after adjustment for other risk factors (including LDL cholesterol). Therefore, modified LDL biomarkers may help identify patients with T1D at high risk for MACCE and CVD events very early in the evolution of the disease, before other signals of disease are apparent.

OBJECTIVE To examine whether cardiovascular autonomic neuropathy (CAN) is an independent risk factor of cardiovascular disease (CVD) events during DCCT/EDIC. RESEARCH DESIGN AND METHODS Standardized cardiovascular autonomic reflex tests (R-R response to paced breathing, Valsalva maneuver, postural changes in blood pressure) were performed at DCCT baseline, every 2 years throughout DCCT, and at two time points in EDIC. CVD events were ascertained throughout the study and adjudicated by a review committee. Cox proportional hazards models were used to estimate the effect of CAN at DCCT closeout on subsequent CVD risk. RESULTS There were 299 adjudicated CVD events in 165 participants following the DCCT closeout assessment: 132 of 1,262 subjects (10%) without CAN at DCCT closeout who experienced 244 CVD events versus 33 of 131 subjects (25%) with CAN at DCCT closeout who experienced 55 events (hazard ratio 2.79, 95% CI 1.91–4.09 for time to first CVD event). The cumulative incidence of the first occurrence of any CVD event during EDIC was significantly higher in participants with CAN at DCCT closeout compared with those without CAN. The association remained marginally significant after adjustment for multiple risk factors, including the EDIC updated mean HbA1c. When analyzed as a continuous variable, R-R variation was significantly lower at DCCT closeout in participants who experienced a CVD event compared with those who did not (P = 0.0012). CONCLUSIONS In the DCCT/EDIC cohort, individuals diagnosed with CAN at DCCT closeout experienced a higher long-term risk of CVD events during follow-up in EDIC. This association was not independent of historic glycemic exposure and its metabolic memory effect, the principal determinant of both long-term CVD risk and CAN in type 1 diabetes.

OBJECTIVE The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study has demonstrated the beneficial effect of intensive therapy on atherosclerosis and clinical cardiovascular outcomes, while identifying hyperglycemia as a dominant risk factor for type 1 diabetes. The current analyses evaluate the extent to which glycemic exposure influences long-term changes in established risk factors for cardiovascular disease (CVD) among patients with type 1 diabetes. RESEARCH DESIGN AND METHODS The DCCT study randomized 1,441 participants to receive intensive or conventional diabetes therapy; and after an average of 6.5 years of follow-up, 96% of the surviving cohort enrolled in the EDIC observational study for an additional 20 years of follow-up. Annual visits included a detailed medical history and physical examination. Blood and urine samples were collected and assayed centrally. Longitudinal models for repeated measurements were used. RESULTS Higher HbA1c level was a significant correlate of the longitudinal changes in all of the traditional CVD risk factors over the 30-year follow-up. The strongest longitudinal associations were among the lipid measurements and concurrent glycemia. CONCLUSIONS A better understanding of the interrelationships between diabetes-related risk factors and traditional CVD risk factors may assist with the development of targeted treatment regimens for persons with type 1 diabetes who are at risk for CVD.

OBJECTIVE This study evaluated associations among cardiovascular autonomic neuropathy (CAN), female sexual dysfunction (FSD), and urinary incontinence (UI) in women with type I diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS We studied 580 women with T1DM in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC). CAN was defined as: 1) R-R variation RESULTS At EDIC year 17, FSD was observed in 41% of women and UI in 30%. No statistically significant associations were observed between measures of CAN at DCCT closeout and subsequent report of FSD or UI. At EDIC year 16/17, there was a 53% increased odds of having UI with a Valsalva ratio ≤1.5. At both EDIC year 13/14 and EDIC year 16/17, a 5-unit increase in R-R variation was associated with a 1.11 greater odds of having FSD. CONCLUSIONS In women with T1DM in the DCCT/EDIC, we found significant increased odds of FSD and UI with specific measures of CAN. In long-standing T1DM, CAN may predict development of FSD and may be a useful surrogate for generalized diabetic autonomic neuropathy.

Risk factors for cardiovascular disease (CVD) are well-established in type 2 but not type 1 diabetes (T1DM). We assessed risk factors in the long-term (mean 27 years) follow-up of the Diabetes Control and Complications Trial (DCCT) cohort with T1DM. Cox proportional hazards multivariate models assessed the association of traditional and novel risk factors, including HbA1c, with major atherosclerotic cardiovascular events (MACE) (fatal or nonfatal myocardial infarction [MI] or stroke) and any-CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure). Age and mean HbA1c were strongly associated with any-CVD and with MACE. For each percentage point increase in mean HbA1c, the risk for any-CVD and for MACE increased by 31 and 42%, respectively. CVD and MACE were associated with seven other conventional factors, such as blood pressure, lipids, and lack of ACE inhibitor use, but not with sex. The areas under the receiver operating characteristics curves for the association of age and HbA1c, taken together with any-CVD and for MACE, were 0.70 and 0.77, respectively, and for the final models, including all significant risk factors, were 0.75 and 0.82. Although many conventional CVD risk factors apply in T1DM, hyperglycemia is an important risk factor second only to age.

AIMS: We assessed whether and to what extent established cardiovascular disease (CVD) risk factors moderate (enhance/reduce) the effect of hyperglycemia on CVD outcomes in the long-term follow-up of the Diabetes Control and Complications Trial type 1 diabetes (T1D) cohort (N=1441). METHODS: Moderation of the effect of glycemia on subsequent risk of major adverse cardiovascular events (MACE: fatal or non-fatal myocardial infarction or stroke) and any-CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure) was assessed separately using interaction terms between HbA1c and other risk factors in Cox proportional hazards models. RESULTS: Over a median follow-up of 29 years, there were 120 MACE cases and 239 any-CVD cases. Higher pulse, higher triglycerides, use of calcium channel blockers, and presence of neuropathy individually enhanced (p

OBJECTIVE To evaluate the prevalence of hearing impairment in participants with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study and compare with that of a spousal control group without diabetes. Among participants with type 1 diabetes, to evaluate the association of hearing impairment with prior DCCT therapy and overall glycemia. RESEARCH DESIGN AND METHODS DCCT/EDIC participants (n = 1,150) and 288 spouses without diabetes were recruited for the DCCT/EDIC Hearing Study. All subjects completed a self-administered questionnaire, medical history, and physical measurements. Audiometry was performed by study-certified personnel; audiograms were assessed centrally. Speech-frequency (pure-tone average [PTA] thresholds at 500, 1,000, 2,000, and 4,000 Hz) and high-frequency impairment (PTA thresholds at 3,000, 4,000, 6,000, and 8,000 Hz) were defined as PTA >25 dB hearing loss. Logistic regression models were adjusted for age and sex. RESULTS DCCT/EDIC participants and spousal control subjects were similar in age, race, education, smoking, and systolic blood pressure. There were no statistically significant differences between groups in the prevalence or adjusted odds of speech- or high-frequency impairment in either ear. Among participants with type 1 diabetes, for every 10% increase in the time-weighted mean HbA1c, there was a 32% (95% CI 1.15–1.50) and 19% (95% CI 1.07–1.33) increase in speech- and high-frequency hearing impairment, respectively. CONCLUSIONS We found no significant difference in the prevalence of hearing impairment between the group with type 1 diabetes and the spousal control group. Among those with type 1 diabetes, higher mean HbA1c over time was associated with hearing impairment.

We examined whether prior intensive glycemic control during the DCCT reduced the risk of diabetic foot ulcer (DFU) and lower extremity amputation (LEA) among participants with type 1 diabetes in the EDIC study. DFU and LEA occurrence were determined by physical examination during annual EDIC follow-up visits that began about one year following DCCT completion. We also assessed DFU and LEA risk by neurovascular measurements, diabetes characteristics, and clinical factors. Data were available from 23 years of EDIC follow-up. Recurrent DFU was defined if reported on a different limb in subsequent years or the same limb in non-consecutive years. Multivariable Cox models were used to estimate the association of intensive glycemic control and other time-updated risk factors with incident or total (incident + recurrent) DFU or incident LEA. Incident DFU was observed in 86 of the 699 former intensive and 109 of the 7former conventional treatment participants (HR 0.78, 95% CI 0.59 to 1.03). Total DFU numbered 117 in intensive (7.3/1000 person-years (p-y)) and 153 in conventional treatment participants (9.6/1000 p-y) for a significant risk reduction (HR 0.76, 95% CI 0.60 to 0.97, p=0.03). Incident LEA occurred in 15 intensive (1.0/1000 p-y) compared to 21 conventional treatment participants (1.4/1000 p-y, HR 0.70, 95% CI 0.36 to 1.36, p=0.30). Greater HbA1c, lower eGFR, albuminuria, confirmed clinical neuropathy, lower nerve conduction velocity, abnormal cardiovascular autonomic function, proliferative retinopathy, and macular edema were independently associated (p Disclosure E.J. Boyko: None. L. Zelnick: None. B. Braffett: None. R. Pop-Busui: Research Support; Self; AstraZeneca. C.C. Cowie: None. G.M. Lorenzi: Advisory Panel; Self; Intarcia Therapeutics, Inc.. R. Gubitosi-Klug: None. B. Zinman: Consultant; Self; Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi, Merck & Co., Inc., Abbott. I. de Boer: Research Support; Self; Medtronic, Abbott. Consultant; Self; Boehringer Ingelheim GmbH, Ironwood Pharmaceuticals, Inc..

Background: Serum uric acid (UA) is associated with the pathogenesis of diabetes complications, including cardiovascular disease (CVD) and kidney injury. Current epidemiological evidence is limited regarding the association between UA and the development of CVD in type 1 diabetes mellitus (T1DM). Objective: To examine associations of serum UA with CVD and major atherosclerotic cardiovascular events (MACE) in T1DM. Methods: UA was measured in sera (1997-2000) from a subset of participants (n=973; males=540, females=433) in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Subsequent CVD events were adjudicated by a review committee masked to DCCT assignment and HbA1c levels, and defined as the time to the first of any of the following: non-fatal myocardial infarction (MI) or stroke, CVD death, silent MI on annual ECG, angina confirmed by ischemic changes with exercise tolerance testing, congestive heart failure, or revascularization; MACE were defined as a composite of CVD death, nonfatal MI, or stroke. Cox proportional hazards models were used to evaluate prospectively the effect of UA as a fixed covariate on CVD and MACE, separately by gender, and adjusted for age and HbA1c. Results: Over 15 years follow-up, there were 201 adjudicated CVD events among 110 participants (HR=1.10 per 1 mg/dl change in UA, 95% CI 0.93-1.30); 61 males experienced 96 events (HR=1.15, 95% CI 0.90-1.46) and 49 females, 105 events (HR=1.17, 95% CI 0.88-1.56). There were 62 adjudicated MACE among 53 participants (HR=1.18, 95% CI 0.93-1.49); 29 males experienced 31 events (HR=1.10, 95% CI 0.77-1.58) and 24 females, 31 events (HR=1.47, 95% CI 1.01-2.14). No significant associations between quartiles of UA and either CVD or MACE were observed in either sex. Conclusions: Our results show UA may not serve as a predictive biomarker for CVD events in T1DM adults. Sex-specific associations with MACE deserve further investigation. Disclosure A. Basu: None. B. Braffett: None. A. Jenkins: Research Support; Self; Medtronic, Mylan, Sanofi-Aventis. I. Bebu: None. R.L. Klein: None. M.F. Lopes-Virella: None. S. Dagogo-Jack: None. T.J. Orchard: None. A. Wallia: Research Support; Self; UnitedHealth Group. Consultant; Self; Glytec Systems, Lexicon Pharmaceuticals, Inc.. Research Support; Self; Eli Lilly and Company. J. Lachin: Board Member; Self; AbbVie Inc., Celgene Corporation. W. Garvey: Advisory Panel; Self; Novo Nordisk Inc., Merck & Co., Inc.. Research Support; Self; Sanofi, Pfizer Inc., Novo Nordisk Inc., AstraZeneca, Merck & Co., Inc., Elcelyx Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Eisai Inc.. T. Lyons: None.

We investigated residual beta cell function in participants from the DCCT/EDIC study with an average of 35 (range 27, 48) years duration of T1D. Between 2015-2017 after 22-24 years of follow-up in EDIC, a 4-hour mixed meal tolerance test was administered to 944 participants and 7 timed plasma specimens were collected and assayed for C-peptide using a chemiluminescent immunoassay (Roche). We defined a significant post-stimulus response as a peak C-peptide concentration >0.03 nmol/L, based on an earlier DCCT study which demonstrated that the risk of microvascular disease progression was markedly higher among participants who entered the trial with values below this concentration. Overall, 71 (7.5%) participants were classified as “responders” with a median peak C-peptide of 0.10 nmol/L (IQR 0.06, 0.15). Among the 873 participants classified as “non-responders”, 46 had detectable peak C-peptide between 0.003 (limit of detection) and 0.029 nmol/L. Responders were slightly older than non-responders (58.5 ± 6.2 vs. 56.5 ± 6.8 y; p=0.02), yet had similar age of onset of diabetes (22.5 ± 7.0 vs. 21.4 ± 7.8 y) and duration of diabetes (35.9 ± 5.1 vs. 35.0 ± 4.9 y). Compared to non-responders, responders had lower HbA1c values (8.6 ± 1.7 vs. 8.9 ± 1.5%; p=0.01) and higher stimulated C-peptide (0.22 ± 0.14 vs. 0.11 ± 0.11 nmol/L; p In conclusion, beta cell function persists in some very long duration T1D patients and is associated with clinically meaningful reductions in the frequency of severe hypoglycemia. Disclosure R. Gubitosi-Klug: None. B. Braffett: None. S.M. Hitt: None. V. Arends: None. M. Steffes: None. A.K. Saenger: Advisory Panel; Self; Alere Inc. J. Lachin: Board Member; Self; AbbVie Inc., Celgene Corporation. J.P. Palmer: None.

OBJECTIVE: The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy for type 1 diabetes delayed the development of microvascular and neuropathic complications compared to conventional therapy. At the end of DCCT, all participants were trained in intensive therapy, care was transferred to community providers, and the difference in HbA1c between treatment groups narrowed and disappeared. Our objective was to describe the outcomes and the quality-of-life and costs associated with those outcomes in participants who maintained excellent vs. poor glycemic control over 30 years. RESEARCH DESIGN AND METHODS: We assessed the incidence of retinopathy, nephropathy, neuropathy, cardiovascular disease, acute metabolic complications, death, quality-of-life, and costs in the tertile of DCCT intensive therapy participants who achieved a mean updated HbA1c of 8.8% (73 mmol/mol) over 30 years. RESULTS: Thirty years of excellent vs. poor glycemic control substantially reduced the incidence of retinopathy requiring laser therapy (5% vs. 45%), end-stage renal disease (0% vs. 5%), clinical neuropathy (15% vs. 50%), myocardial infarction (3% vs. 5%), stroke (0.4% vs. 2%), and death (6% vs. 20%). It also resulted in a gain of ~1.62 quality-adjusted life-years and averted ~$90,900 in costs of complications per participant. CONCLUSIONS: Thirty years of excellent vs. poor glycemic control for T1DM can substantially reduce the incidence of complications, comorbidities, and death, improve quality-of-life, and reduce costs. These estimates represent the benefits that may be achieved with excellent glycemic control.