Diabetes Control And Complications Trial Research Articles

Autonomic neuropathy and urologic complications in diabetes.

Diabetic autonomic neuropathy affects the entire autonomic nervous system and can lead to dysfunction of the cardiovascular, gastrointestinal, and genitourinary organ systems. Genitourinary dysfunction associated with diabetic autonomic neuropathy includes diabetic bladder dysfunction, sexual dysfunction, and recurrent urinary tract infections. Urological complications in diabetes mellitus are very common; in fact, genitourinary complications are more common than diabetic neuropathy or nephropathy. While several studies have reported on genitourinary dysfunction in individuals with diabetes, UroEDIC, an ancillary study to the Diabetes Control and Complications Trial (DCCT) and its observational follow up, the Epidemiology of Diabetes Interventions and Complications study (EDIC), comprehensively characterized the association between urologic complications and cardiovascular autonomic neuropathy. UroEDIC demonstrated significant associations between autonomic neuropathy and urologic complications in type 1 diabetes, specifically erectile dysfunction, female sexual dysfunction, and lower urinary tract symptoms. In this narrative review, we review the current literature on urological complications in diabetes.

Islet Health, Hormone Secretion, and Insulin Responsivity with Low-Carbohydrate Feeding in Diabetes.

Exploring new avenues to control daily fluctuations in glycemia has been a central theme for diabetes research since the Diabetes Control and Complications Trial (DCCT). Carbohydrate restriction has re-emerged as a means to control type 2 diabetes mellitus (T2DM), becoming increasingly popular and supported by national diabetes associations in Canada, Australia, the USA, and Europe. This approval comes from many positive outcomes on HbA1c in human studies; yet mechanisms underlying their success have not been fully elucidated. In this review, we discuss the preclinical and clinical studies investigating the role of carbohydrate restriction and physiological elevations in ketone bodies directly on pancreatic islet health, islet hormone secretion, and insulin sensitivity. Included studies have clearly outlined diet compositions, including a diet with 30% or less of calories from carbohydrates.

Refractive Error and Retinopathy Outcomes in Type 1 Diabetes: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study

To determine the relationship between refractive error and diabetic retinopathy (DR). Clinical trial. Type I diabetes individuals with serial refractive error and DR stage measurements over 30 years in the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study. Stage of DR was measured every 6 months from standard fundus photographs, and refractive error was measured annually during the 6.5 years of DCCT; then, both were staggered every fourth year during EDIC with the full cohort measured at EDIC years 4 and 10. Outcomes of DR were 2- or 3-step progression, presence of proliferative DR (PDR), clinically significant macular edema (CSME), diabetic macular edema (DME), or ocular surgery. Myopia, emmetropia, and hyperopia were defined as a spherical equivalent of ≤-0.5, >-0.5 and <0.5, and ≥0.5, respectively. For each outcome separately, Cox proportional hazard (PH) models assessed the association between the refractive error status and the subsequent risk of that outcome, both without and with adjustment for potential risk factors. Hyperopia was associated with a higher risk of 2-step progression (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.05-1.59), 3-step progression (HR, 1.35; 95% CI, 1.05-1.73), and PDR (HR, 1.40; 95% CI, 1.02-1.92) compared with emmetropia in unadjusted models. These associations remained significant after adjustment for DCCT treatment group, cohort, age, sex, smoking, duration of diabetes, systolic and diastolic blood pressures, pulse, low-density lipoprotein, high-density lipoprotein, triglycerides, albumin excretion rate, and DCCT/EDIC mean updated hemoglobin A1c (HbA1c) (2-step progression: HR, 1.28; 95% CI, 1.03-1.58; 3-step progression: HR, 1.30; 95% CI, 1.00-1.68; PDR: HR, 1.38; 95% CI, 1.00-1.90). Myopia was not associated with any of the 5 DR outcomes in the unadjusted models and only marginally associated with 2-step progression (HR, 1.11; 95% CI, 1.00-1.24) in the adjusted models. Myopia is not associated with DR progression risk. Hyperopia is an independent risk factor for 2-step and 3-step DR progression and PDR.

Longitudinal Plasma Kallikrein Levels and Their Association With the Risk of Cardiovascular Disease Outcomes in Type 1 Diabetes in DCCT/EDIC.

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.

Invincible β-cells in type1 diabetes.

The classical definition of type 1 diabetes, of which the pathogenesis lies in the autoimmune destruction of beta cells that eventually leads to complete loss of insulin secretion capacity, is recently being revisited with the emerging concept of endotype to address the heterogeneity of the disease1 . In the Diabetes Control and Complications Trial (DCCT), it was observed that some individuals retained a clinically meaningful C-peptide persistence years after diagnosis of type 1 diabetes; post-mortem studies of pancreas specimens of long-standing type 1 diabetes also revealed insulin-containing beta cells2 .

DNA methylation mediates development of HbA1c-associated complications in type 1 diabetes.

Metabolic memory, the persistent benefits of early glycemic control on preventing/delaying diabetic complications development, is observed in the Diabetes Control and Complications Trial (DCCT) and in the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study, but mechanisms remain unclear. Here, we show the involvement of epigenetic DNA methylation (DNAme) in metabolic memory by examining its associations with preceding glycemic history, and with subsequent development of complications over an 18-year period in blood DNAs of 499 randomly-selected DCCT/EDIC participants with type 1 diabetes. We demonstrate the associations between DNAme near DCCT-closeout and mean HbA1c during DCCT (mean-DCCT-HbA1c) at 186 CpGs (FDR<15%, including 43 at FDR<5%), many of which are located in complications-related genes. Biological function exploration studies reveal these CpGs are enriched in C/EBP transcription factor binding sites, as well as enhancer/transcription regions in blood cells and hematopoietic stem cells, and open chromatin states in myeloid cells. Mediation analyses show that, remarkably, several CpGs in combination explain 68–97% of the association of mean-DCCT-HbA1c with the risk of complications development during EDIC. In summary, DNAme at key CpGs appears to mediate the association between hyperglycemia and complications in metabolic memory, through modifying enhancer activity at myeloid and other cells.

Smarter Modeling to Enable a Smarter Insulin.

> I dream things that never were, and I say “Why not?” > > —George Bernard Shaw Pancreatic β-cells secrete insulin to maintain physiological health. While the glucose level is the principle driver of insulin secretion, β-cells also respond to other regulatory inputs including circulating metabolites (most notably amino acids), regulatory hormones, gut peptides, and neurotransmitters. Insulin secretion increases when glucose levels are high, thereby increasing total body glucose utilization and suppressing endogenous glucose production. Of critical importance, insulin secretion is suppressed when glucose levels are low, which protects against life-threatening hypoglycemia. There have been remarkable advances to enhance efficacy and safety of insulin therapy since the discovery of insulin 100 years ago. Insulin pharmacokinetics has been optimized through both formulation and modification of the peptide itself. Sophisticated mechanical devices can provide continuous insulin delivery and continuous glucose monitoring. Pancreatic islets can be transplanted, and bihormonal pumps more closely mimic normal physiology. Despite technological advances, most insulin-dependent patients do not achieve physiological glucose control. The risk of severe hypoglycemia is particularly troublesome because it limits the ability to safely achieve optimal glycemic control, which in turn makes it harder to protect against the long-term risk of microvascular complications (1,2). To underscore this point, half of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) cohort experienced severe hypoglycemia (∼40 episodes per 100 patient-years) (3). Furthermore, self-reported severe hypoglycemia is associated with 3.4-fold increased risk of death during a 5-year follow-up period (4). The pursuit of a glucose-responsive insulin (GRI) therapy is an ambitious technical objective. In type 2 diabetes, incretin therapy enhances insulin secretion when glucose levels are high but does not cause hypoglycemia because it does not promote insulin secretion when glucose levels are low. Similarly, GRI technology aims to mimic the ability of β-cells …

Response to Comment on Miller and Orchard: Understanding Metabolic Memory: A Tale of Two Studies. Diabetes 2020;69:291–299

We agree with Lachin et al. (1) that intensive therapy should be started as early as possible after type 1 diabetes onset. The concept of cumulative glycemic exposure in no way alters that clinical message. The intention of our article (2) was to raise the argument that “metabolic memory” has been accepted without a full exploration of a simpler alternative explanation for the observed persistence of benefit in the intensive therapy arm after Diabetes Control and Complications Trial (DCCT) closeout. Importantly, we do not “purportedly disprove metabolic memory” (1) but merely suggest “There is no need [our emphasis] to invoke a ‘metabolic memory’ phenomenon to explain the persistence of a lower incidence of complications …

Diabetes and coronary artery disease: not just a risk factor

### Learning objectives For most of the 20th century, diabetes mellitus was recognised as a condition characterised by the presence of hyperglycaemia with a crippling burden of both microvascular and...

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.

Immunotherapy Strategies for the Prevention and Treatment of Distinct Stages of Type 1 Diabetes: An Overview.

Type 1 diabetes mellitus is a heterogeneous disorder characterized by destruction of pancreatic β cells, culminating in absolute insulin deficiency. The goals of Type 1 diabetes care, established by the Diabetes Control and Complications Trial (DCCT), are to achieve good glycemic control, to prevent hyperglycaemia (which is associated with long-term microvascular and macrovascular complications) and to avoid recurrent episodes of hypoglycaemia (which may have adverse effects on cognitive function). However, despite continuing optimization of insulin therapy regimes, the actual hormonal substitutive administration acts only to treat the symptoms without an effect on disease pathology and etiopathogenesis. In recent decades, a great deal of interest has been focused on prevention approaches in high-risk individuals, based on the hypothesis that a therapeutic intervention, if applied at the early stage of disease, might contribute to maintaining endogenous β cell function by preserving the residual β cell reservoir from autoimmune attack. This manuscript provides an overview of the most important immunotherapeutic interventions established so far for Type 1 diabetes treatment at different stages of disease that have reached an advanced stage of assessment.

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.

Risk Factors for First and Subsequent CVD Events in Type 1 Diabetes: The DCCT/EDIC Study.

OBJECTIVEThe 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 METHODSCVD 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.RESULTSOver 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]).CONCLUSIONSIntensive 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.

Urinary angiotensinogen antedates the development of stage 3 CKD in patients with type 1 diabetes mellitus.

We examined if urinary angiotensinogen (uAOG), a marker of intrarenal renin‐angiotensin system activity, antedates stage 3 chronic kidney disease (CKD) using samples from participants in the Diabetes Control and Complications Trial (DCCT) and later in the Epidemiology of Diabetes Intervention and Complications (EDIC) trial. In a nested case–control design, cases were matched at the outcome visit (eGFR less than 60, 21‐59 mL/min per 1.73 m2) on age, gender, and diabetes duration, with controls: eGFR (95, 75‐119, mL/min per 1.73 m2.) Additionally, in an exploratory analysis progressive renal decline (PRD), defined as eGFR loss >3.5 mL/min per 1.73m2/year, was evaluated using only data from EDIC because no progressions were observed during DCCT. At the EDIC visit, which antedated the GFR outcome visit by 2 years (range 1–7years) the median uAOG/creatinine was markedly higher in cases than in controls (13.9 vs. 3.8 ng/mg P = 0.003) whereas at the DCCT visit, which antedated the GFR outcome by 17 to 20 years it was not (2.75 vs. 3.16 ng/mg, respectively). The Odds Ratio for uAOG and CKD stage 3 development was significant after adjusting for eGFR, HbA1c, and systolic blood pressure 1.82 (1.00–3.29) but no longer significant when Albumin Excretion Ratio (AER) was included 1.21 (0.65–2.24).In the PRD analysis, uAOG/creatinine was sixfold higher in participants who experienced PRD than in those who did not (26 vs. 4.0 ng/mg, P = 0.003). The Odds Ratio for uAOG and PRD was significant after adjusting for eGFR, HbA1c, and systolic blood pressure 2.48 (1.46–4.22) but no longer significant when AER was included 1.32 (0.76–2.30). In people with type1 diabetes, a robust increase in uAOG antedates the development of stage 3 CKD but is not superior to AER in predicting this renal outcome. Increased uAOG moreover is associated with PRD, an index of progression to End Stage Kidney Disease (ESKD).

Screening eye exams in youth with type 1 diabetes under 18 years of age: Once may be enough?

Case series and registry data suggest that diabetic retinopathy requiring treatment is rare in youth with type 1 diabetes (T1D) prior to 18 years of age. We evaluated this question in the standardized clinical trial setting by retrospectively reviewing diabetic retinopathy examinations from participants in the Diabetes Control and Complications Trial (DCCT) who were 13 to <18 years of age at randomization. Standardized stereoscopic 7-field fundus photographs were obtained every 6 months during DCCT (1983-1993). Photographs were graded centrally using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Transitions in diabetic retinopathy status over time were described. A total of 195 participants with median baseline glycated hemoglobin (HbA1c) of 9.3% (103 in the conventional and 92 in the intensive treatment groups) had an average of 5.3 diabetic retinopathy assessments during 2.3 years of follow-up (range 1-11) while under 18 years of age during the DCCT. No participant developed severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy and only one participant (in the intensive group) reached clinically significant macular edema (CSME) while less than 18 years of age. In this incident case, baseline characteristics included diabetes duration 9.3 years, HbA1c 10.3%, LDL 131 mg/dL, and mild non-proliferative diabetic retinopathy (35/35 ETDRS scale); CSME resolved without treatment. Similar analyses using age cut-offs of <19, 20, or 21 years showed a slight rise in diabetic retinopathy requiring treatment over late adolescence. Clinical trial evidence suggests that frequent eye exams may not be universally necessary in youth <18 years of age with T1D.

The Cardiovascular Legacy of Good Glycemic Control: Clues About Mediators From the DCCT/EDIC Study.

Diabetes is defined by hyperglycemia, but whether optimizing glycemic control can reduce its complications was long in doubt. In 1968 Siperstein et al. proposed the hypothesis that microvascular injury accompanying diabetes could be genetically determined (1), and there was concern that, even if the “glucose hypothesis” (2,3) were valid, seeking good control of hyperglycemia was overly risky. Nevertheless, epidemiologic evidence linking hyperglycemia with both microvascular and cardiovascular complications prompted assessment of the effects of intensive glycemic control in the Diabetes Control and Complications Trial (DCCT) for type 1 diabetes (T1D) and the UK Prospective Diabetes Study (UKPDS) for type 2 diabetes (T2D). When the results of the DCCT were reported in Las Vegas on a hot (>110°F) day in June 1993, many people were surprised by the approximately 50% reduction of microvascular changes that was associated with 6.5 years of maintaining hemoglobin A1c (HbA1c) close to 7% (53 mmol/mol) compared with 9% (75 mmol/mol) in the control arm (4). Because the DCCT participants were young, cardiovascular events were too few to analyze and long-term effects on cardiovascular risk remained unknown. Results in T2D from the UKPDS reinforced the message of the DCCT. More intensive glycemic control attaining about a 1% difference in HbA1c in T2D for 10 years led to 25% lower rates of microvascular outcomes (5) and a nonsignificant 16% lower rate of myocardial infarction (5). For more than two decades after these reports the dominant view has been that improving glycemic control reduces eye, nerve, and kidney complications but not cardiovascular risk. Four large randomized clinical trials testing whether seeking HbA1c levels at or below 7% could reduce cardiovascular events showed limited benefits during their periods of active treatment (5–8). Although analysis of data pooled from these four trials …

Incidence of severe hypoglycemia and possible associated factors in pediatric patients with type 1 diabetes in the real-life, post-Diabetes Control and Complications Trial setting: A systematic review.

In 1993, the Diabetes Control and Complications Trial (DCCT) found that intensive antihyperglycemic therapy was effective in the primary and secondary prevention of microvascular complications in patients with type 1 diabetes (T1D) but was associated with a 3-fold greater rate of severe hypoglycemia (SH) than conventional therapy. The aim of this analysis was to determine whether, in the real-world setting, the incidence of SH in pediatric patients with T1D has changed since 1993. A systematic literature search of PubMed for prospective or retrospective observational studies (≥250 participants) on SH epidemiology or related topics in pediatric patients with T1D, published between October 1993 and June 2016, identified 35 articles (involving >55 000 participants). SH incidence data were analyzed in approximate 5-year blocks: 1993-2000, 2001-2005, 2006-2010, and 2011-2016. Information on factors that might influence the incidence of SH was also collected. A trend for a marked reduction in the incidence of SH in the post-DCCT setting (from 62.0 per 100 patient-years to 1.21-30 per 100 patient-years) was apparent. Factors that could have influenced this temporal trend in SH incidence included the increased use of new types of, and methods of administering, insulin, in particular rapid-acting insulin analogs and continuous subcutaneous insulin infusion. SH in pediatric patients with T1D has declined in incidence since the DCCT but remains a common problem. The optimal use of new insulin therapies/regimens/technologies, improved education, and dedicated specialized management teams are needed to help reduce the risk of SH in this population.

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

Early Glomerular Hyperfiltration and Long-Term Kidney Outcomes in Type 1 Diabetes: The DCCT/EDIC Experience.

Glomerular hyperfiltration has been considered to be a contributing factor to the development of diabetic kidney disease (DKD). To address this issue, we analyzed GFR follow-up data on participants with type 1 diabetes undergoing 125I-iothalamate clearance on entry into the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications study. This was a cohort study of DCCT participants with type 1 diabetes who underwent an 125I-iothalamate clearance (iGFR) at DCCT baseline. Presence of hyperfiltration was defined as iGFR levels ≥140 ml/min per 1.73 m2, with secondary thresholds of 130 or 150 ml/min per 1.73 m2. Cox proportional hazards models assessed the association between the baseline hyperfiltration status and the subsequent risk of reaching an eGFR <60 ml/min per 1.73 m2. Of the 446 participants, 106 (24%) had hyperfiltration (iGFR levels ≥140 ml/min per 1.73 m2) at baseline. Over a median follow-up of 28 (interquartile range, 23, 33) years, 53 developed an eGFR <60 ml/min per 1.73 m2. The cumulative incidence of eGFR <60 ml/min per 1.73 m2 at 28 years of follow-up was 11.0% among participants with hyperfiltration at baseline, compared with 12.8% among participants with baseline GFR <140 ml/min per 1.73 m2. Hyperfiltration was not significantly associated with subsequent risk of developing an eGFR <60 ml/min per 1.73 m2 in an unadjusted Cox proportional hazards model (hazard ratio, 0.83; 95% confidence interval, 0.43 to 1.62) nor in an adjusted model (hazard ratio, 0.77; 95% confidence interval, 0.38 to 1.54). Application of alternate thresholds to define hyperfiltration (130 or 150 ml/min per 1.73 m2) showed similar findings. Early hyperfiltration in patients with type 1 diabetes was not associated with a higher long-term risk of decreased GFR. Although glomerular hypertension may be a mechanism of kidney injury in DKD, higher total GFR does not appear to be a risk factor for advanced DKD.

Albuminuria, the High-Density Lipoprotein Proteome, and Coronary Artery Calcification in Type 1 Diabetes Mellitus.

Objective- Albuminuria is an important risk factor for cardiovascular disease in diabetes mellitus. We determined whether albuminuria associates with alterations in the proteome of HDL (high-density lipoprotein) of subjects with type 1 diabetes mellitus and whether those alterations associated with coronary artery calcification. Approach and Results- In a cross-sectional study of 191 subjects enrolled in the DCCT (Diabetes Control and Complications Trial)/EDIC study (Epidemiology of Diabetes Interventions and Complications), we used isotope dilution tandem mass spectrometry to quantify 46 proteins in HDL. Stringent statistical analysis demonstrated that 8 proteins associated with albuminuria. Two of those proteins, AMBP (α1-microglobulin/bikunin precursor) and PTGDS (prostaglandin-H2 D-isomerase), strongly and positively associated with the albumin excretion rate ( P<10-6). Furthermore, PON (paraoxonase) 1 and PON3 levels in HDL strongly and negatively associated with the presence of coronary artery calcium, with odds ratios per 1-SD difference of 0.63 (95% CI, 0.43-0.92; P=0.018) for PON1 and 0.59 (95% CI, 0.40-0.87; P=0.0079) for PON3. Only 1 protein, PON1, associated with both albumin excretion rate and coronary artery calcification. Conclusions- Our observations indicate that the HDL proteome is remodeled in type 1 diabetes mellitus subjects with albuminuria. Moreover, low concentrations of the antiatherosclerotic protein PON1 in HDL associated with both albuminuria and coronary artery calcification, raising the possibility that alterations in HDL protein cargo mediate, in part, the known association of albuminuria with cardiovascular risk in type 1 diabetes mellitus. Visual Overview- An online visual overview is available for this article.