OBJECTIVEThe Diabetes Control and Complications Trial (DCCT) demonstrated the beneficial effects of intensive versus conventional therapy on the development and progression of microvascular complications of type 1 diabetes. These beneficial effects were almost completely explained by the difference between groups in the levels of HbA1c, which in turn were associated with the risk of these complications. We assessed the association of glucose variability within and between quarterly 7-point glucose profiles with the development and progression of retinopathy, nephropathy, and cardiovascular autonomic neuropathy during the DCCT.RESEARCH DESIGN AND METHODSMeasures of variability included the within-day and updated mean (over time) of the SD, mean amplitude of glycemic excursions (MAGE), and M-value, and the longitudinal within-day, between-day, and total variances. Imputation methods filled in the 16.3% of expected glucose values that were missing.RESULTSCox proportional hazards models assessed the association of each measure of glycemic variation, as a time-dependent covariate, with the risk of retinopathy and nephropathy, and a longitudinal logistic regression model did likewise for cardiovascular autonomic neuropathy. Adjusted for mean blood glucose, no measure of within-day variability was associated with any outcome. Only the longitudinal mean M-value (over time) was significantly associated with microalbuminuria when adjusted for the longitudinal mean blood glucose and corrected for multiple tests using the Holm procedure.CONCLUSIONSOverall, within-day glycemic variability, as determined from quarterly glucose profiles, does not play an apparent role in the development of microvascular complications beyond the influence of the mean glucose.

Composite outcomes are common in clinical trials, especially for multiple time-to-event outcomes (endpoints). The standard approach that uses the time to the first outcome event has important limitations. Several alternative approaches have been proposed to compare treatment versus control, including the proportion in favor of treatment and the win ratio. Herein, we construct tests of significance and confidence intervals in the context of composite outcomes based on prioritized components using the large sample distribution of certain multivariate multi-sample U-statistics. This non-parametric approach provides a general inference for both the proportion in favor of treatment and the win ratio, and can be extended to stratified analyses and the comparison of more than two groups. The proposed methods are illustrated with time-to-event outcomes data from a clinical trial.

The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy reduced the development and progression of retinopathy in type 1 diabetes (T1D) compared with conventional therapy. The Epidemiology of Diabetes Interventions and Complications (EDIC) study observational follow-up showed persistent benefits. In addition to glycemia, we now examine other potential retinopathy risk factors (modifiable and nonmodifiable) over more than 30 years of follow-up in DCCT/EDIC. RESEARCH DESIGN AND METHODS The retinopathy outcomes were proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), and ocular surgery. The survival (event-free) probability was estimated using the Kaplan-Meier method. Cox proportional hazards models assessed the association between risk factors and subsequent risk of retinopathy. Both forward-and backward-selection approaches determined the multivariable models. RESULTS Rate of ocular events per 1,000 person-years was 12 for PDR, 14.5 for CSME, and 7.6 for ocular surgeries. Approximately 65%, 60%, and 70% of participants remained free of PDR, CSME, and ocular surgery, respectively. The greatest risk factors for PDR in descending order were higher mean HbA 1c , longer duration of T1D, elevated albumin excretion rate (AER), and higher mean diastolic blood pressure (DBP). For CSME, risk factors, in descending order, were higher mean HbA 1c , longer duration of T1D, and greater age and DBP and, for ocular surgeries, were higher mean HbA 1c , older age, and longer duration of T1D. CONCLUSIONS Mean HbA 1c was the strongest risk factor for the progression of retinopathy. Although glycemic control is important, elevated AER and DBP were other modifiable risk factors associated with the progression of retinopathy. Retinopathy is a major complication of type 1 diabetes. The Diabetes Control and Complications Trial (DCCT) demonstrated that a mean of 6.5 years of intensive diabetes therapy with a mean HbA 1c of ;7% substantially reduced microvascular complications, including retinopathy, compared with conventional therapy with a mean HbA 1c of ;9% (1). Thereafter, observational follow-up of DCCT participants continued in the Epidemiology of Diabetes Interventions and Complications (EDIC) study (1994 to present) (2). Over the first 4 years of EDIC, the former DCCT intensive

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.

In type 1 diabetes (T1D), the course of microalbuminuria is unpredictable and timing of glomerular filtration rate (GFR) loss is uncertain. Thus, there is a need to identify the risk factors associated with the development of more advanced stages of kidney disease through large, long-term systematic analysis. RESEARCH DESIGN AND METHODS Multivariable Cox proportional hazards models assessed the association of baseline and time-dependent glycemic and nonglycemic risk factors for incident macroalbuminuria and reduced estimated GFR (eGFR; defined as <60 mL/min/1.73 m 2) over a mean of 27 years in the Diabetes Control and Complications Trial (DCCT) cohort. RESULTS Higher mean HbA 1c (hazard ratio [HR] 1.969 per 1% higher level [95% CI 1.671-2.319]) and male sex (HR 2.767 [95% CI 1.951-3.923]) were the most significant factors independently associated with incident macroalbuminuria, whereas higher mean triglycerides, higher pulse, higher systolic blood pressure (BP), longer diabetes duration, higher current HbA 1c , and lower mean weight had lower magnitude associations. For incident reduced eGFR, higher mean HbA 1c (HR 1.952 per 1% higher level [95% CI 1.714-2.223]) followed by higher mean triglycerides, older age, and higher systolic BP were the most significant factors. CONCLUSIONS Although several risk factors associated with macroalbuminuria and reduced eGFR were identified, higher mean glycemic exposure was the strongest determinant of kidney disease among the modifiable risk factors. These findings may inform targeted clinical strategies for the frequency of screening, prevention, and treatment of kidney disease in T1D. The lifetime risk of kidney disease in type 1 diabetes (T1D) has traditionally been estimated at ;50% but may exceed 70% (1). Diabetic kidney disease remains the leading cause of end-stage renal disease (ESRD) in North America (2) and is defined by the development of albuminuria or by loss in glomerular filtration rate (GFR). Levels of albuminuria .300 mg/24 h (termed macroalbuminuria) and estimated GFR ,60 mL/min/1.73 m 2 (termed "reduced eGFR") are seen as clinically relevant advanced stages of kidney disease because of their strong association with subsequent ESRD, cardiovascular disease, and mortality (3). The traditional concept of diabetic kidney disease holds that microalbuminuria (albumin excretion rate [AER] $30 mg/24 h) is the fundamental early prognostic variable that heralds macroalbuminuria (4-6), which, after long-term exposure, is