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1.  Significance of Epicardial and Intrathoracic Adipose Tissue Volume among Type 1 Diabetes Patients in the DCCT/EDIC: A Pilot Study 
PLoS ONE  2016;11(7):e0159958.
Type 1 diabetes (T1DM) patients are at increased risk of coronary artery disease (CAD). This pilot study sought to evaluate the relationship between epicardial adipose tissue (EAT) and intra-thoracic adipose tissue (IAT) volumes and cardio-metabolic risk factors in T1DM.
EAT/IAT volumes in 100 patients, underwent non-contrast cardiac computed tomography in the Diabetes Control and Complications Trial /Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study were measured by a certified reader. Fat was defined as pixels’ density of -30 to -190 Hounsfield Unit. The associations were assessed using–Pearson partial correlation and linear regression models adjusted for gender and age with inverse probability sample weighting.
The weighted mean age was 43 years (range 32–57) and 53% were male. Adjusted for gender, Pearson correlation analysis showed a significant correlation between age and EAT/IAT volumes (both p<0.001). After adjusting for gender and age, participants with greater BMI, higher waist to hip ratio (WTH), higher weighted HbA1c, elevated triglyceride level, and a history of albumin excretion rate of equal or greater than 300 mg/d (AER≥300) or end stage renal disease (ESRD) had significantly larger EAT/IAT volumes.
T1DM patients with greater BMI, WTH ratio, weighted HbA1c level, triglyceride level and AER≥300/ESRD had significantly larger EAT/IAT volumes. Larger sample size studies are recommended to evaluate independency.
PMCID: PMC4961378  PMID: 27459689
2.  Factors Affecting the Decline in Incidence of Diabetes in the Diabetes Prevention Program Outcomes Study (DPPOS) 
Diabetes  2014;64(3):989-998.
During the first 7 years of the Diabetes Prevention Program Outcomes Study (DPPOS), diabetes incidence rates, when compared with the Diabetes Prevention Program (DPP), decreased in the placebo (−42%) and metformin (−25%), groups compared with the rates in the intensive lifestyle intervention (+31%) group. Participants in the placebo and metformin groups were offered group intensive lifestyle intervention prior to entering the DPPOS. The following two hypotheses were explored to explain the rate differences: “effective intervention” (changes in weight and other factors due to intensive lifestyle intervention) and “exhaustion of susceptible” (changes in mean genetic and diabetes risk scores). No combination of behavioral risk factors (weight, physical activity, diet, smoking, and antidepressant or statin use) explained the lower DPPOS rates of diabetes progression in the placebo and metformin groups, whereas weight gain was the factor associated with higher rates of progression in the intensive lifestyle intervention group. Different patterns in the average genetic risk score over time were consistent with exhaustion of susceptibles. Results were consistent with exhaustion of susceptibles for the change in incidence rates, but not the availability of intensive lifestyle intervention to all persons before the beginning of the DPPOS. Thus, effective intervention did not explain the lower diabetes rates in the DPPOS among subjects in the placebo and metformin groups compared with those in the DPP.
PMCID: PMC4338587  PMID: 25277389
3.  Progression of Electrocardiographic Abnormalities in Type 1 Diabetes During 16 Years of Follow‐up: The Epidemiology of Diabetes Interventions and Complications (EDIC) Study 
The electrocardiogram (ECG) is an objective tool for cardiovascular disease (CVD) risk assessment.
Methods and Results
We evaluated distribution of ECG abnormalities and risk factors for developing new abnormalities in 1314 patients with type 1 diabetes (T1D) from the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Annual ECGs were centrally read. ECG abnormalities were classified as major and minor according to the Minnesota ECG Classification. At EDIC year 1 (baseline), 356 (27.1%) of the participants had at least 1 ECG abnormality (major or minor) whereas 26 (2%) had at least one major abnormality. During 16 years of follow‐up, 1016 (77.3%) participants developed at least 1 new ECG abnormality (major or minor), whereas 172 (13.1%) developed at least 1 new major abnormality. Independent risk factors for developing new major ECG abnormalities were: age, current smoking, increased systolic blood pressure, and higher glycosylated hemoglobin (hazard ratio [HR] [95% CI]: 1.04 [1.02–1.06] per 1‐year increase, 1.75 [1.22–2.53], 1.03 [1.01–1.05] per 1 mm Hg increase, and 1.16 [1.04–1.29] per 10% increase, respectively). Independent risk factors for developing any new ECG abnormalities (major or minor) were age and systolic blood pressure (HR [95% CI]: 1.02 [1.01–1.03] per 1‐year increase and 1.01 [1.00–1.02] per 1 mm Hg increase, respectively).
New ECG abnormalities commonly occur in the course of T1D, consistent with the recognized increasing risk for CVD as patients age. Advanced age, increased systolic blood pressure, smoking, and higher HbA1c are independent risk factor for developing major ECG abnormalities, which underscores the importance of tight glucose control in T1D in addition to management of common CVD risk factors.
PMCID: PMC4943265  PMID: 26976878
electrocardiogram; The Epidemiology of Diabetes Interventions and Complications Study; type 1 diabetes; Electrocardiology (ECG); Epidemiology
4.  Skin collagen fluorophore LW-1 versus skin fluorescence as markers for the long-term progression of subclinical macrovascular disease in type 1 diabetes 
Skin collagen Long Wavelength Fluorescence (LWF) is widely used as a surrogate marker for accumulation of advanced glycation end-products. Here we determined the relationship of LWF with glycemia, skin fluorescence, and the progression of complications during EDIC in 216 participants from the DCCT.
LW-1 and collagen-linked fluorescence (CLF) were measured by either High Performance Liquid Chromatography (HPLC) with fluorescence detection (LW-1) or total fluorescence of collagenase digests (CLF) in insoluble skin collagen extracted from skin biopsies obtained at the end of the DCCT (1993). Skin intrinsic fluorescence (SIF) was noninvasively measured on volar forearm skin at EDIC year 16 by the SCOUT DS instrument.
LW-1 levels significantly increased with age and diabetes duration (P < 0.0001) and significantly decreased by intensive vs. conventional glycemic therapy in both the primary (P < 0.0001) and secondary (P < 0.037) DCCT cohorts. Levels were associated with 13–16 year progression risk of retinopathy (>3 sustained microaneurysms, P = 0.0004) and albumin excretion rate (P = 0.0038), the latter despite adjustment for HbA1c. Comparative analysis for all three fluorescent measures for future risk of subclinical macrovascular disease revealed the following significant (P < 0.05) associations after adjusting for age, diabetes duration and HbA1c: coronary artery calcium with SIF and CLF; intima-media thickness with SIF and LW-1; and left ventricular mass with LW-1 and CLF.
LW-1 is a novel risk marker that is robustly and independently associated with the future progression of microvascular disease, intima-media thickness and left ventricular mass in type 1 diabetes.
Trial registration NCT00360815 and NCT00360893 at
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0343-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4750185  PMID: 26864236
Glycation; Skin autofluorescence; HbA1c; Retinopathy; Nephropathy; Neuropathy
5.  Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial 
European Heart Journal  2016;37(19):1526-1534.
We previously reported that in the EMPA-REG OUTCOME® trial, empagliflozin added to standard of care reduced the risk of 3-point major adverse cardiovascular events, cardiovascular and all-cause death, and hospitalization for heart failure in patients with type 2 diabetes and high cardiovascular risk. We have now further investigated heart failure outcomes in all patients and in subgroups, including patients with or without baseline heart failure.
Methods and results
Patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo. Seven thousand and twenty patients were treated; 706 (10.1%) had heart failure at baseline. Heart failure hospitalization or cardiovascular death occurred in a significantly lower percentage of patients treated with empagliflozin [265/4687 patients (5.7%)] than with placebo [198/2333 patients (8.5%)] [hazard ratio, HR: 0.66 (95% confidence interval: 0.55–0.79); P < 0.001], corresponding to a number needed to treat to prevent one heart failure hospitalization or cardiovascular death of 35 over 3 years. Consistent effects of empagliflozin were observed across subgroups defined by baseline characteristics, including patients with vs. without heart failure, and across categories of medications to treat diabetes and/or heart failure. Empagliflozin improved other heart failure outcomes, including hospitalization for or death from heart failure [2.8 vs. 4.5%; HR: 0.61 (0.47–0.79); P < 0.001] and was associated with a reduction in all-cause hospitalization [36.8 vs. 39.6%; HR: 0.89 (0.82–0.96); P = 0.003]. Serious adverse events and adverse events leading to discontinuation were reported by a higher proportion of patients with vs. without heart failure at baseline in both treatment groups, but were no more common with empagliflozin than with placebo.
In patients with type 2 diabetes and high cardiovascular risk, empagliflozin reduced heart failure hospitalization and cardiovascular death, with a consistent benefit in patients with and without baseline heart failure.
PMCID: PMC4872285  PMID: 26819227
Cardiovascular disease; Hospitalization; Mortality
6.  Applications of the Wei-Lachin Multivariate One-Sided Test for Multiple Outcomes on Possibly Different Scales 
PLoS ONE  2014;9(10):e108784.
Many studies aim to assess whether a therapy has a beneficial effect on multiple outcomes simultaneously relative to a control. Often the joint null hypothesis of no difference for the set of outcomes is tested using separate tests with a correction for multiple tests, or using a multivariate T2-like MANOVA or global test. However, a more powerful test in this case is a multivariate one-sided or one-directional test directed at detecting a simultaneous beneficial treatment effect on each outcome, though not necessarily of the same magnitude. The Wei-Lachin test is a simple 1 df test obtained from a simple sum of the component statistics that was originally described in the context of a multivariate rank analysis. Under mild conditions this test provides a maximin efficient test of the null hypothesis of no difference between treatment groups for all outcomes versus the alternative hypothesis that the experimental treatment is better than control for some or all of the component outcomes, and not worse for any. Herein applications are described to a simultaneous test for multiple differences in means, proportions or life-times, and combinations thereof, all on potentially different scales. The evaluation of sample size and power for such analyses is also described. For a test of means of two outcomes with a common unit variance and correlation 0.5, the sample size needed to provide 90% power for two separate one-sided tests at the 0.025 level is 64% greater than that needed for the single Wei-Lachin multivariate one-directional test at the 0.05 level. Thus, a Wei-Lachin test with these operating characteristics is 39% more efficient than two separate tests. Likewise, compared to a T2-like omnibus test on 2 df, the Wei-Lachin test is 32% more efficient. An example is provided in which the Wei-Lachin test of multiple components has superior power to a test of a composite outcome.
PMCID: PMC4201485  PMID: 25329662
8.  Skin collagen advanced glycation endproducts (AGEs) and the long-term progression of sub-clinical cardiovascular disease in type 1 diabetes 
We recently reported strong associations between eight skin collagen AGEs and two solubility markers from skin biopsies obtained at DCCT study closeout and the long-term progression of microvascular disease in EDIC, despite adjustment for mean glycemia. Herein we investigated the hypothesis that some of these AGEs (fluorescence to be reported elsewhere) correlate with long-term subclinical cardiovascular disease (CVD) measurements, i.e. coronary artery calcium score (CAC) at EDIC year 7–9 (n = 187), change of carotid intima-media thickness (IMT) from EDIC year 1 to year 6 and 12 (n = 127), and cardiac MRI outcomes at EDIC year 15–16 (n = 142).
Skin collagen AGE measurements obtained from stored specimens were related to clinical data from the DCCT/EDIC using Spearman correlations and multivariable logistic regression analyses.
Spearman correlations showed furosine (early glycation) was associated with future mean CAC (p < 0.05) and CAC >0 (p = 0.39), but not with CAC score <100 vs. >100. Glucosepane and pentosidine crosslinks, methylglyoxal hydroimidazolones (MG-H1) and pepsin solubility (inversely) correlated with IMT change from year 1 to 6(all P < 0.05). Left ventricular (LV) mass (cMRI) correlated with MG-H1, and inversely with pepsin solubility (both p < 0.05), while the ratio LV mass/end diastolic volume correlated with furosine and MG-H1 (both p < 0.05), and highly with CML (p < 0.01). In multivariate analysis only furosine (p = 0.01) was associated with CAC. In contrast IMT was inversely associated with lower collagen pepsin solubility and positively with glucosepane,
In type 1 diabetes, multiple AGEs are associated with IMT progression in spite of adjustment for A1c implying a likely participatory role of glycation and AGE mediated crosslinking on matrix accumulation in coronary arteries. This may also apply to functional cardiac MRI outcomes, especially left ventricular mass. In contrast, early glycation measured by furosine, but not AGEs, was associated with CAC score, implying hyperglycemia as a risk factor in calcium deposition perhaps via processes independent of glycation.
Trial registration: Registered at Clinical trial reg. nos. NCT00360815 and NCT00360893,
PMCID: PMC4560872  PMID: 26341632
AGEs; A1c; DCCT/EDIC; Coronary artery calcium; Intima media thickening; Cardiac indices
9.  Association between seven years of intensive treatment of type 1 diabetes and long term mortality 
JAMA  2015;313(1):45-53.
Whether mortality in type 1 diabetes mellitus is affected following intensive glycemic therapy has not been established.
To determine whether mortality differed between the original intensive and conventional treatment groups in the long-term follow-up of the Diabetes Control and Complications Trial (DCCT) cohort.
Design, Setting, and Participants
After the DCCT (1983–1993) ended, participants were followed up in a multisite (27 US and Canadian academic clinical centers) observational study (Epidemiology of Diabetes Control and Complications [EDIC]) until December 31, 2012. Participants were 1441 healthy volunteers with diabetes mellitus who, at baseline, were 13 to 39 years of age with 1 to 15 years of diabetes duration and no or early microvascular complications, and without hypertension, preexisting cardiovascular disease, or other potentially life-threatening disease.
During the clinical trial, participants were randomly assigned to receive intensive therapy (n = 711) aimed at achieving glycemia as close to the nondiabetic range as safely possible, or conventional therapy (n = 730) with the goal of avoiding symptomatic hypoglycemia and hyperglycemia. At the end of the DCCT, after a mean of 6.5 years, intensive therapy was taught and recommended to all participants and diabetes care was returned to personal physicians.
Main Outcomes
Total and cause-specific mortality was assessed through annual contact with family and friends and through records over 27 years mean follow-up.
Vital status was ascertained for 1429 (99.2%) participants. There were 107 deaths, 64 in the conventional and 43 in the intensive group. The absolute risk difference was −109 per 100 000 patient-years (95%CI, −218 to −1), with lower all-cause mortality risk in the intensive therapy group (hazard ratio [HR] = 0.67 [95%CI, 0.46–0.99]; P = .045). Primary causes of death were cardiovascular disease (24 deaths; 22.4%), cancer (21 deaths; 19.6%), acute diabetes complications (19 deaths; 17.8%), and accidents or suicide (18 deaths; 16.8%). Higher levels of glycated hemoglobin (HbA1c) were associated with all-cause mortality (HR = 1.56 [95%CI, 1.35–1.81 per 10% relative increase in HbA1c]; P < .001), as well as the development of albuminuria (HR = 2.20 [95%CI, 1.46–3.31]; P < .001).
Conclusions and Relevance
After a mean of 27 years’ follow-up of patients with type 1 diabetes, 6.5 years of initial intensive diabetes therapy was associated with a modestly lower all-cause mortality compared with conventional therapy.
PMCID: PMC4306335  PMID: 25562265
10.  Update on Cardiovascular Outcomes at 30 Years of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study 
Diabetes Care  2013;37(1):39-43.
To describe the beneficial long-term effects of an average of 6.5 years of intensive diabetes therapy (INT) in type 1 diabetes on measures of atherosclerosis, cardiac structure and function, and clinical cardiovascular events observed in the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study.
The DCCT was a randomized clinical trial of 1,441 participants assigned to receive INT or conventional therapy (CON). It was conducted between 1983–1993 with an average follow-up of 6.5 years. EDIC (1994–present) is an observational follow-up of the DCCT cohort. Cardiovascular events have been recorded throughout. During EDIC common carotid intima-media thickness (IMT) was measured with ultrasound, coronary artery calcification with computed tomography, and cardiac structure and function with cardiac magnetic resonance imaging.
DCCT INT and lower levels of HbA1c during DCCT/EDIC were associated with thinner carotid IMT, less coronary calcification, and a lower incidence of clinical cardiovascular events including myocardial infarction, stroke, and cardiac death. While there were no significant differences in cardiac structure and function between the former INT and CON groups, they were significantly associated with higher HbA1c during DCCT/EDIC.
DCCT INT and the attendant 6.5 years of lower HbA1c had long-term salutary effects on the development and progression of atherosclerosis and cardiovascular disease during the subsequent follow-up during EDIC.
PMCID: PMC3868002  PMID: 24356596
11.  Evaluating the Role of Epigenetic Histone Modifications in the Metabolic Memory of Type 1 Diabetes 
Diabetes  2014;63(5):1748-1762.
We assessed whether epigenetic histone posttranslational modifications are associated with the prolonged beneficial effects (metabolic memory) of intensive versus conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study. We performed chromatin immunoprecipitation linked to promoter tiling arrays to profile H3 lysine-9 acetylation (H3K9Ac), H3 lysine-4 trimethylation (H3K4Me3), and H3K9Me2 in blood monocytes and lymphocytes obtained from 30 DCCT conventional treatment group subjects (case subjects: mean DCCT HbA1c level >9.1% [76 mmol/mol] and progression of retinopathy or nephropathy by EDIC year 10 of follow-up) versus 30 DCCT intensive treatment subjects (control subjects: mean DCCT HbA1c level <7.3% [56 mmol/mol] and without progression of retinopathy or nephropathy). Monocytes from case subjects had statistically greater numbers of promoter regions with enrichment in H3K9Ac (active chromatin mark) compared with control subjects (P = 0.0096). Among the patients in the two groups combined, monocyte H3K9Ac was significantly associated with the mean HbA1c level during the DCCT and EDIC (each P < 2.2E-16). Of note, the top 38 case hyperacetylated promoters (P < 0.05) included >15 genes related to the nuclear factor-κB inflammatory pathway and were enriched in genes related to diabetes complications. These results suggest an association between HbA1c level and H3K9Ac, and a possible epigenetic explanation for metabolic memory in humans.
PMCID: PMC3994951  PMID: 24458354
12.  Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA®) 
CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (NCT01243424) is an ongoing, randomized trial in subjects with early type 2 diabetes and increased cardiovascular risk or established complications that will determine the long-term cardiovascular impact of linagliptin versus the sulphonylurea glimepiride. Eligible patients were sulphonylurea-naïve with HbA1c 6.5%–8.5% or previously exposed to sulphonylurea (in monotherapy or in a combination regimen <5 years) with HbA1c 6.5%–7.5%. Primary outcome is time to first occurrence of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina. A total of 631 patients with primary outcome events will be required to provide 91% power to demonstrate non-inferiority in cardiovascular safety by comparing the upper limit of the two-sided 95% confidence interval as being below 1.3 for a given hazard ratio. Hierarchical testing for superiority will follow, and the trial has 80% power to demonstrate a 20% relative cardiovascular risk reduction. A total of 6041 patients were treated with median type 2 diabetes duration 6.2 years, 40.0% female, mean HbA1c 7.2%, 66% on 1 and 24% on 2 glucose-lowering agents and 34.5% had previous cardiovascular complications. The results of CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes may influence the decision-making process for selecting a second glucose-lowering agent after metformin in type 2 diabetes.
PMCID: PMC4390606  PMID: 25780262
Type 2 diabetes; cardiovascular complications; macrovascular; dipeptidyl-peptidase-4 inhibitor; sulphonylurea
13.  Relationship of Glycated Albumin to Blood Glucose and HbA1c Values and to Retinopathy, Nephropathy, and Cardiovascular Outcomes in the DCCT/EDIC Study 
Diabetes  2013;63(1):282-290.
The association of chronic glycemia, measured by HbA1c, with long-term complications of type 1 diabetes has been well established in the Diabetes Control and Complications Trial (DCCT) and other studies. The role of intermediate-term and acute glycemia and of glucose variability on microvascular and cardiovascular disease (CVD) is less clear. In order to examine the interrelationships among long-term, intermediate-term, and acute measures of glucose and its daily variability, we compared HbA1c, glycated albumin (GA), and seven-point glucose profile concentrations measured longitudinally in a case-cohort subpopulation of the DCCT. HbA1c and GA were closely correlated with each other and with the mean blood glucose (MBG) calculated from the seven-point profile. The associations of glucose variability and postprandial concentrations with HbA1c and GA were relatively weak and were further attenuated when MBG was included in multivariate models. In the case-cohort analyses, HbA1c and GA had similar associations with retinopathy and nephropathy, which were strengthened when both measures were considered together. Only HbA1c was significantly associated with CVD. The demonstrated interrelationships among different measures of glycemia will need to be considered in future analyses of their roles in the development of long-term complications of type 1 diabetes.
PMCID: PMC3868040  PMID: 23990364
14.  Identifying Change Points in a Covariate Effect on Time-to-Event Analysis with Reduced Isotonic Regression 
PLoS ONE  2014;9(12):e113948.
Isotonic regression is a useful tool to investigate the relationship between a quantitative covariate and a time-to-event outcome. The resulting non-parametric model is a monotonic step function of a covariate X and the steps can be viewed as change points in the underlying hazard function. However, when there are too many steps, over-fitting can occur and further reduction is desirable. We propose a reduced isotonic regression approach to allow combination of small neighboring steps that are not statistically significantly different. In this approach, a second stage, the reduction stage, is integrated into the usual monotonic step building algorithm by comparing the adjacent steps using appropriate statistical testing. This is achieved through a modified dynamic programming algorithm. We implemented the approach with the simple exponential distribution and then its extension, the Weibull distribution. Simulation studies are used to investigate the properties of the resulting isotonic functions. We apply this methodology to the Diabetes Control and Complication Trial (DCCT) data set to identify potential change points in the association between HbA1c and the risk of severe hypoglycemia.
PMCID: PMC4256386  PMID: 25473827
15.  Validity of Self Report in Type 1 Diabetic Subjects for Laser Treatment of Retinopathy 
Ophthalmology  2013;120(12):10.1016/j.ophtha.2013.06.002.
This study sought to determine the validity of self report of prior pan-retinal photocoagulation (PRP) and focal photocoagulation (FP) compared to fundus photography.
Prospective cohort study.
1363 type 1 diabetic subjects from the Epidemiology of Diabetes Interventions and Complications (EDIC) Study, a subset of the 1441 subjects originally enrolled in the multi-center Diabetes Control and Complications Trial.
At each annual visit, subjects were asked by EDIC staff whether they had PRP and/or FP since the last completed annual clinic visit. Fundus photographs were collected in one quarter of the cohort each year and in the whole cohort at EDIC years 4 and 10. Photographs were graded for the presence and extent of PRP and FP. Seventeen years of subject reporting and photograph grading of PRP and FP were compared in EDIC subjects.
Main Outcome Measures
Kappa, sensitivity, specificity, and positive and negative predictive values were calculated for subject-reported PRP and FP. Factors influencing subject misreporting were investigated.
For subject reporting, 1244 (96%) of 1296 subjects with gradable photographs accurately reported whether they had a history of PRP in one or both eyes, and 1259 (97.5%) of 1291 with valid photographs correctly reported their history of FP. Sensitivities for PRP and FP were 90.4 and 74.0%; specificities, 96.0 and 98.8%; positive predictive values, 75.9 and 80.3%; negative predictive values, 98.9 and 98.4%; and kappa 0.80 and 0.76. Risk factors associated with misreporting include prior laser for diabetic retinopathy and prior ocular surgery (each p <0.04).
For subjects with type 1 diabetes, in the absence of a clinical exam or fundus photographs, subject self report could be a reliable tool in a well-monitored study for assessing laser treatment type in diabetic retinopathy.
PMCID: PMC3818390  PMID: 23890420
17.  Sample Size and Power for a Logrank Test and Cox Proportional Hazards Model with Multiple Groups and Strata, or a Quantitative Covariate with Multiple Strata 
Statistics in medicine  2013;32(25):4413-4425.
General expressions are described for the evaluation of sample size and power for the K group Mantel-logrank test or the Cox PH model score test. Under an exponential model, the method of Lachin and Foulkes [1] for the 2 group case is extended to the K ≥ 2 group case using the non-centrality parameter of the K – 1 df chi-square test. Similar results are also shown to apply to the K group score test in a Cox PH model. Lachin and Foulkes [1] employed a truncated exponential distribution to provide for a non-linear rate of enrollment. Expressions for the mean time of enrollment and the expected follow-up time in the presence of exponential losses-to-follow-up are presented. When used with the expression for the non-centrality parameter for the test, equations are derived for the evaluation of sample size and power under specific designs with R years of recruitment and T years total duration.
Sample size and power are also described for a stratified-adjusted K group test and for the assessment of a group by stratum interaction. Similarly computations are described for a stratified-adjusted analysis of a quantitative covariate and a test of a stratum by covariate interaction in the Cox PH model.
PMCID: PMC3775959  PMID: 23670965
Sample size; power; logrank test; Cox Proportional Hazards Model; multiple groups; exponential survival; stratified analysis; interactions
18.  Effects of Prior Intensive Versus Conventional Therapy and History of Glycemia on Cardiac Function in Type 1 Diabetes in the DCCT/EDIC 
Diabetes  2013;62(10):3561-3569.
Intensive diabetes therapy reduces the prevalence of coronary calcification and progression of atherosclerosis and the risk of cardiovascular disease (CVD) events in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. The effects of intensive therapy on measures of cardiac function and structure and their association with glycemia have not been explored in type 1 diabetes (T1DM). We assess whether intensive treatment compared with conventional treatment during the DCCT led to differences in these parameters during EDIC. After 6.5 years of intensive versus conventional therapy in the DCCT, and 15 years of additional follow-up in EDIC, left ventricular (LV) indices were measured by cardiac magnetic resonance (CMR) imaging in 1,017 of the 1,371 members of the DCCT cohort. There were no differences between the DCCT intensive versus conventional treatment in end diastolic volume (EDV), end systolic volume, stroke volume (SV), cardiac output (CO), LV mass, ejection fraction, LV mass/EDV, or aortic distensibility (AD). Mean DCCT/EDIC HbA1c over time was associated with EDV, SV, CO, LV mass, LV mass/EDV, and AD. These associations persisted after adjustment for CVD risk factors. Cardiac function and remodeling in T1DM assessed by CMR in the EDIC cohort was associated with prior glycemic exposure, but there was no effect of intensive versus conventional treatment during the DCCT on cardiac parameters.
PMCID: PMC3781466  PMID: 23520132
19.  Haptoglobin Genotype and the Rate of Renal Function Decline in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study 
Diabetes  2013;62(9):3218-3223.
Many patients with type 1 diabetes develop renal disease despite moderately good metabolic control, suggesting other risk factors may play a role. Recent evidence suggests that the haptoglobin (HP) 2-2 genotype, which codes for a protein with reduced antioxidant activity, may predict renal function decline in type 1 diabetes. We examined this hypothesis in 1,303 Caucasian participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. HP genotype was determined by polyacrylamide gel electrophoresis. Glomerular filtration rate was estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and albumin excretion based on timed urine samples. Participants were followed up for a mean of 22 years. HP genotype was significantly associated with the development of sustained estimated glomerular filtration rate (GFR) <60 mL/min/1.73 m2 and with end-stage renal disease (ESRD), with HP 2-2 having greater risk than HP 2-1 and 1-1. No association was seen with albuminuria. Although there was no treatment group interaction, the associations were only significant in the conventional treatment group, where events rates were much higher. We conclude that the HP genotype is significantly associated with the development of reduced GFR and ESRD in the DCCT/EDIC study.
PMCID: PMC3749329  PMID: 23761102
20.  Aortic Distensibility in Type 1 Diabetes 
Diabetes Care  2013;36(8):2380-2387.
To evaluate the relationship between long-term glycemia, traditional cardiovascular disease (CVD) risk factors, and ascending aortic stiffness in type 1 diabetes.
Eight hundred seventy-nine subjects in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study were evaluated. The stiffness/distensibility of the ascending thoracic aorta (AA) was measured with magnetic resonance imaging. Associations of AA distensibility and CVD risk factors, mean HbA1c, and cardiovascular complications including macroalbuminuria were assessed using multivariate linear regression models.
The mean age of the subjects was 50 ± 7 years (47% women, mean diabetes duration of 28 years). Over 22 years of follow-up, 27% of participants had cardiovascular complications. After adjusting for gender and cohort, AA distensibility was lower with increasing age, mean systolic blood pressure, LDL, and HbA1c measured over an average of 22 years (−26.3% per 10 years, −11.0% per 10 mmHg SBP, −1.8% per 10 mg/dL of LDL, and −9.3% per unit mean HbA1c [%], respectively). Patients with macroalbuminuria had 25% lower AA distensibility compared with those without (P < 0.0001). Lower AA distensibility also was associated with greater ratio of left ventricular mass to volume (−3.4% per 0.1 g/mL; P < 0.0001).
Our findings indicate strong adverse effects of hypertension, chronic hyperglycemia and macroalbuminuria on AA stiffness in type 1 diabetes in the DCCT/EDIC cohort.
PMCID: PMC3714531  PMID: 23474588
21.  Circulating Vitamin D Metabolites and Subclinical Atherosclerosis in Type 1 Diabetes 
Diabetes Care  2013;36(8):2423-2429.
People with type 1 diabetes are at high risk of premature atherosclerosis. Existing evidence suggests that impaired vitamin D metabolism may contribute to the development of atherosclerosis. We tested associations of circulating vitamin D metabolite concentrations with subclinical atherosclerosis among 1,193 participants with type 1 diabetes in the DCCT/EDIC study.
We measured plasma concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D by mass spectrometry at the end of the DCCT. In a staggered cross-sectional design, we tested associations with coronary artery calcium (CAC), measured by computed tomography a median of 10 years later, and with common and internal carotid intima-media thickness (IMT), measured by B-mode ultrasonography on two occasions a median of 4 years later and a median of 10 years later. We hypothesized that lower concentrations of each vitamin D metabolite would be associated with increased risk of CAC and greater carotid IMT.
At the time metabolites were measured, mean age was 32.4 years and mean duration of diabetes was 7.5 years. The prevalence and severity of CAC tended to be lower—not higher—with lower concentrations of each vitamin D metabolite. For instance, in a fully adjusted multinomial logistic model, a 25 nmol/L lower 25-hydroxyvitamin D was associated with a 0.8-fold decrease in the odds of having higher CAC (95% CI 0.68–0.96, P = 0.01). No vitamin D metabolite was associated with either common or internal mean IMT.
We did not find evidence linking impaired vitamin D metabolism with increased subclinical atherosclerosis in type 1 diabetes.
PMCID: PMC3714470  PMID: 23530012
22.  Rationale and Design of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) 
Diabetes Care  2013;36(8):2254-2261.
The epidemic of type 2 diabetes (T2DM) threatens to become the major public health problem of this century. However, a comprehensive comparison of the long-term effects of medications to treat T2DM has not been conducted. GRADE, a pragmatic, unmasked clinical trial, aims to compare commonly used diabetes medications, when combined with metformin, on glycemia-lowering effectiveness and patient-centered outcomes.
GRADE was designed with support from a U34 planning grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The consensus protocol was approved by NIDDK and the GRADE Research Group. Eligibility criteria for the 5,000 metformin-treated subjects include <5 years' diabetes duration, ≥30 years of age at time of diagnosis, and baseline hemoglobin A1c (A1C) of 6.8–8.5% (51–69 mmol/mol). Medications representing four classes (sulfonylureas, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, and insulin) will be randomly assigned and added to metformin (minimum–maximum 1,000–2,000 mg/day). The primary metabolic outcome is the time to primary failure defined as an A1C ≥7% (53 mmol/mol), subsequently confirmed, over an anticipated mean observation period of 4.8 years (range 4–7 years). Other long-term metabolic outcomes include the need for the addition of basal insulin after a confirmed A1C >7.5% (58 mmol/mol) and, ultimately, the need to implement an intensive basal/bolus insulin regimen. The four drugs will also be compared with respect to selected microvascular complications, cardiovascular disease risk factors, adverse effects, tolerability, quality of life, and cost-effectiveness.
GRADE will compare the long-term effectiveness of major glycemia-lowering medications and provide guidance to clinicians about the most appropriate medications to treat T2DM. GRADE begins recruitment at 37 centers in the U.S. in 2013.
PMCID: PMC3714493  PMID: 23690531
23.  Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™) 
Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME™ trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes.
Patients who were drug-naïve (HbA1c ≥7.0% and ≤9.0%), or on background glucose-lowering therapy (HbA1c ≥7.0% and ≤10.0%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until ≥691 confirmed primary outcome events have occurred, providing a power of 90% to yield an upper limit of the adjusted 95% CI for a hazard ratio of <1.3 with a one-sided α of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved.
Between Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41% from Europe, 20% from North America, and 19% from Asia). At baseline, the mean age was 63 ± 9 years, BMI 30.6 ± 5.3 kg/m2, HbA1c 8.1 ± 0.8%, and eGFR 74 ± 21 ml/min/1.73 m2. The study is expected to report in 2015.
EMPA-REG OUTCOME™ will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection.
Trial registration NCT01131676
PMCID: PMC4072621  PMID: 24943000
Blood pressure; Body weight; Empagliflozin; Glycemic control; Macrovascular; Microvascular; SGLT2 inhibitor; Type 2 diabetes
24.  The association between skin collagen glucosepane and past progression of microvascular and neuropathic complications in type 1 diabetes 
We determined the association between novel and acid-labile skin collagen-linked advanced glycation endproducts (AGEs) and the progression of microvascular and neuropathic complications from baseline to near study closeout in the Diabetes Control and Complications Trial (DCCT).
From a skin biopsy obtained near the close of the DCCT, proteolytic collagen digests were analyzed by liquid chromatography/mass spectrometry (LC/MS/MS) for glucosepane (GSPNE), glyoxal and methylglyoxal hydroimidazolones (G-H1 and MG-H1) and the glycation product fructose-lysine(FL) using isotope dilution method.
GSPNE and MG-H1 correlated with age and diabetes duration (p<0.02), while GSPNE and FL correlated with the history of glycemia expressed as mean A1c(p≤0.003). Age and duration-adjusted GSPNE and FL levels were lower in intensive (INT) vs. conventional (CONV) treatment subjects in the primary prevention DCCT cohort (p < 0.0001), and FL lower in INT in the secondary intervention cohort (p < 0.0001). GSPNE was associated with increased incidence of retinopathy progression (odds ratio (OR)/unit increase in GSPNE: 2.5 for 3 step progression on the ETDRS scale, p=0.003) and sustained ≥ 3 microaneurysms (MA) (OR=4.8, p<0.0001) from DCCT baseline up to the time of the biopsy, and prevalence of microalbuminuria or AER>40 mg/24 hr (OR=5.3, P<0.0001), and confirmed clinical neuropathy (OR=3.4, p=0.015) at the time of the biopsy. GSPNE adjusted for mean A1c remained significant for ≥ 3 MA (p=0.0252) and AER (p=0.0006). The strong association of complications with A1c was reduced or eliminated when adjusted for GSPNE.
Glucosepane is a novel AGE marker of diabetic complications that is robustly associated with nephropathic, retinopathic and neuropathic outcomes despite adjustment for A1c, suggesting that it could be one mediator of these complications with possible diagnostic implications.
PMCID: PMC3577949  PMID: 23153673
Glycemia; retinopathy; nephropathy; collagen; methylglyoxal; advanced glycation endproducts (AGEs)
25.  Power of the Mantel-Haenszel and Other Tests for Discrete or Grouped Time-to-event Data Under a Chained Binomial Model 
Statistics in medicine  2012;32(2):220-229.
Power for time-to-event analyses is usually assessed under continuous time models. Often, however, times are discrete or grouped, as when the event is only observed when a procedure is performed. Wallenstein and Wittes (Biometrics, 1993) describe the power of the Mantel-Haenszel test for discrete life-tables under their chained binomial model for specified vectors of event probabilities over intervals of time. Herein the expressions for these probabilities are derived under a piecewise exponential model allowing for staggered entry and losses to follow-up.
Radhakrishna (Biometrics, 1965) showed that the Mantel-Haenszel test is maximally efficient under the alternative of a constant odds ratio and derived the optimal weighted test under other alternatives. Lachin (Biostatistical Methods: The Assessment of Relative Risks, 2011) describes the power function of this family of weighted Mantel-Haenszel tests. Prentice and Gloeckler (Biometrics, 1978) describe a generalization of the proportional hazards model for grouped time data, and the corresponding maximally efficient score test. Their test is also shown to be a weighted Mantel-Haenszel test and its power function is likewise obtained.
There is trivial loss in power under the discrete chained binomial model relative to the continuous-time case provided that there is a modest number of periodic evaluations. Relative to the case of homogeneity of odds ratios, there can be substantial loss in power when there is substantial heterogeneity of odds ratios, especially when heterogeneity occurs early in a study when most subjects are at risk, but little loss in power when there is heterogeneity late in a study.
PMCID: PMC3634579  PMID: 22807191
Sample size; power; Mantel-Haenszel test; chained binomial model; Cox Proportional Hazards Model; Prentice-Gloeckler discrete Proportional Hazards Model

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