Diabetes Control And Complications Trial Pdf
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- Diabetes Control And Complications Trial Pdf
- Diabetes Control and Complications Trial (DCCT)
- Early Worsening of Diabetic Retinopathy in the Diabetes Control and Complications Trial
- The Diabetes Control and Complications Trial: the gift that keeps giving
Diabetes Control And Complications Trial Pdf
Cumulative incidence of sustained 3-step or more progression from the level of retinopathy present at 18 months for those with and those without 3-step or more early worsening.
Left, Conventional treatment group. Right, Intensive treatment group. Spline-smoothed estimates of the distribution of the reduction in hemoglobin A 1c HbA 1c level at 6 months from the level of HbA 1c at screening in the conventional and the intensive treatment groups negative values represent increases in HbA 1c level.
The density estimate is the estimated integrand such that the total area under each curve is 1. Note that nearly one half of intensively treated patients had a reduction of 2 U or more, while few conventionally treated patients did so. Proportion of patients in the intensive and conventional treatment groups experiencing any early worsening within tertiles thirds of the distribution of the screening hemoglobin A 1c HbA 1c value and, for each, within tertiles of the distribution of the month 6 reduction in HbA 1c level from the initial screening value.
The respective regression coefficients corresponding to the average reduction in HbA 1c level were 0. These intercepts include all other covariate effects evaluated at their mean values. Arch Ophthalmol.
Retinopathy severity was assessed in 7-field stereoscopic fundus photographs taken at baseline and every 6 months. The risk of 3-step or greater progression from the retinopathy level present 18 months after entry into the trial was greater in patients who previously had had early worsening than in those who had not.
However, the large long-term risk reduction with intensive treatment was such that outcomes in intensively treated patients who had early worsening were similar to or more favorable than outcomes in conventionally treated patients who had not. The most important risk factors for early worsening were higher hemoglobin A 1c level at screening and reduction of this level during the first 6 months after randomization.
We found no evidence to suggest that more gradual reduction of glycemia might be associated with less risk of early worsening. Early worsening led to high-risk proliferative retinopathy in 2 patients and to clinically significant macular edema in 3; all responded well to treatment.
Although no case of early worsening was associated with serious visual loss, our results are consistent with previous reports of sight-threatening worsening when intensive treatment is initiated in patients with long-standing poor glycemic control, particularly if retinopathy is at or past the moderate nonproliferative stage. Ophthalmologic monitoring before initiation of intensive treatment and at 3-month intervals for 6 to 12 months thereafter seems appropriate for such patients.
In patients whose retinopathy is already approaching the high-risk stage, it may be prudent to delay the initiation of intensive treatment until photocoagulation can be completed, particularly if hemoglobin A 1c is high. THERE HAVE been many reports of the curious, unanticipated, and seemingly paradoxical worsening of diabetic retinopathy after rapid improvement of blood glucose control.
In some cases worsening was striking and led to permanent visual impairment, 1 - 6 , 15 , 16 , 18 while in others it was transient and apparently benign. In some reports worsening occurred more frequently in women. The Diabetes Control and Complications Trial DCCT was a multicenter, randomized clinical trial designed to assess the benefits and risks of intensive as compared with conventional diabetes treatment in persons with insulin-dependent diabetes mellitus of 1 to 15 years' duration and with retinopathy at baseline ranging from none to the moderate nonproliferative stage.
Design and methods have been presented in detail 19 , 20 and summarized 21 , 22 previously. Briefly, major eligibility criteria were age of 13 to 39 years, insulin dependence as evidenced by deficient C-peptide secretion, general good health without hypertension or hypercholesterolemia, and willingness, after a detailed informed consent process, to accept random assignment to intensive or conventional treatment. The trial followed the principles of the Declaration of Helsinki and was approved by the institutional review boards for research in human subjects of the participating centers.
Participants were randomly assigned to receive either conventional or intensive treatment. Conventional treatment consisted of 1 or 2 daily insulin injections, daily self-monitoring of urine or blood glucose levels, and diet and exercise education. The goals of treatment were freedom from symptoms of hyperglycemia and from severe or frequent hypoglycemia, as well as maintenance of normal growth and development and ideal body weight.
Intensive treatment consisted of insulin administered 3 or more times daily by injection or an external pump, with doses adjusted according to self-monitored blood glucose levels measured at least 4 times per day and to anticipated diet intake and exercise.
The goals were preprandial blood glucose levels of 3. Seven-field stereoscopic color fundus photographs were taken by certified photographers every 6 months and were graded centrally with graders masked to treatment according to the ETDRS modification of the Airlie House classification.
This classification provides a grade for the severity of each type of lesion of diabetic retinopathy for each eye. Grades for the various lesions were used to derive overall retinopathy severity levels for each patient according to the ETDRS final scale. Fundus photographs were also obtained at 3 months for the initial patients enrolled in the trial, after which this assessment was dropped from the protocol.
The first 3 definitions are not mutually exclusive. The analysis of any 1 definition of EW included each patient who met the criteria for that definition, regardless of whether that patient also did or did not meet the criteria for other definitions of EW.
To evaluate the longer-term clinical impact of EW, we analyzed rates of subsequent progression from the level of retinopathy present at the month visit, using the criterion of progression by 3 or more steps on the ETDRS final scale sustained for 2 consecutive 6-month visits sustained 3-step progression. The subsequent event was counted at the time of the first of the 2 consecutive "positive" visits. We also compared change in retinopathy severity between the baseline and 4-year visits in those with vs those without EW.
Simple proportions were computed to describe the prevalence of the 4 types of EW within the intensive and conventional treatment groups, stratified by the baseline retinopathy severity level, and then for all the baseline levels combined. Within each baseline retinopathy stratum, a logistic regression model 24 was used to compute the maximum likelihood estimate of the log odds of EW in the intensive treatment group relative to the conventional treatment group.
Analyses were also conducted comparing EW vs no EW and intensive vs conventional treatment within different subgroups based on selected baseline covariates.
These regression models were used to describe the expected probability of EW as a function of the reduction in HbA 1c during the first 6 months of intensive therapy. For an individual patient with covariate values X 1 ,. In these models, X 13 is the value of the reduction in HbA 1c from screening to the average at months 4 and 5.
To describe the average risk of EW as a function of the reduction in HbA 1c , these estimated probabilities were obtained for a hypothetical patient with the average value of the other covariates.
The relative risk of 3-step or more progression for those with EW relative to those without EW was computed by means of the proportional hazards regression model, 27 and the log relative risk log hazard ratio was estimated via the regression coefficients.
These proportional hazards analyses were performed separately within baseline retinopathy strata, and then for all strata combined, both with and without stratifying for the levels of retinopathy at month The proportional hazards regression model was also used to compute the risk of 3-step or more progression in the intensive treatment group relative to the conventional treatment group, among those with EW and among those without EW, again separately within baseline retinopathy strata, and then for all the strata combined.
Additional analyses comparing the relative risks of intensive vs conventional treatment among those with vs those without EW were performed by testing for significant differences between the log of the relative risks by means of a standard z test.
The distribution of the number of steps of change in the level of retinopathy from that at baseline to that at year 4 was compared between those with EW and those without EW by means of the Mann-Whitney test, 28 separately for each of the 2 treatment groups. These analyses were performed with and without stratification adjustment for the baseline levels of retinopathy.
In the stratified analysis, the overall test of differences between those with and those without EW was obtained with the Wei-Lachin test of stochastic ordering 28 among the Mann-Whitney analyses within strata, using equal weights for each of the retinopathy strata.
The data are summarized by presenting the proportion of patients whose retinopathy level at year 4 relative to the baseline level was better, the same, worse by 1 or 2 steps, or worse by 3 or more steps, separately among those with EW and among those without EW.
The differences between the intensive vs conventional treatment groups were also examined, separately among those with EW and among those without EW, by means of the Mann-Whitney test, with and without stratification for baseline retinopathy levels.
The Wei-Lachin test 28 was also used to test treatment group differences combined over strata and across those with and those without EW. Additionally, the Mann-Whitney difference between the groups was compared between those with EW and those without EW by means of a standard z test.
Selected baseline characteristics stratified by baseline retinopathy severity level are shown in Table 1. More patients in the intensive treatment group experienced EW than in the conventional treatment group, particularly at the 6-month visit. The occurrence of 3-step or more EW at the 6-month visit was almost 3 times greater in the intensive than the conventional treatment group: 3.
In the intensive group, 19 of these 25 cases had recovered to less than 3 steps worse at the next visit at month 12, while 6 of these 25 cases persisted. At the month visit, 17 new cases were added, for a total of 23 3. In the conventional treatment group at 12 months, 5 of the 9 cases from 6 months had recovered, while 14 new cases were observed, for a total of 18 2. A similar analysis of any EW at the 3-month visit was conducted data not shown for the patients who had 3-month photographs.
The occurrence of any EW at the 3-month visit was 3. Among the 25 cases of clinically important EW at 6 or 12 months, there were 3 eyes of 2 patients with high-risk PDR. Both patients had moderate NPDR at baseline and were in the intensive treatment group.
All 3 eyes were treated with scatter photocoagulation and the new vessels regressed. Table 3 presents the incidence and ORs of EW occurring at 6 or 12 months within subgroups of severity of retinopathy at baseline.
Clinically important EW occurred almost exclusively in the 2 most severe baseline retinopathy categories, where its frequency was similar to that of 3-step or more EW. The ORs for intensive vs conventional treatment varied somewhat among the baseline severity categories, but the differences between categories were not significantly different tests of homogeneity yielded P values ranging from.
Adjusting for the baseline level of retinopathy, ORs were 1. Table 4 presents the incidence of any EW with intensive vs conventional treatment within patient subgroups defined by baseline factors. Table 4 also indicates that the risk of any EW increased significantly with increasing levels of screening HbA 1c and duration of diabetes within both treatment groups, and with increasing levels of AER in the intensive treatment group.
Figure 1 presents the cumulative incidence of sustained 3-step or more progression ie, present at 2 or more consecutive 6-month visits from the level present at the month visit within each treatment group for patients who had and those who had not experienced 3-step or more EW.
Table 5 presents rates of sustained 3-step or more progression of retinopathy from the level present at the month visit for patients who had and those who had not experienced EW according to each definition. In addition to the crude rates, the adjusted relative risk of subsequent progression was computed comparing those with and those without previous EW, with adjustment for the actual level of retinopathy present at 18 months. Overall, the risk of subsequent progression was 1. For clinically important EW Table 5 , in the conventional treatment group, there was a similar 2-fold increase in risk of subsequent progression in participants with vs those without such EW, although this was not significant after adjusting for the level of retinopathy at 18 months.
Within the intensive treatment group, there was no increased risk of subsequent progression among those with clinically important EW.
Comparison of rates of subsequent progression between the intensive and the conventional treatment groups Table 5 shows the striking beneficial effect of intensive treatment, even in patients who experienced EW. Among those with 3-step or more EW Table 5 , the overall risks of subsequent progression with intensive and conventional treatment were 4.
The corresponding relative risk intensive-conventional is 0. An alternate approach, which takes into consideration both the change occurring between baseline and 18 months and that occurring subsequently, is to consider the change between baseline and a fixed, long-term follow-up visit.
For this purpose, we chose the change from baseline to 4 years, when the greatest number of subjects had long-term follow-up. Table 6 presents a summary of the distributions of the degree of change in retinopathy severity between the baseline and 4-year visits for participants with and without EW, according to each of the definitions. For participants with 3-step or more EW, mean change was about 4 steps worse in the conventional treatment group and about 2 steps worse in the intensive treatment group, compared with 1.
Analysis of the mean number of steps worse reflects the distance along the scale under the assumption of equal intervals of retinopathy severity between steps, but because the intervals cannot be assumed to be equal, statistical tests were not performed on the differences between these means.
The Mann-Whitney difference is an appropriate statistic for use with the ordinal retinopathy severity scale because the actual number of steps of difference along the scale is not considered, only their relative ordering.
If the distributions among those with and without EW were identical the null hypothesis , then the Mann-Whitney difference on average would be 0. For 3-step or more EW, the Mann-Whitney difference stratified-adjusted for baseline retinopathy category was 0. Table 7 presents logistic regression models for the risk OR of any EW as a function of a set of baseline characteristics selected a priori separately for the intensive and conventional treatment groups.
Since the results were similar for each type of EW, only the models for any EW are presented. Within each treatment group, the screening before randomization level of HbA 1c was among the most important predictors of EW, as reflected by the relative magnitude of the R 2 value for each covariate. The risk of EW also tended to increase with increasing duration of diabetes in both cohorts and both treatment groups and to decrease in women in the conventional treatment group.
Figure 2 shows the distribution of the change in HbA 1c level from the screening visit to the 6-month visit in each treatment group. At the 6-month visit, the median reduction in HbA 1c level from the value at screening was 1. The change in HbA 1c level from screening to 6 months, however, was highly associated with the initial screening value; those entering the trial with the highest screening HbA 1 c values experienced the greatest reduction in HbA 1c with intensive therapy.
Diabetes Control and Complications Trial (DCCT)
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Early Worsening of Diabetic Retinopathy in the Diabetes Control and Complications Trial
The Diabetes Control and Complications Trial DCCT is a randomized, controlled clinical trial designed to assess the relationship between glycemic control and the development, progression, or amelioration of early vascular complications in persons with insulin-dependent diabetes. After a mean follow-up of approximately 16 years. The Diabetes Control and Complications Trial DCCT is a randomized, controlled clinical trial designed to assess the'relationship between glycemic control and the development, progression, or amelioration of early vascular complications in persons with insulin-dependent diabetes mellitus IDDM. The DCCT consists of two parallel studies: a primary prevention study and a. The Diabetes Control and Complications Trial 1 DCCT was a multicenter clinical trial conducted between and It was designed to determine whether intensive therapy with the aim of.
In patients with T1DM, how does strict glycemic control with intensive therapy compare with conventional therapy in preventing microvascular complications? The Diabetes Control and Complications Trial DCCT demonstrated that strict glycemic control targeting lower HbA1c goals among patients with T1DM can both delay the onset of retinopathy, nephropathy, and neuropathy and slow the progression of existing microvascular complications. This came at the expense of a threefold higher risk of hypoglycemia, underlying the fact that HbA1c goals should be tailored to the individual. DCCT was unable to demonstrate a reduction in CV events, likely because the study population was relatively young at the time.
Study record managers: refer to the Data Element Definitions if submitting registration or results information. Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus IDDM.
The Diabetes Control and Complications Trial: the gift that keeps giving
The DCCT — was a controlled clinical trial in 1, subjects with T1DM comparing intensive therapy INT , aimed at achieving levels of glycemia as close to the nondiabetic range as safely possible, with conventional therapy CON , which aimed to maintain safe asymptomatic glucose control. INT utilized three or more daily insulin injections or insulin pump therapy guided by self-monitored glucose. The major adverse effect of INT was a threefold increased risk of hypoglycemia, which was not associated with a decline in cognitive function or quality of life.
Cumulative incidence of sustained 3-step or more progression from the level of retinopathy present at 18 months for those with and those without 3-step or more early worsening. Left, Conventional treatment group. Right, Intensive treatment group. Spline-smoothed estimates of the distribution of the reduction in hemoglobin A 1c HbA 1c level at 6 months from the level of HbA 1c at screening in the conventional and the intensive treatment groups negative values represent increases in HbA 1c level. The density estimate is the estimated integrand such that the total area under each curve is 1. Note that nearly one half of intensively treated patients had a reduction of 2 U or more, while few conventionally treated patients did so. Proportion of patients in the intensive and conventional treatment groups experiencing any early worsening within tertiles thirds of the distribution of the screening hemoglobin A 1c HbA 1c value and, for each, within tertiles of the distribution of the month 6 reduction in HbA 1c level from the initial screening value.
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