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CLINICAL TRIALS OF INTENSIVE TREATMENT OF GLYCEMIA
Diabetes Control and Complications Trial
The DCCT was designed to compare intensive with conventional diabetes therapy with regard to their effects on the development and progression of retinopathy in persons with type 1 diabetes (3). The study was designed to make recommendations regarding the benefits and risks associated with intensive therapy. Two of the main questions asked in the study were (1) Will intensive therapy prevent the development of diabetic retinopathy in patients with no retinopathy (primary prevention)? and (2) Will intensive therapy affect the progression of early retinopathy (secondary intervention)? Other issues investigated in the DCCT involved the magnitude of the effect of intensive insulin treatment on progression and regression of retinopathy, the degree to which this effect changes over time, and the relation of the effect to the level of severity of the retinopathy at baseline (3, 66, 69). Persons included in the DCCT at baseline were 13–39 years of age and did not have hypertension, hypercholesterolemia, or severe complications associated with diabetes. From 1983 to 1989, 1,441 persons were randomized to either conventional or intensive insulin therapy (3). Conventional therapy consisted of one or two daily injections of insulin per day, daily self-monitoring of urine or blood glucose, and education about exercise and diet. No attempts were made to do daily adjustments of the insulin dosage. The most important primary outcome measure was a sustained (at two consecutive 6-month visits) three-step progression of diabetic retinopathy along an ordinal ETDRS severity scale based on retinopathy scores in both eyes.
An important finding of the trial was the significant reduction in risk of sustained incidence of retinopathy of approximately 50% in the intensive therapy group compared to the conventional therapy group in the primary-prevention cohort after 5 years of follow-up (Fig. 11) (3). Intensive treatment was found to reduce the adjusted mean risk of retinopathy progression by three or more steps by 76%. In the secondary-intervention cohort, patients assigned to the intensive-therapy group had a reduction of average risk of progression by 54% during the entire study period compared to patients assigned to the conventional-therapy group. In addition, when both cohorts were combined, the intensive-therapy group also had a reduction in risk for development of severe nonproliferative retinopathy or PDR by 47% and of treatment with photocoagulation by 51%. These findings were statistically significant. There was a decrease in the incidence of CSME in the group assigned to intensive therapy compared to those assigned to conventional therapy. However, this difference did not reach statistical significance.
On average, it took about 3 years to demonstrate the beneficial effect of intensive treatment. After 3 years, the beneficial effect of intensive insulin treatment increased over time. An early worsening of retinopathy in the first year of treatment of the intensive therapy group in the secondary-intervention cohort was observed. This was similar to what previously had been reported by earlier feasibility clinical trials of intensive treatment in patients with insulin-dependent diabetes mellitus (IDDM) (70–74).
The DCCT investigators also examined whether there was an association of glycosylated hemoglobin values < 8% vs. those > 8% for progression of retinopathy and found no support to the concept of a glycemic threshold regarding progression of retinopathy (69). These finding are consistent with the lack of a glycemic threshold found in the WESDR.
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Fig. 11. Cumulative incidence of a sustained change in retinopathy in patients with type 1 diabetes mellitus receiving intensive or conventional therapy in A, the primary-prevention and B, the secondaryintervention arms of the Diabetes Control and Complications Trial.
Source: From Ref. 3. Copyright © 1993 Massachusetts Medical Society. All rights reserved.
The most important adverse event found in the DCCT was a two-to-threefold increase in severe hypoglycemia in the intensive insulin treatment group compared to the conventional group (3) There was a 33% increase in the mean adjusted risk of becoming overweight (body weight more than 120% above the ideal) in persons in the intensive compared to the conventional insulin treatment group.
The DCCT investigators concluded that intensive therapy should form the backbone of any health care strategy aimed at reducing the risk of visual loss from diabetic retinopathy
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in persons with IDDM (75). Their analyses showed that intensive therapy, as practiced in the DCCT, would result in a gain of 920,000 years of sight, 691,000 years free from end-stage renal disease, 678,000 years free from lower extremity amputation, and 611,000 years of life at an additional cost of 4 billion dollars over the lifetime of the 120,000 persons with type 1 diabetes in the United States who meet DCCT eligibility criteria. The incremental cost per year of life gained was $28,661, and when adjusted for quality of life, intensive therapy costs $19,987 per quality of life year gained. These findings were similar to cost-effectiveness ratios for other medical interventions in the United States.
After the trial phase of the DCCT was finished, long-term follow-up of the cohort showed a long-term advantage in terms of reduction in incidence and progression of retinopathy by intensive glycemic control that remained more than four years later despite comparability of glycosylated hemoglobin levels between conventionally and intensively treated subjects (Fig. 12) (76). Thus, while there is a suggestion of reduction of risk at any point in time after diagnosis of diabetes, more benefit appears to result if lowering of blood sugar occurs earlier in the course of the type 1 diabetes. The reason for this is not fully understood.
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Fig. 12. Estimated cumulative incidence of progression of retinopathy 3 steps on the Early Treatment Diabetic Retinopathy Scale from the level at Diabetes Control and Complications Trial closeout over 7 years of Epidemiology of Diabetes Interventions and Complications. At each EDIC year, approximately one-fourth of the treatment groups were examined by fundus photography, except for year 4 when approximately 85% were examined. Risk reduction with intensive therapy is 62% (95% confidence interval, 51–70%; P<.001). The curves show the cumulative incidences estimated by a proportional hazards regression model for interval-censored event times that are assumed to follow an underlying Weibull distribution. Error bars represent 95% confidence intervals.
Source: Reprinted from Ref. 76. Copyright © 2002 American Medical Association. All rights reserved.
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The United Kingdom Diabetes Prospective Study (UKPDS)
The UKPDS was a randomized controlled clinical trial involving 3,867 newly diagnosed patients with type 2 diabetes (4,77,78). Patients with a mean of two fasting plasma glucose concentrations of 6.1–15.0 mmol/L were randomly assigned to intensive glycemic control with either insulin, a sulfonylurea, or conventional glycemic control. The latter group was further divided into those who were overweight or not. Metformin was included as one of the treatment arms for 1,704 overweight patients and analyses included comparison of the effect of metformin against conventional therapy in overweight patients.
There was a reduction in the 12-year rate of progression of diabetic retinopathy of 21% and reduction in need for laser photocoagulation of 29% in the intensive vs. the conventional treatment group (4). In addition, there were no differences in reduction in the incidence of the retinopathy endpoints among the three agents used in the intensive treatment group (glibenclamide, chlorpropamide, and insulin), but the chlorpropamide treatment group failed to show a reduced rate of retinopathy requiring photocoagulation. Furthermore, there was no difference in vision outcomes between conventional and intensive treatments. The study concluded that metformin was preferred as the first-line pharmacological therapy in newly diagnosed type 2 diabetic patients who were overweight based on their finding of a significant (39%) reduction in myocardial infarction compared to the conventional treatment group.
The intensive treatment group suffered significantly more major hypoglycemic episodes and weight gain than patients in the conventional group. Economic analyses of the clinical trial data suggested that intensive glucose control increased treatment costs but substantially reduced complication costs and increased the time free of such complications (78).
Two new clinical trials which permit evaluation of near normalization of glycemic level on the incidence of cardiovascular disease and retinopathy are underway. The first, the Glycemic Control and Complications in Diabetes Mellitus Type 2, is an ongoing 7-year randomized controlled parallel-treatment trial, and its secondary objective is the evaluation of glycemic control on the incidence and progression of diabetic retinopathy in American war veterans, 41 years of age or older whose glycemia is inadequately controlled on maximal therapy (79). The approach used in this trial is an intensification of combination therapy and frequent blood glucose monitoring to achieve glycosylated hemoglobin A1c levels within normal limits (at or below 6.0%). Another new large randomized controlled clinical trial that began in February 2003, the Action to Control Cardiovascular Risk in Diabetes (ACCORD), is studying the effect of near normalization of blood glucose (defined as keeping glycosylated hemoglobin A1c levels close to 6%) on the incidence and progression of retinopathy in persons with type 2 diabetes. Both studies should provide additional information regarding the risks and benefits of intensive treatment resulting in near normalization of glycemic level in persons with type 2 diabetes, a level of control not achieved in the UKPDS.
In summary, based on the results of the DCCT and the UKPDS, in the absence of preventing diabetes itself, intensive therapy is the primary public health care strategy for reducing the risk of visual loss from diabetic retinopathy in persons with both type 1 and 2 diabetes. Data from the DCCT and UKPDS have provided further support for