Pediatric Annals

Lessons for Pediatricians From the Diabetes Control and Complications Trial

John I Malone, MD

Abstract

Diabetes in children is caused by destruction of the insulin-producing beta cells that reside in the pancreatic islets of Langerhans. During the first few months after clinical recognition of insulin-dependent diabetes mellitus (IDDM), residual beta cell function continues and IDDM is relatively easy to manage, regardless of the therapeutic approach. Once all of the functional beta ceils have been destroyed, however, the individual has no endogenous capacity to make insulin, and therefore is unable to lower blood glucose levels. The islets aíso contain alpha cells, which make and release glucagon, a hormone that counters the action of insulin by raising glucose levels, thereby providing a balancing mechanism for maintaining stable glucose concentrations. Although the alpha cells are not destroyed by the process causing IDDM, they become dysfunctional after the beta cells have been destroyed, and serum glucagon levels may be inappropriately eievated when the blood glucose is high and unresponsive when the blood glucose level is low. Thus, the body's system that is responsible for maintaining stable glucose levels becomes nonfunctional by about 1 year after the clinical onset of IDDM.

Total insulin deficiency is not compatible with life. Administration of exogenous animal insulin, started in the 1920s, has been sufficient to prevent hyperglycémie ketoacidosis and thereby prevent the death that inevitably results from insulin deficiency. Improvement in the quality of injectable insulin, as well as sustainedrelease preparations that assure the continuous presence of biologically active insulin, has been associated with improved health and quality of life for children with IDDM. Dramatic changes in treatment strategies recommended for children with IDDM have been the result of improved technology that allows a more physiologic approach. Nonetheless, the techniques available remained so crude that it was not certain until the Diabetes Control and Complications Trial (DCCT) concluded that the large personal effort required to safely implement the most intensified treatment pían would produce a significant positive result.1

The DCCT compared two different treatment approaches in a group of individuals with IDDM who were evaluated and monitored for diabetes complications prospectively during 3 to 9 years of carefully documented management.1 Subjects were randomly assigned to treatment approaches termed conventional and intensive,

CONVENTIONAL THERAPY

Subjects assigned to conventional therapy were encouraged to be free of the symptoms of poorly controlled diabetes mellitus. A primary goal of management was absence of increased thirst and urination, and of frequent or severe hypoglycemia. Growth velocity (height and weight) was regularly monitored to avoid growth failure in growing children. Insulin was administered one or two times a day, and nutritional counseling provided as required to achieve the goals mentioned above. Hemoglobin A1C levels were measured every 3 months with no effort made to lower them unless they exceeded 13%, which was 2 standard deviations above the mean of a group of insulin-dependent non-DCCT patients who were treated conventionally.

INTENSIVE THERAPY

The subjects in this group were encouraged to achieve normal blood glucose levels with the following goals: a premeal glucose of 70 to 120 mg/dL, a 2-hour postprandial glucose of <180 mg/dL, and a 3:00 AM glucose of >65 mg/dL. To achieve these goals, they were taught to measure their blood glucose levels at appropriate times and to administer premeal doses of insulin calculated to achieve the glucose goals noted above. The 3 AM glucose level was measured to detect and avoid nocturnal hypoglycemia - a risk increased by this type of treatment. This approach required multiple doses of regular insulin superimposed on a baseline of insulin provided either as intermediate- or long-acting insulin or by continuous subcutaneous insulin infusion vìa an insulin pump. Hemoglobin AIC content »as…

Diabetes in children is caused by destruction of the insulin-producing beta cells that reside in the pancreatic islets of Langerhans. During the first few months after clinical recognition of insulin-dependent diabetes mellitus (IDDM), residual beta cell function continues and IDDM is relatively easy to manage, regardless of the therapeutic approach. Once all of the functional beta ceils have been destroyed, however, the individual has no endogenous capacity to make insulin, and therefore is unable to lower blood glucose levels. The islets aíso contain alpha cells, which make and release glucagon, a hormone that counters the action of insulin by raising glucose levels, thereby providing a balancing mechanism for maintaining stable glucose concentrations. Although the alpha cells are not destroyed by the process causing IDDM, they become dysfunctional after the beta cells have been destroyed, and serum glucagon levels may be inappropriately eievated when the blood glucose is high and unresponsive when the blood glucose level is low. Thus, the body's system that is responsible for maintaining stable glucose levels becomes nonfunctional by about 1 year after the clinical onset of IDDM.

Total insulin deficiency is not compatible with life. Administration of exogenous animal insulin, started in the 1920s, has been sufficient to prevent hyperglycémie ketoacidosis and thereby prevent the death that inevitably results from insulin deficiency. Improvement in the quality of injectable insulin, as well as sustainedrelease preparations that assure the continuous presence of biologically active insulin, has been associated with improved health and quality of life for children with IDDM. Dramatic changes in treatment strategies recommended for children with IDDM have been the result of improved technology that allows a more physiologic approach. Nonetheless, the techniques available remained so crude that it was not certain until the Diabetes Control and Complications Trial (DCCT) concluded that the large personal effort required to safely implement the most intensified treatment pían would produce a significant positive result.1

The DCCT compared two different treatment approaches in a group of individuals with IDDM who were evaluated and monitored for diabetes complications prospectively during 3 to 9 years of carefully documented management.1 Subjects were randomly assigned to treatment approaches termed conventional and intensive,

CONVENTIONAL THERAPY

Subjects assigned to conventional therapy were encouraged to be free of the symptoms of poorly controlled diabetes mellitus. A primary goal of management was absence of increased thirst and urination, and of frequent or severe hypoglycemia. Growth velocity (height and weight) was regularly monitored to avoid growth failure in growing children. Insulin was administered one or two times a day, and nutritional counseling provided as required to achieve the goals mentioned above. Hemoglobin A1C levels were measured every 3 months with no effort made to lower them unless they exceeded 13%, which was 2 standard deviations above the mean of a group of insulin-dependent non-DCCT patients who were treated conventionally.

INTENSIVE THERAPY

The subjects in this group were encouraged to achieve normal blood glucose levels with the following goals: a premeal glucose of 70 to 120 mg/dL, a 2-hour postprandial glucose of <180 mg/dL, and a 3:00 AM glucose of >65 mg/dL. To achieve these goals, they were taught to measure their blood glucose levels at appropriate times and to administer premeal doses of insulin calculated to achieve the glucose goals noted above. The 3 AM glucose level was measured to detect and avoid nocturnal hypoglycemia - a risk increased by this type of treatment. This approach required multiple doses of regular insulin superimposed on a baseline of insulin provided either as intermediate- or long-acting insulin or by continuous subcutaneous insulin infusion vìa an insulin pump. Hemoglobin AIC content »as measured monthly to provide frequent feedback to the patient and reemphasize that the HbA,c goal was a level <6.05% (the upper level for persons without diabetes in the central laboratory used for the study). The intensively treated subjects were contacted, counseled, and encouraged at least monthly by members of the "diabetes team" (diabetes nurse educators, dietitians, behavioral scientists, and physicians). The team members were available 24 hours a day, and consultations occurred at any time.

RESULTS OF THE DCCT

Metabolic Control

The patient population (1441) evaluated in this study ranged in age from 13 to 39 years at entry. Approximately 14% (195) of the group were 13 to 18 years old at entry,1 As one might predict, the mean glycosylated hemoglobin (HbAlc) levels in the adolescents during the DCCT intervention was higher than similarly treated adult subjects.2 This observation indicates that the ideal treatment plan for IDDM has not been found. The adolescents participating in the DCCT study were spread throughout the 29 centers and were exposed to the same treatment teams and programs as the adults who achieved lower HbAlc levels.

The results of the DCCT indicate that an intensified effort directed at lowering the HbA,c level will be successful in a number of patients if they are interested in that goal and receive the ongoing attention of a group of health professionals dedicated to the success of the treatment plan. It should be remembered, however, that this effort did not result in the correction of the metabolic defect. Those individuals in the intensive treatment group of the DCCT continued to have less than ideal control of their blood glucose levels (<5% maintained HbAlc levels in the nondiabetic range). In addition, the intensively treated group had a significant increase in episodes of severe hypoglycemia. Severe hypoglycemia in this study was defined as "an event with symptoms consistent with hypoglycemia in which the patient required the assistance of another person and was associated with a blood glucose <50 mg/dL or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration."3 Thus, our best efforts at managing IDDM today continue to result in unstable glucose levels that are both too high and too low on a recurring basis. This instability is caused by inability of the patient with IDDM to release insulin and glucagon in an appropriate fashion. The best treatment protocols available today cannot compensate for that defect in IDDM.

Severe hypoglycemia occurred three times more frequently in the subjects participating in the intensive treatment protocol than in those treated conventionally.1·' Half of the severe hypoglycémie episodes occurred during sleep, and about one third of the daytime episodes occurred without apparent warning.4 Although severe hypoglycemia occurred more frequently in the intensively treated subjects, they did not have any evidence of long-term brain dysfunction.1 Two fatal motor vehicle accidents may have been associated with hypoglycemia. It also must be remembered that study participants were all over 13 years of age at entry into the study; younger children with continuing brain development and maturation were not included. It is likely, therefore, that the threefold increase in severe hypoglycemia associated with intensive therapy could have a more devastating effect on brain development and intellectual function of younger children, as suggested by another study of school performance in children with IDDM.5

Retinopathy

Although less than ideal, the intensive treatment plan (directed toward providing more physiologic insulin levels) was positively associated with a significant reduction in HbAlc levels and a reduction in the progression of diabetic retinopathy.1 A 2% reduction in glycosylated hemoglobin from baseline was noted about 3 months after starting intensified therapy and remained relatively constant throughout the study. Even though the HbAIc levels were lower 3 months after implementing the two different treatment protocols, it required 3 years before a difference in the progression of retinopathy was recognized. It appears that the effect of lowering glucose levels will require 3 or more years of correction before it will have any measurable effect on the tissue damage associated with IDDM.4

There was, unfortunately, one apparent early effect of intensified therapy. That was the deterioration of retinopathy during the first year in approximately one of eight patients who had retinopathy at baseline.1 This initial progression of retinopathy, however, stopped after 18 months of improved control.

There were two groups of patients evaluated in the DCCT to answer two related study questions. The first group had no evidence of retinopathy as determined by stereo color photography and duration of diabetes between 1 and 5 years at baseline. The second group had evidence of early retinopathy on fundus photographs and duration of diabetes between 1 and 15 years at baseline. One half of each patient group was treated intensively and one half conventionally. More than 50% of the intensivetherapy group progressed from no retinopathy to the presence of one or more documented microaneurysms during 7 years of intensive therapy.6 The number with this degree of early retinopathy in the intensively treated subjects was 27% less than found in the conventional treatment group. The DCCT, however, defined "clinically important retinopathy" as a sustained change of at least three steps in the staging system used by the Early Treatment Retinopathy Study.7 Using that criterion, 23 patients in the intensive therapy group and 91 patients in the conventional therapy group developed retinopathy during a mean of 6 years of foliow-up.1 This represents a reduced risk (76%), but not total prevention of retinopathy for those individuals involved in intensive therapy.

Many individuals with préexistent mild or moderate retinopathy at entry into the study had a threestep progression of that retinopathy. Progression occurred in 7.8 of 100 patient years in the conventional therapy group and 3.7 of 100 patient years in the intensive therapy group. Thus, intensive therapy reduced the average risk for progression to 54%. It was observed that improved blood glucose control at later stages of retinopathy resulted in less progression.4 A lesson learned from the DCCT was that perseverance in maintaining lower mean blood glucose levels begins to pay off after 3 years and has incremental benefits at 8 to 9 years of lower blood glucose levels.4 The DCCT showed a conclusive reduction in the progression of retinopathy in intensively treated subjects, but retinopathy did progress in that treatment group

Even though severe hypoglycemia increased exponentially with reduction in the HbAIc levels, that risk was not considered unreasonable when compared with the large reduction in risk for significant eye changes, particularly when it appears that the severe hypoglycemia resulted in no measurable brain damage. One should not overlook, however, that there were individuals participating in this study who had mean HbA,c levels in the nondiabetic range during the interval when they had a three-step progression of their retinopathy.1 Thus, intensive management of subjects with IDDM reduced the risk of developing the first microaneurysm by 27% and the evolution of clinically important retinopathy by 76%; nonetheless, there was a threefold increase in severe hypoglycemia and a failure of absolute prevention of retinopathy and its progression in some subjects who maintained near normal HbAlc levels. Intensive treatment, although effective, is not ideal.

Nephropathy

The DCCT was designed to evaluate the influence of hyperglyceraia on the development and progression of the microvascular complications of diabetes as documented in the retinal vasculature. Renal function also was evaluated by periodic measures of glomerular filtration rate and urinary albumin excretion. Those in the intensive therapy group had a reduction in the appearance of both persistent microalbuminuria (40 to 300 mg/day) and more severe albuminuria (5*300 mg/day) by 34% and 56%, respectively, compared with conventionally treated patients. Although it is believed that this information indicates that the development of clinically important nephropathy is delayed by intensive management, longer follow-up is required to be certain.

Table

TABLELessons Learned From the Diabetes Control and Complications Trial (DCCT)

TABLE

Lessons Learned From the Diabetes Control and Complications Trial (DCCT)

Neuropathy

An assessment of peripheral nerve function (nerve conduction velocity, autonomie function, history, and physical examination) was used in the EKXT study Intensive therapy reduced the risk of impaired peripheral nerve function. This observation strengthens the conclusion that intensive therapy that results in a reduction of the HbAlc level results in an important reduction in the onset and progression of all the complications associated with chronic diabetes mellitus.

IMPLICATIONS OF THE DCCT FOR PEDIATRIC CARE

We are now left with the task of applying this information to the care of children who have IDDM. Concerned parents are usually willing to have their children take three or more shots of insulin each day if that will prevent them from going blind because of diabetes. On the other hand, parents are rarely aware of the vagaries involved in predicting a patient's blood glucose response to variable doses of insulin, food, and exercise required of individuals participating in an intensive therapy program. Transient hetniparesis and seizures that may result from severe hypoglycemia associated with intensive therapy can become an overwhelming concern of parents who have witnessed these acute side effects in their children. It is important to remember that success in lowering HbAlc levels in the intensive treatment group of the FJCCT was caused in large pan by the effort and desire of the patient, combined with the support and guidance of a concerned and dedicated staff

The successful intensively treated individuals in the DCCT were self-motivated and were not participating in the DCCT solely at the request of a third party (parents). Pediatricians were counseled that the type of personal involvement in self-care required for intensive therapy is not a personality trait common to children under age 13 years.8 Although there are no objective data available, it seems unlikely that intensive therapy, as described in the DCCT, is workable or appropriate for children younger than 13 years of age. This does not mean that HbA1 levels above the nondiabetic range are desirable for those children. Normal blood glucose levels are still best and should be the goal in a child with IDDM at any age, if possible without causing severe hypoglycemia or emotional problems for the child and the family. Pediatricians should not counsel families that it is desirable to achieve higher than normal blood sugar levels to avoid hypoglycemia. One should implement strategies designed to avoid hypoglycemia rather than promoting hyperglycemia.

The DCCT results show that it takes approximately 3 years of lower HbAlc levels before the benefits become manifest as reduced tissue damage (complications). One should not take too much solace from the idea that the prepubertal years are relatively free of complications,9 because that is not an absolute truth and those early years are likely to be important in the evolution of the tissue damage that can become apparent as early as adolescence or young adulthood. 10-12

A secondary analysis of DCCT data (Table) showed a continuously decreasing risk of sustained progression of diabetic retinopathy in association with decreasing HbAlc values. An important lesson learned from the DOCT was that although more patients in the intensive insulin therapy group achieved lower HbAlc values, there were some conventionally treated subjects taking one or two daily injections of insulin who also achieved nearly normal HbAIc levels. The design of the DCCT demanded the conclusion that the specific treatment technique be associated with reduced risk for complications, but the regression line estimate of the relation between in' creasing HbAlc levels and progression of diabetic retinopathy supports the impression that higher blood sugar concentrations do contribute to the onset and progression of diabetes-associated complications.1 The technique for achieving normal levéis of HbA lc is not likely to be as important as the end result. This should be kept in mind as one designs treatment plans for children who have diabetes. The goal is treatment that provides continuous nondiabetic HbAlc levels in children with no episodes of severe hypoglycemia.

We are left with an important issue unresolved by the DCCT: the best techniques currently available for the treatment of IDDM do not uniformly normalize the blood glucose levels of patients (particularly adolescents) with IDDM or prevent the onset or the progression of the microvascular complications. This makes it even more important today to pursue re' search directed toward more effective treatment (a cure) and prevention of IDDM to eliminate the problems associated with this second most common chronic health problem of childhood.

REFERENCES

1. The Diabetes Control and Complications Trial Research Group. The effect at intensive [réarment of diabetes on the development and progression of long-term complications in Insulin-dependeni diabetes mellitus. N Eng! J Med. 1993;329#77986.

2. Dtash AL. The chrtd, the adolescent and the Diabetes Control and Complication Trial. Oabttts Cms. 1993:16:1515-1516.

3. The Diabetes Control and Complications Trial Research Group. Epidemiology of severe hypogiycemia in the Diabetes Control and CompiicanonJ Trial Am J MeA 1991 #0*50-459.

4. Santiago JV. Perspectives in diabetes: lesions from the Diabetes Control and Complications Trial. Diabtua. 1993;42:1549·1554.

5. Puciynski S, Puctyn&ki MS, Ryan CM. Hypogtycemia in children with intulin dependent diabetes mellicus. Diofc Ed. I992;I8:151-IÎ3.

6. The Diabetes Control and Complications Trial Update. Presented at the 53rd Annual Meeting of the American Diabetes Association; June 13, 1993; La» Vegas, Nevada.

7 Early Treatment Diabetic Rftinopathy Study Research Group. Grading diabetic retinopathy from stereoscopic color fundus photographs - an extension of the modified Airlie House Classification: ETDRS Report No 10. Opfufcormdcgj. 1991;98(suppl):766-7B5.

8. Ma Lt me Jl. Diabetes mellitus in childhood and adokscence, Conn's Current Therapy. Philadelphia, Pa: WB SaundersCo; 1983:425-432.

9. Kostraha JN, Durman JS, Orchaid TJ, et al. Contribution of diabetes duration before puberty to development ii microvascular complications in IDDM subjects. Diabetes Core. 1989·,11:686-6?.

10. Daneman Q Drash AL, Lobes LA, Becker DJ. Baker LM, Tfavis LB. Progressive retinopathy with improved contini in diabetic dwarfism (Mauriaci syndrome). Diabetes Care. 1981:4:360-365.

11. De Clue TJ, Campi« A. Diabetic nephropatriy in a prepubercal diabetic female. Journal of ftdiao-ic Endocrinology 1994;7:43-46.

12. Gamsiorp 1. Conduction velocity of peripheral motor nerves in mental retardation. Diabetes and various neurologie diseases in childhood Acia fbaüair. ?964;53:40ß416.

TABLE

Lessons Learned From the Diabetes Control and Complications Trial (DCCT)

10.3928/0090-4481-19940601-08

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