It is estimated that there are more than 130,000 children with diabetes in the United States and 13,000 new cases of type I diabetes mellitus each year.1 Acute metabolic decompensation and symptomatic hypoglycemia pose day-to-day threats, but the late microvascular, macrovascular, and neurologic complications are the major sources of longterm morbidity and death.2 In adults, type I diabetes mellitus has become a leading cause of blindness, end-stage renal disease, peripheral and autonomic neuropathy, and premature coronary, cerebral, and peripheral vascular disease.3 For these reasons, diabetes in childhood and adolescence continues to challenge pediatric health care providers.
For nearly 60 years, physicians have argued whether improved glycémie control could prevent or delay these complications. The Diabetes Control and Complications Trial pCCT) was the first large, multicenter study to examine this question.4 The DCCT studied the onset and progression of diabetic complications in patients treated with intensive insulin therapy compared with conventional treatment.
Not all patients were eligible to participate in the DCCT. Only patients who met the following criteria were enrolled: age 13 to 39 years, insulin dependence, deficient C-peptide secretion, and the absence of hypertension, hypercholesterolemia, frequent hypoglycemia, and severe diabetic complications or comorbid conditions.2*5 More than 7,000 patients were screened, but only 1,441 were enrolled (726 in a primary prevention cohort and 715 in a secondary intervention cohort).3 Research centers were initially asked to recruit approximately 33% of subjects between 13 and 17 years of age.3 However, only 9% were adolescents (108 of 1,163), and for the entire study, on average only 3 adolescents received intensive therapy at each institution.3 Selection was thus designed to include only patients deemed likely to succeed with intensive therapy.3"
Once enrolled, patients were randomly assigned to either intensive or conventional treatment as discussed in this issue by Newman. Two cohorts were studied. The first was a primary prevention cohort, in which the patients had to have had type I diabetes mellitus for 1 to 5 years and no retinopathy or albuminuria.2 The second was a secondary intervention cohort, in which the patients had to have had type I diabetes mellitus for 1 to 15 years, mild to moderate nonproliferating retinopathy, and an elevated urinary albumin excretion that was less than 200 mg per 24 hours.2 These two cohorts were studied to answer two different, but related, questions: (1) will intensive therapy prevent the onset of diabetic retinopathy (primary prevention); and (2) will intensive therapy delay the progression of early retinopathy (secondary intervention)?5 The study concluded in June 1993 after an average follow-up of 6.5 years.3 Outcome measures included retinopathy, nephropathy, neuropathy, cardiovascular effects, neuropsychologic testing, and the frequency of adverse events.5
DCCT WITH RESPECT TO ADOLESCENTS
Of the 1,441 patients in the DCCT, 14% (n - 195, with 125 in the primary prevention cohort and 70 in the secondary intervention cohort) were adolescents (13 to 17 years of age) and all were pubertal (Tanner stage II or beyond).2,3 Adolescent patients were observed for a mean of 7.4 years.2 Few adolescents were able to achieve or maintain hemoglobin A (HbA ) levels in the nondiabetic range. In the conventional treatment group, the median HbAJc level was 9.02% and only 20.3% of patients had an HbAlc level of 8% or less. In the intensive treatment group, the median HbA, level was 7.07%, and 83.4% of patients had a mean HbA level of 8% or less. The HbAn values in adolescents in the intensive treatment group were higher than those obtained in adults in the DCCT, although adolescent total insulin doses were greater.1 HbA levels were also higher for adolescents in the conventional treatment group as compared with adults receiving conventional treatment, so that the mean improvement (net difference in HbA,c levels) between intensive and conventional treatment groups was similar for adolescent and adult patients in each group. This is important because it shows that as many as 80% of motivated adolescents can achieve HbA, levels of 8% or less. The risk of all complications was significantly reduced by as little as a 10% reduction in HbA .6 This is critically important because it shows that improvement at any level (eg, HbA 13% -» 12% or 9% ->8%) is of direct benefit to the patient and will lower the risk of complications.
As shown in the table, intensive therapy significantly reduced the risks of retinopathy and microalbuminuria in adults and adolescents.2 The number of patients with clinical neuropathy was small. Even so, by the fifth year of the study, peripheral motor and sensory nerve conduction velocities were decreased in patients in the conventional treatment group compared with patients in the intensive treatment group.2
The rates for diabetic ketoacidosis were similarly low in both groups (4.7 and 2.8 episodes per 100 patient-years in the intensive and conventional groups, respectively).4 Intensive treatment caused an increase in the risk of obesity and severe hypoglycemia similar to that seen in adults.3 Severe hypoglycemia was much more common in adolescents than in adults.3,7 Hypoglycemia requiring assistance or resulting in seizure or coma developed in 82% of adolescents in the intensive treatment group.7 This finding is supported by other studies that have shown that 20% to 30% of school-age children and 15% to 20% of teenagers with diabetes have serious hypoglycemia each year.8 However, there was again no difference in neuropsychologic function or quality of life between the conventional and the intensive treatment groups.2 In newly diagnosed patients, intensive therapy also slowed (by 57%) the decline in insulin secretion that parallels β-cell destruction.9
Percent Reductions in Long-Term Diabetic Complications in the Primary Prevention Cohort Versus the Secondary Intervention Cohort
DECIDING WHO SHOULD HAVE INTENSIVE MANAGEMENT: BACKGROUND INFORMATION
The findings of the DCCT should be considered in relation to background data from additional studies that examined the outcome of children and adolescents with diabetes. Kernel! et al. evaluated 611 children and adolescents who had type I diabetes mellitus before age 15 years.10 They found that retinopathy was more common in older patients compared with younger patients, with longer disease duration, and after puberty.10
HoIl et al. showed that the risk of retinopathy was lower in patients with later onset of diabetes and in those with better glycémie control.11 When diabetes developed before puberty, the onset of retinopathy was much faster, only 10.9 years after onset, as compared with 15.1 years if diabetes developed during puberty."
It had been previously thought that puberty might be required for diabetic nephropathy and that the duration of prepubertal diabetes was unimportant. However, retrospective analyses of adults have shown that both prepubertal and postpubertal diabetes contribute to nephropathy.12
Although the DCCT evaluated neurocognitive function in study patients, it, of course, dealt with only children who were 13 years of age or older. Several studies have shown a correlation between cognitive function and the age of onset of diabetes. This is believed to relate to a greater incidence and more profound effects of hypoglycemia in younger children. Ro vet et al. found that young children diabetes diagnosed before 5 years of age) had decreased visual-spatial performance.1 Ryan et al. reported decreased intelligence, speed, memory, and coordination for young children with diabetes.1 However, other studies have failed to corroborate these findings. It seems intuitive to suggest that the risk of hypoglycemia on the developing central nervous system is greatest in young children, but a definitive answer will require a longitudinal, multicenter study to evaluate cognitive function over time.
IMPLICATIONS FOR ADOLESCENTS WITH DIABETES
The results of the DCCT apply directly to children older than 13 years of age and have shown that the risk of microvascular complications is reduced with intensive insulin treatment. The risks of hypoglycemia and obesity are significantly increased. However, motivated adolescents with no previous history of hypoglycemia are likely to achieve HbAlc levels of 8% or less and to benefit from intensive insulin therapy.
IMPLICATIONS FOR CHILDREN WITH DIABETES
Patients younger than 13 years of age were not included in the DCCT. The risk-to-benefit ratio of intensive insulin therapy is unknown in schoolage children, and possibly unfavorable for infants and toddlers. It would seem prudent to exercise caution in attempting intensive therapy in prepubertal children, who have more erratic eating and exercise patterns and are more likely to have hypoglycemia.313
The optimal level of glycémie control for children with diabetes is still under debate. The 1993 American Diabetes Association Position Statement stated that tight control was contraindicated in infants younger than 2 years of age and should be undertaken with extreme caution in children between 2 and 7 years of age.3'14 In younger patients, physicians must be careful to avoid mild, asymptomatic hypoglycemia, which can still induce cognitive dysfunction.1 However, the best way to prevent hypoglycemia may be through increased monitoring and more frequent injections, both of which are an integral part of intensive insulin therapy. Some authors argue that, for children of all ages, acceptable targets are mean blood glucose levels less than 170 mg/dL and HbAlc levels less than 8%, provided there is no significant hypoglycemia.1 Others do not believe it is safe to attempt strict glycémie control in any child younger than 5 years of age and possibly not in children younger than 10 years of age.1
Pediatric treatment teams should not be overwhelmed by the improbability of reducing markedly elevated HbA1 levels to near the nondiabetic range. The DCCT data suggest that if patients with very poorly controlled diabetes are able to achieve and maintain even a modest reduction of HbAlc levels, there will be substantial benefit. Every 10% reduction in HbAlc level is associated with a 40% to 45% reduction in the risk of retinopathy.1 This debate poses the single most important dilemma in the care of children with diabetes. Although specific guidelines must be individualized, the pediatrician should attempt to achieve the lowest possible HbAlc level without inducing hypoglycemia. Any improvement in glycémie control, even at levels above 8%, is associated with a reduction in the risk of long-term complications.
When should the pediatrician refer a child with diabetes for retinopathy screening? The American Academy of Pediatrics recommends referral 3 to 5 years after diagnosis if the patient is older than 9 years of age.15 Follow-up examinations should be done annually and an ophthalmologic examination should be performed prior to intensification of therapy.15 Any patient who becomes pregnant should be examined by an ophthalmologist during the first trimester, and every 3 months until delivery.15
Several points are critical when extrapolating the DCCT to the entire population of children with diabetes. First, the pediatrician should be careful to select patients for intensive therapy who are free of comorbid conditions and previous severe hypoglycemia, adherent with prescribed treatment, and sufficiently motivated to participate. Intensive insulin therapy is not a cure for diabetes, and it requires a great deal of effort on the part of the patient and the family.
Second, the pediatrician should be aware of the costs of intensive insulin therapy. The DCCT required approximately 36 person-hours per patient per month, and cost approximately $165 million ($15,000 per patient per year).13 It is estimated that in practice, intensive therapy would range from $3,779 to $8,800 per patient per year and would require 7.3 person-hours per patient per month.13 One should balance these costs, however, against the fact that 1 of every 7 health care dollars in the United States is spent for the care of patients with diabetes (this includes both type I and type II).
Third, patients in the DCCT were all highly motivated. A more recent study examined the effect of intensive therapy in adolescents with type I diabetes mellitus. More than 40% of the invited adolescents refused to participate. The four most common reasons for refusal to participate were (1) increased clinic visits (42%); (2) increased injections (30%); (3) increased frequency of blood glucose monitoring (28%); and (4) transportation difficulties (19%).16 Fears of hypoglycemia and weight gain were not mentioned.
The DCCT showed that any improvement in glycémie control decreases the risk of long-term complications. Although expensive, time consuming, and associated with increased risks of hypoglycemia and obesity, improved glycémie control is of benefit as long as hypoglycemia is avoided. Specific HbAlc target levels must be individualized and age appropriate.
1. Kaufman F. Diabetes in children and adolescents: areas of controversy. Med Clin North Am. 1998;82:721-735.
2. The DCCT Research Group. Effect of intensive diabetes treatment on the development and progression of longterm complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. J Pediatr. 1994;125:177-188.
3. Tamborlane WV, Acheron J. Implications and results of the Diabetes Control and Complications Trial. Pediatr Clin North Am. 1997;44:285-299.
4. The DCCT Research Group. Diabetes Control and Complications Trial (DCCT) update. Diabetes Care. 1990;13:427-433.
5. The DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl } Med. 1993;329:977-986.
6. The DCCT Research Group. The absence of a glycémie threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial. Diabetes. 1996;45:1289-1298.
7. The DCCT Research Group. Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes. 1997;46:271-286.
8. Ludvigsson J, Nordfeldt S. Hypoglycemia during intensified insulin therapy of children and adolescents. J Pediatr Endocrinol Metab. 1998;11:159-166.
9. The DCCT Research Group. Effect of intensive therapy on residual ß-cell function in patients with type I diabetes in the Diabetes Control and Complications Trial. Ann Intern Med. 1998;128:517-523.
10. Kernell A, Dedorsson I, Johansson B, et al. Prevalence of diabetic retinopathy in children and adolescents with IDDM: a population-based multicentre study. Diabetologia. 1997;40:307-310.
11. HoIl RW, Lang GE, Grabert M, et al. Diabetic retinopathy in pediatric patients with type-I diabetes: effect of diabetes duration, prepubertal onset of diabetes, and metabolic control. J Pediatr. 1998;132:790-794.
12. Lawson ML, Sochett EB, Ghait PG, Balfe JW, Danemann D. Effect of puberty on markers of glomerular hypertrophy and hypertension in IDDM. Diabetes. 1996;45:51-55.
13. Peterson CK, Smith KA. The DCCT findings and standards of care for diabetes. Am Earn Physician. 1995; 52:1092-1098.
14. American Diabetes Association. Implications of the Diabetes Control and Complications Trial: position statement. Diabetes. 1993;42:1555-1558.
15. American Academy of Pediatrics. Screening for retinopathy in the pediatric patient with type I diabetes mellitus. Pediatrics. 1998;101:313-314.
16. Tercyak KP, Kirkpatrick KA, Johnson SB, Silverstein JH. Offering a randomized trial of intensive therapy for IDDM to adolescents: reasons for refusal, patient characteristics, and recruiter effects. Diabetes Care. 1998;21:213215.
Percent Reductions in Long-Term Diabetic Complications in the Primary Prevention Cohort Versus the Secondary Intervention Cohort