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Yale University Schools of Medicine and Nursing and the Yale Children’s Clinical Research Center New Haven, Connecticut 06520
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Introduction |
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 Top Introduction Is strict control of...Is intensive treatment safe...Can the risk of...References |
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This part of the "Therapeutic Controversy" is easy to answer in the affirmative. The results of the Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy of type 1 diabetes was able to delay the onset and slow the progression of early diabetic complications to an extent that even the most optimistic proponent of strict diabetes control did not anticipate. Not only did intensive therapy delay the onset and progression of retinopathy, the primary end point of the DCCT, it also markedly lowered the risk of developing microalbuminuria, clinical proteinuria, and clinical neuropathy (1). It is noteworthy that the benefits of intensive vs. conventional treatment have persisted even 4 yr after completion of the study (2).
Because only approximately 14% of subjects were between 13 and 17 yr
of age on entry into the DCCT, the most obvious question is whether
intensive therapy was as beneficial in the adolescent subset of
patients in the DCCT as it was in adults. This is a valid question
because biologic factors, such as elevated concentrations of GH and
insulin-like growth factor-I that are observed during puberty,
might independently influence the response to the two treatments,
especially with respect to retinopathy (3). To address this issue,
separate subset analyses were carried out in the 195 patients who were
between 13 and 17 yr of age on entry into the DCCT (125 primary
prevention and 70 secondary intervention patients), and their results
were compared with those in adults who were entered into the trial. In
both age groups, intensive therapy lowered the risk of developing
retinopathy by 
30%, of retinopathy progression by 60%, and of
developing microalbuminuria by 35–45% (4). Although the incidence of
neuropathy and macrovascular complications was minimal or nonexistent
in adolescent subjects in the DCCT, intensive treatment also improved
nerve conduction velocities and caused a modest lowering of fasting
low-density lipoprotein concentrations in this age group.
Results of the UKPDS provide further evidence that glycemic
control has a pre-eminent role in the pathogenesis of the microvascular
complications of diabetes (5). In that study, aggressive management of
type 2 diabetes using combinations of oral agents and/or insulin in
older adult subjects resulted in a reduction in risk for microvascular
complications that was quite comparable with those in the DCCT subjects
(Table 1
). Thus, it is reasonable to
extrapolate that adolescents with type 2 diabetes and preadolescents
with type 1 diabetes will also derive long-term benefits with respect
to microvascular complications by strictly controlling their diabetes.
However, the degree of benefit in the younger age groups remains to be
determined.
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Is strict control of diabetes feasible in children and adolescents? |
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6.0%). In contrast, directors of
Pediatric Diabetes Centers attending a recent meeting sponsored by the
American Diabetes Association reported clinic-wide mean
HbA1c levels ranging between 7.8–8.8%
(unpublished data). Such HbA1c levels compare
quite favorably with the mean HbA1c level
achieved by intensively treated adolescents in the DCCT
(i.e. 8.1%), especially when differences in
HbA1c assay methods are taken into
consideration. The above observations underscore the importance of the availability of multidisciplinary treatment teams that effectively teach diabetes self-management skills. The teams should include nurses, dietitians, mental health professionals, and diabetologists who are not only experienced in the management of diabetes in children, but also are familiar with intensive treatment regimens (11, 12). Despite the demonstrated efficacy and feasibility of intensive management of youth with diabetes, a worsening problem in providing comprehensive services to children with diabetes is that current reimbursement policies pay only a small fraction of the real costs of specialized diabetes care in children. In addition, hospitals and academic medical centers are finding it increasingly difficult to subsidize the uncovered costs of multidisciplinary treatment teams. The failure of enough young pediatricians to pursue training in pediatric endocrinology to meet ever-increasing demands is also a threat to future care of children with diabetes.
As pediatric treatment teams have been challenged to find more effective ways to achieve intensive treatment goals in youth with diabetes, there has been increasing use of unconventional regimens, including a marked increase in the number of children and adolescents using continuous sc insulin infusion (CSII) pump therapy. As recently as 1996, sales data from MiniMed, Inc. indicated that less than 5% of patients starting pump therapy were less than 20 yr of age. In contrast, the number of youth starting on pump treatment has increased by 3- to 6-fold over the past 2 yr.
CSII has been used by a substantial number of adolescents participating in our prospective study that is examining whether DCCT recommendations can be implemented in a large group of adolescents treated at a single center (10). As in the DCCT, patients enrolled in our study were allowed to select their method of insulin administration. Among the first 75 patients who have completed a year of follow-up, 50 selected MDI and 25 selected CSII. After 12 months, HbA1c levels improved in the MDI group (from 8.8 ± 1.6 to 8.4 ± 1.3%) and to an even greater extent in the CSII group (8.4 ± 0.9 to 7.5 ± 0.9%). Despite lower HbA1c levels, the rate of severe hypoglycemic events was 50% lower with CSII than MDI (76 vs. 134 events/100 patient yr) (13). Thus, CSII offers a treatment option that can lead to improved control and lower the risk for severe hypoglycemia in teenagers. These benefits were obtained even though almost all of the pump-treated patients used regular, rather than lispro, insulin during the first year of the study.
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Is intensive treatment safe in most children and adolescents? |
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The obvious concern is that repeated episodes of moderate to severe hypoglycemia will have adverse consequences on neurocognitive development and performance. These concerns are heightened by reports indicating that children and adolescents with type 1 diabetes have higher rates of mild cognitive dysfunction and electroencephalogic abnormalities, especially with early-onset diabetes that was complicated by hypoglycemic seizures (15, 16, 17). Fortunately, in the DCCT and other large-scale prospective studies involving adolescents and adults, no apparent long-term sequelae occurred from repeated episodes of severe hypoglycemia (1, 18). However, those data do not allay the fears that the developing brain of children 6 yr of age or less may be particularly vulnerable to hypoglycemia (19). Unfortunately, in the pediatric age range, young children also seem to be at the greatest risk for symptomatic and asymptomatic hypoglycemia, especially at night during sleep (14, 20). Although large-scale prospective studies to define the impact of hypoglycemia on cognitive function of young diabetic children would be desirable, major obstacles make a definitive study unlikely in the foreseeable future. Most important, there is currently no way to quantitate the true frequency and severity of hypoglycemia except in crude clinical terms.
The threat of hypoglycemia should have little impact on many aspects of
the intensive treatment program because the best way of trying to
prevent hypoglycemia is through more frequent blood glucose monitoring,
more frequent insulin injections, and more frequent patient contact.
Greater attention to the prevention of even mild asymptomatic
hypoglycemia may improve counterregulatory hormone responses and reduce
the risk of a more serious insulin reaction (21). Nevertheless, in the
absence of a feedback regulated insulin delivery system, some
hypoglycemia is almost unavoidable, especially in strictly controlled
patients who have a small margin of error. Thus, clinicians need to use
their own clinical judgment in setting target levels of
HbA1c and blood glucose that provide the most
favorable benefit to risk ratio in the individual patient. The goal for
most of the youngsters attending our clinic is to maintain
HbA1c under 8.0%, and the majority of patients
have been able to achieve this target level (Fig. 1).
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Can the risk of severe hypoglycemia be reduced? |
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Potentially the most important advance in the management of type 1 diabetes in the past 20 yr has been the development of systems for continuous online measurements of plasma glucose levels. The Food and Drug Administration has already approved the continuous glucose monitoring system developed by MiniMed, Inc., and several other systems are in development. The approved system consists of a small pager-like device connected via a tiny cable to a small flexible electroenzymatic glucose sensor that is inserted sc. The sensor measures extracellular fluid glucose concentrations that are calibrated against capillary blood glucose measurements using a conventional blood glucose meter. Although clinical trials of the sensor were successful enough in adults to achieve Food and Drug Administration approval for use of the device as a Holter-style glucose monitor, the system has not yet been tested in children. Nevertheless, the development of glucose monitoring systems, in combination with the remarkable increase in use of the insulin pumps and the more physiologic pharmacokinetic profiles of fast-acting insulin analogs, suggests that we may finally be at the threshold of achieving strict diabetes control with a markedly reduced risk of severe hypoglycemia in children and adolescents with diabetes. If anything, the benefit to risk ratio is more favorable now that it was 5 yr ago when the DCCT recommended that most youth with diabetes should receive intensive therapy.
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This article has been cited by other articles:
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  A. T. Soliman, M. Omar, M. M. Rizk, A. El Awwa, and F. M. AlGhobashy Glycaemic Control with Modified Intensive Insulin Injections (MII) Using Insulin Pens and Premixed Insulin in Children with Type-1 Diabetes: A Randomized Controlled Trial J Trop Pediatr, August 1, 2006; 52(4): 276 - 281. [Abstract] [Full Text] [PDF]
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 A. L. Rosenbloom Is Strict Glycemic Control of Diabetes Necessary and Feasible in Most Children and Adolescents? J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 514 - 515. [Full Text]
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