Studies such as the Diabetes Control and Complications Trial have shown that, as in adult patients, intensive diabetes management in adolescent patients results in better glycemic control and delays the onset and slows the progression of vascular and neurological complications (1). However, a cross-sectional multinational study showed that less than one-third of the children and adolescents who underwent treatment for diabetes had adequate metabolic control (2). Providing a constant supply of basal insulin that mimics that of healthy individuals is an essential aspect of maintaining tight glycemic control in patients with type 1 diabetes. The traditional NPH insulin and ultralente basal insulin formulations do not provide a constant and reliable 24-h basal insulin supply because their duration of action is too short, and unwanted peaks of action in the night can cause nocturnal hypoglycemia (3). This is of particular relevance in children and adolescents, who are more prone to hypoglycemic episodes (4,5).
A new long-acting insulin analog has been developed using recombinant DNA technology. Insulin glargine differs from human insulin by the addition of two additional arginines on the COOH terminus of the B-chain and the replacement of an asparagine residue with glycine on the A-chain (6). The resulting molecule has a peakless, prolonged time-action profile and can be used once daily. These features enable insulin glargine to provide sufficient basal insulin over 24 h when used in a basal-bolus regimen while limiting the incidence of hypoglycemic, particularly nocturnal hypoglycemic, episodes (7). The objective of this study was to compare the metabolic effect and safety of insulin glargine with NPH insulin in children and adolescents with type 1 diabetes.
In a multicenter open-label randomized study, 349 patients with type 1 diabetes, aged 5–16 years, who were using at least three daily preprandial injections of normal insulin and who had an HbA1c value of <12%, were treated for 6 months. Patients received insulin glargine once daily (at bedtime), irrespective of their prior regimen (174 patients), whereas the regimen for patients receiving NPH insulin was either once (at bedtime in 114 patients) or twice daily (in the morning and at bedtime in 61 patients), based on their prior treatment regimen. Titration of the bedtime dose of insulin was related to fasting blood glucose (FBG), with a target of 4.4–8.8 mmol/l. Regular insulin was injected before meals according to the habits of the patients. Insulin glargine and NPH insulin treatment groups had a similar distribution in terms of sex, age (11.8 ± 2 vs. 11.5 ± 2 years), BMI (18.8 ± 2 vs. 18.9 ± 2 kg/m2), ethnic group, puberty stage (preadolescent 32.8 vs. 35.4%; and adolescent 67.2 vs. 64.6%), and age at onset of diabetes (7.4 ± 3.17 vs. 7.4 ± 3.31 years).
The primary efficacy measure was mean change from baseline in GHb levels, which was determined by analysis of covariance (ANCOVA). The difference in mean change from baseline between insulin glargine and NPH insulin was estimated using adjusted means together with the associated SE and 95% CI from the ANCOVA model. The secondary efficacy measures were mean change in FBG levels from baseline (analyzed by ANCOVA) and incidence of hypoglycemia (compared between treatment groups using rank analysis of variance). Hypoglycemia was catergorized as either symptomatic (with clinical symptoms that could be confirmed by blood glucose levels <2.8 mmol/l) or asymptomatic (any event with a confirmed blood glucose level <2.8 mmol/l but without any symptoms). Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia in which the patient required assistance from another person and which was associated with a blood glucose level <2.8 mmol/l or prompt recovery after oral carbohydrate or intravenous glucose or glucagon administration (8).
There was no difference between insulin glargine and NPH insulin in terms of change in GHb from baseline to end point (0.28 ± 0.09% vs. 0.27 ± 0.09%, P = 0.93). However, FBG decreased more from baseline to end point in the insulin glargine group (−1.29 mmol/l) than in the NPH insulin group (−0.68 mmol/l; P = 0.02). At end point, a higher percentage of insulin glargine–treated patients (43.9%) than NPH insulin–treated patients (39.0%) reached the target range of 4.4–8.8 mmol/l. These improved FBG levels could be due to the extended time-action profile of insulin glargine.
During the entire study period, the percentage of subjects reporting at least one episode of symptomatic hypoglycemia was similar for insulin glargine and NPH insulin treatment (78.9 and 79.3%, respectively); however, fewer patients in the insulin glargine versus the NPH insulin group reported severe hypoglycemia (23.0 vs. 28.6%, respectively; P = 0.22, Cochran-Mantel-Haenszel test) and severe nocturnal hypoglycemia (12.6 vs. 17.7%, respectively; P = 0.19), although these differences were not statistically significant.
Both insulin glargine and NPH insulin treatments were well tolerated. Of note, injection site reactions, categorized as adverse events of special interest, were evenly distributed between the insulin glargine and NPH insulin groups (9.2 vs. 8.6%, respectively). Serious adverse events were observed more often in the NPH insulin group than in the insulin glargine group (13.7 vs. 5.8%, respectively; P < 0.02, Fisher’s exact test).
In conclusion, a once-daily subcutaneous dose of insulin glargine provides glycemic control that is at least as effective as once- or twice-daily NPH insulin in children and adolescents with type 1 diabetes, with significantly lower FBG levels and a trend toward fewer episodes of severe hypoglycemia and nocturnal hypoglycemia.
Investigators for the Pediatric Study Group of Insulin Glargine
Austria: Peter Kitzler, MD; Klaus Schmitt, MD; Edith Schober, MD; Belgium: Jean De Schepper, MD; Raoul Rooman, MD; Croatia: Katarina Cvijovic, MD; Czech Republic: Stanislava Kolouskova, MD, Jan Lebel, MD; Libuse Osickova, MD; Jaroslav Skvor, MD; Jirina Venhacova, MD; Finland: Marja-Liisa Kaar, MD; Paevi Tapanainen, MD; Raisa Lounamaa, MD; Matti Salo, MD; Germany: Juergen Herwig, MD; Eberhard Kauf, MD; Andreas Lemmer, MD; Ulf Wendel, MD; Bernd Schulze-Schleppinghoff, MD; South Africa: Larry Distiller, MD; L. Robertson, MD; J. Van Dyk, MD; Switzerland: Eugen Schoenle, MD; the Netherlands: Mieke Houdijk, MD; Joan Schermer-Rotte, MD; Adrianus van Rhijn, MD; U.K.: David Dunger, MD.
Address correspondence to Edith Schober, University Children’s Hospital, Waehringer Guertel 18-20, 1090 Vienna, Austria. E-mail: firstname.lastname@example.org.
E.S. received supporting funds from Aventis Pharma. J.V.D. was paid consultation fees by Aventis for each participating patient. K.W.-P. holds stock in Aventis Pharma Germany.