This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Optimal treatment of type 1 diabetes mellitus (T1DM) should focus on physiologic insulin replacement. Insulin glargine is used as a long acting insulin (LAI) analog. Glargine is superior to NPH in decreasing nocturnal hypoglycemia and improving glycemic control. Glargine, as per manufacturer, must be given separate from rapid acting insulin (RAI), resulting in undesired multiple insulin injections. This is especially problematic in pediatric T1DM. In pediatric patients, glargine action is less than 24 hrs. We have previously demonstrated that mixing glargine with RAI, and given twice daily compared to separately given injections of RAI and glargine does not adversely affect glucose excursions. Furthermore, we demonstrated that 3 months of twice-daily glargine mixed with RAI results in a 30% improvement in HbA1C as compared to standard therapy of NPH and RAI. Detemir is a new long-acting insulin analog. In this proposal, we aim to study the efficacy of detemir in pediatric T1DM, and compare it to the gold standard of using glargine. Since there is no data regarding mixing insulin, in this protocol, detemir will be mixed with RAI in the same syringe, and be compared with giving them as separate injections twice-daily. 1. Insulin detemir mixed with RAI analog given twice daily will have equivalent effects on lowering blood glucose vs. giving insulin detemir and RAI as separate injections twice daily, in the treatment of pediatric T1DM. 2. Glucose excursions will be similar with the use of either detemir or glargine when either of the two is given mixed with RAI as a twice-daily injection.
SPECIFIC AIMS 1. To determine the effects on glucose concentration of mixing detemir with RAI in the same syringe and comparing them to insulin detemir administered as a separate injection. 2. To determine if glucose excursions differ with twice-daily injections of detemir compared to giving glargine twice a day. The goal of treatment in the management of type 1 diabetes mellitus (T1DM) is achieving near normal glycemic control. This prevents and/or delays the onset of long-term complications [1]. This goal is achieved by delivering insulin in a physiologic manner by using an insulin pump or with the use of a long-acting insulin analog that mimics basal insulin profile and rapid-acting insulin (RAI) analog such as lispro and aspart for meal related glucose excursions. Insulin glargine and more recently detemir are new basal insulin analogs developed to treat T1DM. Insulin glargine was the first long-acting insulin analog to be produced by recombinant DNA technology [2,3]. Early pharmacokinetic (pK) studies with insulin glargine in healthy volunteers reported a duration of action of up to 30 h [4]. However, the duration was significantly shorter with mean plasma glucose levels in euglycemic clamp studies rising 16 h after glargine administration with the mean duration of action for the entire study population being 20.5 h [5]. There are limited pK data available in the pediatric population and clinical practice suggests that glargine lasts for a much shorter period of time in some patients with T1DM [6]. Despite the benefits of intensive insulin management, the use of long-acting analogs is associated with poor compliance [7] and adherence to treatment plans. This is due to the increased number of injections that are required to maintain euglycemia as compared to standard therapy of NPH as a basal injection. To overcome this obstacle we hypothesized that although there may be some pK variation when insulin glargine is mixed with short acting analogs it may not affect pharmacodynamic (pD) profile significantly. To prove this, we recruited subjects who were on once a day insulin glargine and used continuous glucose monitoring system (CGMS) to obtain 3 days glucose profiles. Subjects were then randomized to either receiving insulin glargine twice a day mixed with RAI analogs or insulin glargine given twice a day separate from the RAI analogs. CGMS was obtained after each of these treatment plans and no difference in glucose concentrations were detected when insulin glargine was given mixed or given separately from the RAI [8]. However, the long-term effects of mixing on glycemic control could not be evaluated because subjects were on this regimen for only 10 days. In trial 2, currently in progress, long-term glycemic effects of mixing insulin glargine with RAI and administering it as a twice-daily dose and comparing its effect to twice-a-day NPH is being examined (See preliminary data). New onset T1DM subjects were recruited and at 3 months were randomized to either receiving NPH and RAI mixed and given as a twice a day regimen vs. insulin glargine and RAI mixed and given as a twice a day regimen. At the end of 3 months, we found that subjects on twice daily glargine mixed with had a significantly better hemoglobin A1c (HbA1c) (NPH vs. glargine 7.5% Vs 6.3%) as compared to the NPH arm (p<0.03). These studies suggest that some pK variation when insulin glargine is mixed with RAI (discussions with Sanofi-Aventis) may not be of clinical significance. Furthermore, the ability to mix insulins results in fewer injections, which increases compliance in all T1DM subjects but makes an immense difference in children with T1DM. Insulin detemir recently received FDA approval for use in type 1 and 2 diabetes. Insulin detemir [LysB29(N?- tetradecanoyl) des(B30) human insulin] is the first of a new class of long-acting soluble insulin analogs. Its prolonged duration of action is attributable to a combination of increased self-association (hexamer stabilization and hexamer- hexamer interaction) and albumin binding due to acylation of the amino acid lysine in position B29 with a 14C fatty acid (myristic acid). Insulin detemir binds to albumin with high affinity and is demonstrated to have a protracted metabolic action with a slow onset of action and less peak as compared to that observed with NPH [9]. Insulin detemir is a clear neutral solution and its absorption is not dependent on resuspension like NPH or on the formation and dissolution of microprecipitates like glargine. These properties result in a more uniform absorption and a significant more predictable glucose-lowering effect than both NPH and glargine [10]. Although, these properties would suggest that detemir could be mixed with insulin aspart, currently detemir is being marketed as separate injections citing pK variations. Like glargine, there is lack of information of the mixture of glargine with RAI and its effect on glucose excursions, which is what would be clinically important and aid in decreasing the number of insulin injections/day. To study the inter-subject pK and pD effect of insulin detemir as compared to NPH and glargine, a randomized double- blinded study was undertaken. In 54 adults under the hyperinsulinemic euglycemic clamp conditions, 24 hr period post-dosing of basal insulin preparations were studied. The glucose infusion rate (GIR) area under the curve (AUC) (0-12 h) 27% (detemir) vs. 59% (NPH) vs. 46% (glargine) was noted. Furthermore, insulin detemir had Cmax 18 vs. 24 vs. 34%;Insulin (INS) AUC (0- ?) 14 vs. 28 vs. 33%[11]. These results indicate a lower within-subject variability of insulin detemir and may result in a lowering of the day-to-day fluctuations seen with other basal insulins. Most of the studies reported non-superiority of detemir as compared to standard care of NPH [12-14]. In a more recent study, the STEADINESS study group reported in a sample of 408 T1DM subjects that when subjects received detemir in a randomized control study the HbA1c was improved by 0.18% [15]. A 26-week study using insulin detemir as compared to NPH demonstrated that HbA1c's were comparable. However, there was a lower risk of hypoglycemia by 22% with the use of detemir as compared to NPH [13] and nocturnal blood glucose concentrations were less variable and more """"""""smooth"""""""". Although these studies suggest that detemir may have slight advantage over NPH, there are no studies to date comparing detemir to insulin glargine. To truly study efficacy of long acting insulin analog detemir, it is now important to compare it to insulin glargine since insulin glargine has been used for a more extended period of time. Although insulin detemir has a neutral pH, no studies on the mixing of detemir with RAI are published. Danne et al reported the pK effects of insulin detemir as compared to insulin NPH in children with T1DM in two age groups: 6-12 years and 13-17 years. These subjects were also compared to adults with T1DM. Data is reported on 10 children, 10 adolescents and 9 adults. No statistical differences were observed between the insulins or between age groups. However, the data was fraught with missing values and a very small sample size. The t ? for insulin detemir was shorter in children (302 min) and adolescents (301 min) as compared to adults. Interestingly, no effects on glucose were reported in this paper. Furthermore, NPH and insulin detemir demonstrated temporary decline in concentrations between 2- 4 and 4-6 h after injection, respectively. This is the only published study of the use of insulin detemir in pediatric patients with T1DM [16]. In summary, there is a paucity of data on the use of detemir in pediatric T1DM. Furthermore, intensive insulin management using long acting analogs is difficult to achieve because of the number of insulin injections required. These studies aim to improve glycemic control, increase adherence to intensive insulin management by simplifying regimens and decreasing the number of injections and thus pain. Furthermore we would like to study novel compounds that are brought to market that could benefit children but there is lack of safety and efficacy data for this population.
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