Efficacy, Safety, and Pump Compatibility of Insulin Aspart Used in Continuous Subcutaneous Insulin Infusion Therapy in Patients With Type 1 Diabetes

This was a single-center randomized open-label study in which patients received CSII therapy with either insulin aspart or buffered regular human insulin for 7 weeks. The study was conducted in accordance with the Declaration of Helsinki, and patients gave written informed consent.

Enrolled patients were men or women with a diagnosis of type 1 diabetes(C-peptide—negative) for 2-25 years before enrollment and who had been treated continuously for the previous 3 months with CSII therapy. Patients with a history of hypoglycemia unawareness, recurrent severe hypoglycemia, or deficiency of hypoglycemic counter regulation were excluded from enrollment. Patients with a history of significant cardiovascular, renal, or retinal disease were also excluded.

At the screening visit, patients were supplied with infusion sets (Sof-set canula 42″ MMT-315, reservoir 3 ml MMT-103; MiniMed, Sylamar, CA) and instructed to continue using their own infusion pump (MiniMed models 506, 507,or 507C) and their current CSII insulin (all patients were using insulin lispro, Humalog; Eli Lilly, Indianapolis, IN) until the baseline visit 2 weeks later. Eligible patients were then randomly assigned (2:1 ratio) to receive either insulin aspart or buffered regular human insulin (Velosulin BR; Novo Nordisk, Bagsvaerd, Denmark) as replacement for their current CSII insulin. Basal and bolus doses were transferred from the patient's prestudy regimen. Bolus dosing of buffered regular human insulin was administered 30 min before meals, whereas insulin aspart bolus administration was immediately before meals. Patients were instructed to replace their insulin and tubing at 48-h(maximum) intervals during the first 6 weeks of treatment and were then allowed to use the same tubing continuously for 7 days during week 7.

Study visits occurred at the end of each treatment week. During the week,patients self-monitored their blood glucose levels using a One Touch Profile glucose meter (LifeScan, Milpitas, CA) and recorded the results four times daily (before breakfast, lunch, and dinner and before bedtime) in a diary. Patients also recorded insulin dose settings, change of infusion set and/or insulin, and any possible occurrences of system obstruction or leakage.

Patients were instructed to adjust their insulin dose using a target blood glucose range of 3.9-8.3 mmol/l (70-150 mg/dl)(12,13). Bolus doses were based on premeal blood glucose values, and basal doses were based on pre-bedtime and pre-breakfast blood glucose values. Patients were also instructed to use a premeal correction (supplement) bolus to correct out-of-range values (13).

The insulin in the reservoir and distal tubing was microscopically examined by two trained observers at the weekly visits for transparency, color changes,particle or crystal formation (scale: 0 = none, 1 = minimal, 2 =moderate/many), and pH. Serum fructosamine was measured (reportable range<5-1,000 μmol/l) at baseline and at the end of treatment weeks 2, 6, and 7. HbA_lc was measured (reportable range 4.2-20.4%, normal range<7%) at baseline and at the end of 6 weeks of treatment from whole blood samples by Quest Diagnostics (San Juan Capistrano, CA).

Safety was assessed based on physical examinations, adverse experiences,and the occurrence of hypoglycemic or hyperglycemic episodes. Patients were educated in avoiding and treating symptomatic hypoglycemia and instructed to record the number of episodes of “unexplained” hypoglycemic events(blood glucose meter reading <2.5 mmol/l [45 mg/dl] without an appropriate explanation, e.g., delaying a meal after taking a bolus dose) and hyperglycemic events (blood glucose meter reading >19 mmol/l [350 mg/dl]without an appropriate explanation, e.g., eating a meal without taking a bolus insulin dose).

Descriptive statistics (mean, SD, range, frequency counts, and relative frequency) were used to summarize the data. Between-treatment comparisons were made using either the two-sample t test or Wilcoxon's rank-sum test.

There were 29 patients who were enrolled and 28 patients who completed the 7 weeks of treatment. One patient in the insulin aspart group moved away and withdrew from treatment after study week 2 and was lost to follow-up. Patient demographic characteristics are shown in Table 1.

Patients entered the study with good glycemic control, and both insulin aspart and buffered regular human insulin were effective in maintaining this control throughout the study (Table 2). Serum fructosamine and HbA_lc levels remained at or near baseline levels for both groups, although a small decrease in HbA_lc level was observed for the insulin aspart group. Daily self-monitored blood glucose levels averaged ∼8.3 mmol/l (150 mg/dl)throughout the study for patients in both groups. Average premeal blood glucose values within each group were not significantly different from the overall average daily value, indicating that both insulin formulations were effective in controlling blood glucose fluctuations during the course of the day (Table 3).

Approximately four infusion sets were used per patient per week during the first 6 weeks of treatment in both groups. Time elapsed since changing of the infusion set did not affect blood glucose control in either group, with average glucose levels remaining consistent during the 48 h between catheter tubing changes and with an ∼0.2-0.4 mmol/l (4-7 mg/dl) difference between the first and second 24-h periods. Average daily glucose levels began to increase (∼1-2.2 mmol/l, 20-40 mg/dl) in both groups during continuous use of the catheter tubing in treatment week 7. There were no significant differences between the groups for any blood glucose level during this period.

No patient in the insulin aspart group required a significant dose adjustment when being transferred to insulin aspart, and average daily basal or bolus insulin doses did not significantly change during the study for patients in either group. Mean bolus doses at weeks 1 and 6 were 23 ±6.0 and 22 ± 6.6, respectively, for the insulin aspart group and 21± 8.0 and 21 ± 7.9 for the buffered insulin group. Patients in the insulin aspart group did require a slightly higher basal dose (23 ±6.0 at week 1 and 23 ± 5.4 at week 6) compared with patients in the buffered regular human insulin group (20 ± 8.0 at week 1 and 21± 6.7 at week 6). However, there were no statistically significant differences between the two groups for mean bolus, basal, and total insulin doses.

Both insulins appeared to be compatible with pump use. No color or transparency changes were noted for either insulin when the pump tubing and reservoir were examined. The average pH of the insulin in the reservoir and the distal tubing was maintained at 7.4 and 7.2, respectively, in both the insulin aspart and the buffered regular human insulin groups. Some insulin crystal formation occurred in both groups, although there was significantly(P ≤ 0.05) less crystallization for the insulin aspart group compared with the buffered regular human insulin group in the reservoir (0.3± 0.3 vs. 1.1 ± 0.4) and distal tubing (0.3 ± 0.3 vs. 0.7± 0.4). Possible obstructions were reported by seven patients in the insulin aspart group and two patients in the buffered regular human insulin group. Set leakages were infrequent, being reported by four patients in the insulin aspart group and two patients in the buffered regular human insulin group. There were no changes in the assessments of pump compatibility associated with continuous 7-day use of the catheter tubing during week 7 in either treatment group.

Both treatments appeared to be well tolerated. There were 14 (74%) patients in the insulin aspart group and 6 (60%) patients in the buffered regular human insulin group who reported unexplained hypoglycemic events. The 14 patients in the insulin aspart group experienced fewer events (2.9 events/patient) than did the 6 patients in the buffered regular human insulin group (6.2 events/patient). Unexplained hyperglycemic events were reported by 14 (74%,3.5 events/patient) patients in the insulin aspart group and 6 (60%, 3.0 events/patient) in the buffered regular human insulin group.

Adverse experiences, most commonly upper respiratory infections, were reported by six (32%) patients in the insulin aspart group and three (30%)patients in the buffered regular human insulin group. No injection site reactions were reported by patients in either group. One patient in the buffered regular human insulin group was treated in the emergency room for hypoglycemia with tonic clonic seizures occurring after strenuous physical activity (skiing). Mean values for BMI were unchanged from screening to the end of week 7 in both treatment groups. No other clinically significant changes in clinical laboratory test results or vital signs were noted for any patient.

Insulin aspart is a rapid-acting insulin analog,and its efficacy and safety in patients with type 1 diabetes receiving multiple daily insulin injection (MDI) therapy have been previously reported(14,15,16,17,18). The results of this study indicate that insulin aspart is also effective when used in CSII therapy.

Data from the Diabetes Control and Complications Trial and subsequent clinical studies have demonstrated the effectiveness of CSII therapy in providing sustained improvement in glycemic control(19,20,21,22). In the present study, the patients had previously been on CSII therapy and entered the study with HbA_lc values at or near the American Diabetes Association target of 7%(23). Both treatments were effective in maintaining HbA_lc levels, although a small decrease was observed for the insulin aspart treatment group. There was no statistical difference between the groups for this change; however, significant improvements in glycemic control compared with regular human insulin have been demonstrated in CSII studies using insulin lispro, another fast-acting analog(22,24). The relatively small number of patients in the present study may not have allowed enough statistical power to detect a significant difference between the groups.

Postprandial blood glucose levels were not specifically measured in this study; however, previously reported studies in which insulin aspart was used as the mealtime component of an MDI regimen have shown significantly improved control of postprandial blood glucose excursions with insulin aspart compared with regular human insulin(15,17,18). Improved postprandial control of blood glucose may show a similar advantage for insulin aspart in CSII compared with regular human insulin, although such studies have not yet been conducted.

The results of this study also indicate that the use of insulin aspart is compatible with the external infusion pump. Both insulins were associated with few reports of possible obstructions and leakages of the external infusion pump and tubing. Some insulin crystal formation occurred for both insulins in the reservoir and distal tubing, but significantly less so for patients using insulin aspart.

Insulin aspart—treated patients did require a slightly higher basal insulin dose than did patients treated with buffered regular human insulin. This observation is consistent with previously reported studies in which patients with type 1 diabetes receiving subcutaneous injections of insulin aspart used 7-10% higher doses of NPH insulin compared with patients treated with regular human insulin(16,17). An increased amount of basal insulin has also been reported for insulin lispro in CSII (24). It may therefore be advisable to specifically caution patients using a rapid-acting insulin analog to maintain adequate administration rates of their basal insulin.

In this study, insulin aspart was associated with fewer unexplained hypoglycemic events per patient than buffered regular human insulin (2.9 vs. 6.2) among those patients having such events. These results may suggest a potential advantage with regard to hypoglycemia risk with insulin aspart, but additional studies are needed to further investigate this possibility. However, all patients undergoing intensive insulin therapy should be adequately cautioned about the potential for an increased risk of hypoglycemia compared with their previous therapy regimen.

Because many patients may not change their catheter tubing as often as instructed, the seventh week of this study was added to assess the effect of continuous 7-day use of the same tubing. Overall, no negative effects on glycemic control, occurrence of hypo- or hyperglycemia, or pump compatibility were observed for either group. However, serum glucose levels did begin to increase the longer the tubing was used, and patients should continue to be advised of the importance of replacing the catheter and tubing on a regular basis.

Insulin aspart and buffered regular human insulin were both effective and well tolerated and provided similar pump compatibility when used in CSII therapy. This study indicates that the efficacy and safety of the rapid-acting insulin analog insulin aspart make it suitable for use with an external pump in CSII therapy in patients with type 1 diabetes.