Efficacy and Safety of Insulin Aspart in Patients with Type 1 Diabetes Mellitus

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1 Clin Pediatr Endocrinol 2002; 11(2), Copyright 2002 by The Japanese Society for Pediatric Endocrinology Original Efficacy and Safety of Insulin Aspart in Patients with Type 1 Diabetes Mellitus Toshikazu Takahashi Department of Pediatrics,Takahashi Clinic, Shinko Hospital, Kobe, Japan Abstract. Rapid-acting insulin aspart was studied for efficacy and safety in seven patients with type 1 diabetes mellitus for more than 72 weeks. Pharmacokinetic profiles showed serum insulin levels peaking at 30 min, not the 90 min for regular insulin. Average HbA1C tended to decrease for 24 weeks, but did not change for 120 weeks thereafter. There were no statistically significant body weight changes over six months. The amounts of insulin and insulin aspart antibodies measured after 12 and 24 weeks of insulin aspart administration were not statistically significant. No adverse events were reported. All subjects appreciated the convenience of injection immediately before meals. Rapid-acting insulin aspart is safe and convenient for patients with type 1 diabetes. Through its use, they may improve their quality of life and get insulin levels to mimic those of non-diabetics. Key words: type 1 diabetes, insulin aspart, insulin antibody, insulin aspart antibody Introduction The Diabetes Control and Complications Trial (DCTT) confirmed that intensified treatment, with daily multiple subcutaneous injections to mimic normal insulin secretion, reduces the incidence and progression of vascular complications in type1 diabetes mellitus. But, delays in absorption and insulin's propensity to produce dimmers and hexamers at the injection sites make it necessary to inject insulin regularly 30 to 60 min before meals. Insulin aspart (Novo Nordisk, Denmark), a rapidacting insulin analog produced by recombinant technology replacing the proline at position 28 on the insulin B-chain with negatively charged aspartic acid, consists of hexamers that rapidly Received: April 2, 2002 Accepted: July 24, 2002 Correspondence: Dr. Toshikazu Takahashi, Iwaya Kitamachi, Nada-ku, Kobe , Japan dissociate into monomers and dimmers after subcutaneous injection, so it is rapidly absorbed and can therefore be injected immediately before meals and still mimic normal insulin kinetics. The purpose of this study was to compare the efficacy and safety of insulin aspart and regular insulin in patients with type 1 diabetes mellitus. Subjects and Methods Seven patients aged yrs received insulin aspart (Novo Nordisk, Denmark) for 24 weeks (one patient) or 120 weeks (six patients). They had been diagnosed with type 1 diabetes mellitus and had received regular and NPH insulin for at least 3 yrs prior to this study. They gave written informed consent. Patients with a history of cardiovascular, renal or retinal diseases were excluded. Only two patients had body mass indexes over 25. Daily insulin doses were

2 88 Takahashi Vol.11 / No.2 Table 1 Patients characteristics Patient Age (years) Sex F F M M F M F Body Mass Index HbA1C Diabetes history (years) Insulin dose before therapy Penfill R (before meals) 8/8/8 14/14/14 14/14/16 12/8/8 12/12/12 12/10/14 12/12/12 Penfill N(bedtime) U/kg. The patients received insulin aspart following the same schedule as before the study: Penfill R injections three times a day, before meals, and a Penfill N injection at bedtime. Table 1 summarizes the patients characteristics. This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. For two controls and patient 1, 2 and 3, blood glucose and serum IRI levels were measured before the lunchtime injection and 15, 30, 45, 60, 90, 100, 120, 240, 360 and 480 min after. Blood glucose was assayed with glucose oxidase, and serum free IRI level with a commercial radioimmunoassay kit. For all seven patients, HbA1C levels were measured by HPL chromatography, once a month for the first 24 weeks and every 24 weeks thereafter for the duration of this study (120 weeks). Insulin and insulin aspart antibody levels were determined at 0, 12 and 24 weeks by radioimmunoassay. In principle, antibodies were detected by their ability to bind to the tracers ( 125 I- labeled regular insulin or insulin aspart) and the ability of polyethylene glycol precipitation to separate antibody-bound tracer from unbound tracer. The results were expressed as the percent bound radioactivity relative to the total amount of radioactive present. Body weight was measured once a month. Patients completed a short questionnaire about the use of insulin aspart after six months (24 weeks) of treatment. Results Fig. 1 shows the insulin aspart (A) and regular insulin profiles (B) for the patients in this study. The peak serum IRI concentration after insulin aspart was at min, which is earlier than the 90 min with regular insulin. These insulin concentrations returned to baseline levels after 5 6 h with insulin aspart, but not within the first 7 h with regular insulin. Plasma glucose levels after insulin aspart injection showed a large variation in three patients, indicating the difficulty of lowering plasma glucose levels. The average HbA1C levels tended to decrease over the first 24 weeks (Fig. 2A), but did not change for the next 120 weeks (Fig. 2B). Average body weight did not change significantly over the course of the study (Fig. 3). No insulin or insulin aspart antibodies were detected in these patients at 0, 12 or 24 weeks (Table 2). In a short questionnaire (Table 3) completed six months into the study, all the patients appreciated the convenience of insulin aspart injection immediately before meals. No serious adverse events were reported. No patients withdrew from the trial for the first six months.

3 December 2002 Insulin Aspart in Type 1 Diabetes 89 Fig. 1 Serum IRI and plasma glucose levels in patients with type 1 diabetes after injection of insulin aspart (upper) and regular insulin (lower). There were no changes in clinical or laboratory parameters. Discussion There are two rapid-acting insulin analogs currently available: insulin lispro (Eli lily, USA) and insulin aspart (Novo Nordisk, Denmark). Reports cite immediate absorption from subcutaneous injection sites and a sharp decrease after 3 4 h. My results also showed similar data for Fig. 2 Body weight (kg) over course of insulin aspart treatment.

4 90 Takahashi Vol.11 / No.2 Fig. 3 HbA1C levels over first 24 weeks (A) and subsequent 120 weeks (B) of insulin aspart treatment. Table 2 Serum levels of Insulin antibody (%)/insulin aspart antibody (%) during 24 weeks 0 weeks 12 weeks 24 weeks 1 0.4/ / / / / / / / / / /2.7 NS/NS 5 0.0/ / / / / / / /7.5 NS/NS NS : not enough samples for reanalysis. a faster peak and prompt disappearance of insulin aspart compared to regular insulin. The benefits of rapid-acting analogs are a decrease in postprandial hyperglycemia and prevent from preprandial and early morning hypoglycemia (1, 2). These mean lowering HbA1C levels of the patients with type 1 diabetes and lead to protection from diabetic complications. The efficacy and safety of insulin lispro, commercially used in other countries for more than five years now, has already been reported (3). The recommendation to inject regular insulin at least 30 min prior to a meal represents a daily inconvenience for patients with type 1 diabetes mellitus. Most patients are known to leave less time before eating. The present study demonstrates that the use of this rapid-acting insulin analog allows them to shorten this interval. For infants and small children, easily susceptible to influenza, diarrhea and other infections as well as other impediments to prior food intake, it might even be possible to delay injection of this rapidacting insulin until immediately after eating. This new therapeutic option of post-prandial administration of rapid-acting insulin has already been investigated (4). The upper normal range was reported to be 0.5% bound/total (B/T) for insulin antibodies, and

5 December 2002 Insulin Aspart in Type 1 Diabetes 91 Table 3 Patients questionnaire positive/7 Before joining this study, when were you generally injecting regular insulin? 30 minutes before meals 2 15 minutes before meals 0 Immediately before meals 3 Varied daily 2 How inconvenient was it to inject 30 minutes before meals? Very inconvenient 2 Somewhat inconvenient 5 Not so inconvenient 0 Not inconvenient at all 0 How necessary is it for you to be able to inject rapid-acting insulin immediately before meals? Very necessary 3 Somewhat necessary 4 Not so necessary 0 Not necessary at all 0 How convenient was the change in injection time to immediately before meals? Very convenient 5 Somewhat convenient 2 Did not change much 0 Inconvenient 0 Would you want to use insulin aspart after this trial? By all means 4 If possible 3 regular insulin is better 0 4.6% (B/T) for insulin asprt antibody (5). Neither antibody was detected during this study. Laboratory data for the seven patients did not change and no adverce events were reported in more than two years use of insuslin aspart. No severe hypoglycemia was found during this study. This study confirms that insulin aspart is both convenient and effective for patients with type 1 diabetes mellitus. Regular exercise, meals, and ergotherapy are the three pillars of diabetes mellitus treatment. The patients also have to exercise proper control over insulin injections and blood sugar measurements. The advent of immediate acting insulin analogs reduces these burdens, increasing the patient s freedom of movement and thus contributing to better quality of life. References 1. Brunner GA, Hirschbergert S, Sendelhofer G, Wutte A, Ellmerer M, Balent B, et al. Post-prandial administration of the insulin analogue insulin aspart in patients with Type 1 diabetes mellitus. Diabetic Med 2000;17: Mortensen HB, Lindholm A, Olsen BS, Hylleberg B. Rapid appearance and onset of action of insulin aspart in paediatric subjects with type 1 diabetes. Eur J Pediatr 2000;159:483 8.

6 92 Takahashi Vol.11 / No.2 3. Gary SK, Anderson JH, Perry S, et al. Long-term efficacy of Humalog in subjects with type 1 diabetes mellitus. Diabetes Med 1999;16: Schernthaner G, Wein W, Sandholzer K, Equiluz- Bruck S, Bates PC, Birkett MA. Postprandial insulin lispro a new therapeutic option for type 1 diabetic patients. Diabetes Care 1998;21: Lindholm A, Jensen LB, Home PD, Raskin P, Boehm BO, Rástam J, et al. Immune responses to insulin aspart and biphasic insulin aspart in people with type 1 and type 2 diabetes. Diabetes Care 2002;25: