Immune responses to insulin aspart and biphasic insulin aspart in people with type 1 and type 2 diabetes

OBJECTIVE: The antibody responses to a novel rapid-acting insulin analog, insulin aspart (IAsp), and their potential clinical correlates were studied with a specifically developed method in 2,420 people with diabetes treated for up to 1 year with preprandial subcutaneous injections of IAsp. RESEARCH DESIGN AND METHODS: Circulating insulin antibodies were analyzed by radioimmunoassay with (125)I insulin or IAsp tracers and polyethylene glycol precipitation. Four multinational, open, parallel group studies were conducted in Europe and North America, with a total of 1,534 people with diabetes exposed to IAsp and 886 people exposed to human insulin (HI) as meal-related insulin for 6-12 months. RESULTS: Insulin antibodies specific to HI or IAsp were absent in a majority of patients throughout the 6- to 12-month study periods. A majority of the patients (64-68%) had antibodies cross-reacting between HI and IAsp when entering the studies, with baseline levels (means +/- SD of percent bound/total) of 16.6 +/- 16.3% in study 1 and 10.3 +/- 14.0% in study 4. In all four studies, cross-reactive antibodies increased in patients exposed to IAsp, with a maximum at 3 months, and thereafter there was a decline toward baseline levels at 9-12 months (levels at 3 and 12 months: 22.3 +/- 19.7 and 16.8 +/- 16.5% in study 1 and 21.5 +/- 21.9 and 16.9 +/- 17.4% in study 4). Antibody levels showed similar changes in people with type 1 and type 2 diabetes, and there was no consistent relationship between antibody formation and glycemic control or between antibody formation and safety in terms of adverse events. CONCLUSIONS: Treatment with IAsp is associated with an increase in cross-reactive insulin antibodies, with a subsequent fall toward baseline values, without any indication of clinical relevance because no effect on efficacy or safety could be identified.