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 I-125 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.