Immune Responses to Insulin Aspart and Biphasic Insulin Aspart in People With Type 1 and Type 2 Diabetes

Abstract

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 125I 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 Ϯ SD of percent bound/total) of 16.6 Ϯ 16.3% in study 1 and 10.3 Ϯ 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 Ϯ 19.7 and 16.8 Ϯ 16.5% in study 1 and 21.5 Ϯ 21.9 and 16.9 Ϯ 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. Diabetes Care 25:876 -882, 2002A nti-insulin antibodies are common in people with diabetes treated with subcutaneous human insulin (HI) (1). It has been shown that up to 80% of people treated with subcutaneous insulin may develop anti-insulin antibodies (1). Hypothetically, anti-insulin antibodies could affect the pharmacokinetics of the exogenously administered insulin by several mechanisms, which would either enhance or reduce the pharmacodynamic response. Antibodies could enhance and prolong the pharmacodynamic action by serving as a carrier, or they could reduce insulin action by neutralization. As the insulin-binding sites of the antibodies produced vary from individual to individual, the pharmacodynamic effect could be expected to vary from subject to subject in an unpredictable manner.Insulin aspart (IAsp) is, together with insulin lispro (2), one of the two available rapid-acting insulin analogs with the advantage of being able to mimic the peripheral insulin response to a meal more closely than soluble HI, even when administered immediately before the meal (3-5). This has been made possible by substitution of aspartic acid for proline in position B28, thereby reducing the tendency to fo...

Intensive Therapy With Inhaled Insulin via the AERx Insulin Diabetes Management System

“…The increase in antibodies in this study is consistent with those seen in long-term insulin analog trials where no effects on efficacy and safety could be attributed to changes in antibody levels (23,24). Increased insulin antibody serum binding, with no apparent clinical changes, has also been observed with another inhaled insulin device (25,26), as well as with treatment with implantable insulin pumps (27).…”

Evaluation of insulin antibodies and placental transfer of insulin aspart in pregnant women with type 1 diabetes mellitus

“…Our results, which suggest that insulin antibodies do not develop during pregnancy when using either IAsp or HI, are reassuring and comparable to previous data involving non-pregnant participants with type 1 and type 2 diabetes [6] and those with gestational diabetes mellitus treated with IAsp or insulin lispro [8,9]. Overall, there was a small reduction in cross-reacting insulin antibodies in the IAsp group, perhaps similar to the decrease in levels seen with other types of antibody during pregnancy, such as serum antithyroglobulin [10].…”

“…Laboratory analyses Antibody analyses were performed by MDS Pharma Services (Fehraltorf, Switzerland) using a RIA method [6]. The results are expressed as the percentage of bound radioactivity relative to the total.…”

Allergy reactions to insulin: effects of continuous subcutaneous insulin infusion and insulin analogues

“…Structural changes leading to insulin lispro and insulin aspart (monomeric insulins) were initially reported to result in decreased immunogenicity in in vivo studies [17,18]. However, recent studies with both insulin lispro [42,43] or insulin aspart [44] rather reported results supporting similar immunogenicity of the two analogues when compared to human regular insulin. A multinational, multicentre combination of controlled and non-controlled, open-label studies of 4.5 years' duration showed that the incidence of insulin allergy in patients receiving subcutaneous administration of insulin lispro was not different from that in patients treated with recombinant regular human insulin [42].…”

“…A multinational, multicentre combination of controlled and non-controlled, open-label studies of 4.5 years' duration showed that the incidence of insulin allergy in patients receiving subcutaneous administration of insulin lispro was not different from that in patients treated with recombinant regular human insulin [42]. Lindholm et al [44] reported that insulin aspart caused allergic reactions as frequently as regular human insulin, although there was no consistent relationship between antibody formation and adverse events.…”