Immune Responses to Insulin Aspart and Biphasic Insulin Aspart in People With Type 1 and Type 2 Diabetes ANDERS LINDHOLM, MD, PHD 1 LISBETH B. JENSEN, MSC, PHD 1 PHILIP D. HOME, DM, DPHIL 2 PHILIP RASKIN, MD 3 BERNHARD O. BOEHM, MD, PHD 4 JACOB RÅSTAM, BSC 1 FOR THE EUROPEAN AND NORTH AMERICAN STUDY GROUPS ON INSULIN ASPART 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 anti- bodies 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 max- imum 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. Diabetes Care 25:876 – 882, 2002 A 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 sev- eral mechanisms, which would either en- hance 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 individ- ual, 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 ad- vantage of being able to mimic the periph- eral insulin response to a meal more closely than soluble HI, even when ad- ministered immediately before the meal (3–5). This has been made possible by substitution of aspartic acid for proline in position B28, thereby reducing the ten- dency to form hexamers (6). Absorption from the subcutaneous tissue is promoted and is no longer limited by dissolution of the hexamers (6,7). Clinical experimental studies have shown lower postprandial glucose with IAsp injected just before a meal than with HI injected 30 min before a meal (5,8). In longer-term studies, IAsp provided glucose control, assessed by HbA 1c , that was at least as good or better than that obtained with HI (9 –11). IAsp is also in clinical testing in a mixed rapid- and intermediate-acting formulation, bi- phasic IAsp (BIAsp) (12). Any substance not normally found in the human body may serve as an antigen. This includes insulin analogs. For IAsp, there are three types of antibodies of in- terest, namely antibodies specific to HI (versus IAsp), antibodies specific to IAsp (versus HI), and antibodies cross-reactive to both IAsp and HI. A method was de- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From 1 Novo Nordisk, Bagsvaerd, Denmark; the 2 University of Newcastle Upon Tyne, Newcastle Upon Tyne, U.K.; the 3 University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; and the 4 Division of Endocrinology and Diabetes, Ulm University, Ulm, Germany. Address correspondence and reprint requests to Anders Lindholm, Project Management, Novo Nordisk Ltd., Broadfield Park, Crawley, U.K. E-mail: andl@novonordisk.com. P.D.H., P.R., and B.O.B. provide consultation to and hold research grants from all the major insulin manufacturers, including Novo Nordisk. They served as consultants or speakers for the following compa- nies: Asta Medica, Aventis, Bayer, Bristol Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Sanwa, SmithKlein Beecham, Takeda America, and Therasense. They received grant/research support from the American Dia- betes Association, Asta Medica, Bayer, Bristol Myers Squibb, Eli Lilly, Glaxo Wellcome, Merck, Novartis, Novo Nordisk, Pfizer, and SmithKlein Beecham. Received for publication 25 August 2001 and accepted in revised form 25 January 2002. Abbreviations: BIAsp, biphasic insulin aspart; BHI, biphasic human insulin; B/T, bound/total; C max , maximum glucose concentration; HI, human insulin; IAsp, insulin aspart; PEG, polyethylene glycol; t max , time of maximum concentration. A table elsewhere in this issue shows conventional and Syste `me International (SI) units and conversion factors for many substances. Pathophysiology/Complications O R I G I N A L A R T I C L E 876 DIABETES CARE, VOLUME 25, NUMBER 5, MAY 2002 Downloaded from http://diabetesjournals.org/care/article-pdf/25/5/876/663796/dc0502000876.pdf by guest on 10 June 2022