Effect of Long-Term Exposure to Insulin Lispro on the Induction of Antibody Response in Patients With Type 1 or Type 2 Diabetes

Effect of Long-Term Exposure to Insulin Lispro on the Induction of Antibody Response in Patients With Type 1 or Type 2 Diabetes S. Edwin Fineberg , MD 1 , Jie Huang , PHD 2 , Rocco Brunelle , MS 2 , K. S. Gulliya , PHD 2 and James H. Anderson, Jr , MD 1 2 1 Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 2 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana Abstract OBJECTIVE —To determine the long-term effects of insulin lispro on inducing lispro-specific, insulin-specific, and cross-reactive (reactive with both insulin lispro and human insulin) antibodies. RESEARCH DESIGN AND METHODS —A multinational, multicenter combination of controlled and noncontrolled, open-label studies of 4.5 years’ duration was designed to evaluate the long-term immunologic profile of subcutaneously administered insulin lispro. A total of 1,221 patients (men and women; 12–81 years of age) with type 1 or type 2 diabetes were enrolled. Circulating anti-insulin antibodies were measured using radioimmunoassays. RESULTS —Insulin-specific and lispro-specific antibody responses were within the background noise levels of the assays. Significant elevations of antibody were confined to a cross-reactive antibody response. Antibody levels resulting from prior exposure to long- and short-acting insulins changed little after transfer to insulin lispro and remained within or near the baseline levels. De novo exposure to insulin lispro resulted in increases in cross-reactive but not insulin- or lispro-specific antibody levels. Cross-reactive insulin antibodies developed more readily in patients with type 1 diabetes than in those with type 2 diabetes. Long-term antibody responses tended to decrease over time and returned to baseline or near-baseline levels by the end of the long-term studies. No evidence of an anamnestic antibody response could be found in individuals treated intermittently with insulin lispro. CONCLUSIONS —The immunogenic profile of patients treated with insulin lispro was comparable to that of patients treated with recombinant human insulin. Inductions of significant levels of specific or cross-reactive antibodies were not observed in patients who had received insulin previously. No significant antibody-dependent increases in insulin dosage requirements were noted in these patients. The incidence of insulin allergy was not different from that in patients treated with recombinant regular human insulin. ISA, insulin-speci