Development of Insulin Detemir/Insulin Aspart Cross-Reacting Antibodies Following Treatment with Insulin Detemir: 104-week Study in Children and Adolescents with Type 1 Diabetes Aged 2-16 Years

Nandu Thalange, Abdullah Bereket, Lisbeth Bjerring Jensen, Line Conradsen Hiort, Valentina Peterkova, Nandu Thalange, Abdullah Bereket, Lisbeth Bjerring Jensen, Line Conradsen Hiort, Valentina Peterkova

Abstract

Background: To study the long-term development (104 weeks) of insulin antibodies during treatment with insulin detemir (IDet) and insulin aspart (IAsp) in children with type 1 diabetes aged 2-16 years.

Methods: A 52-week, two-arm, randomized trial comparing IDet and neutral protamine Hagedorn insulin, both in combination with IAsp, was followed by a one-arm, 52-week extension trial of the IDet + IAsp arm. The present analysis was conducted in children who completed the randomized trial and entered into the extension trial.

Results: Of the 177 children randomized to IDet treatment, 146 entered the extension trial. IDet-IAsp cross-reacting antibodies peaked within the first 39 weeks of treatment before gradually declining. A similar pattern was seen for IDet-specific and IAsp-specific antibodies. At end of trial (EOT), no correlation was observed between the level of IDet-specific or IAsp-specific antibodies or IDet-IAsp cross-reacting antibodies and either glycated hemoglobin (HbA1c) or basal insulin dose. Mean HbA1c was stable during the treatment period, with a slight increase over time from 8.41% (68.4 mmol/mol) at baseline to 8.74% (72 mmol/mol) at EOT. Mean IDet dose increased from 0.43 U/kg at baseline to 0.66 U/kg at EOT. Mean IAsp dose increased from 0.46 U/kg to 0.51 U/kg at EOT.

Conclusion: Although treatment with IDet and IAsp is associated with development of specific and cross-reacting antibodies, no correlation between insulin antibodies and basal insulin dose or HbA1c was found.

Funding: Novo Nordisk A/S. ClinicalTrials.gov identifiers: NCT00435019 and NCT00623194.

Keywords: Children; Clinical trial; Glycemic control; Immunity; Insulin aspart; Insulin detemir; Insulin therapy; Type 1 diabetes.

Figures

Fig. 1
Fig. 1
Observed mean antibodies (%B/T) over the total treatment period for children participating in the extension trial: a IDet–IAsp cross-reacting antibodies by age; b IDet-specific antibodies by age; c IAsp-specific antibodies by age. %B/T percent bound radioactivity relative to the total amount of radioactivity present, IAsp insulin aspart, IDet insulin detemir
Fig. 2
Fig. 2
Cross-reacting antibodies at EOT for children participating in the extension trial: a by HbA1c; b by daily basal insulin dose per kg. %B/T percent bound radioactivity relative to the total amount of radioactivity present, EOT end of trial, HbA1c glycated hemoglobin
Fig. 3
Fig. 3
Observed mean daily insulin dose (LOCF) (U/kg) over the total treatment period for children participating in the extension trial: a basal insulin dose; b bolus insulin dose. LOCF last observation carried forward
Fig. 4
Fig. 4
Observed mean a HbA1c and b FPG over the total treatment period for children participating in the extension trial. FPG fasting plasma glucose, HbA1c glycated hemoglobin

References

    1. Schernthaner G. Immunogenicity and allergenic potential of animal and human insulins. Diabetes Care. 1993;16(Suppl. 3):155–165. doi: 10.2337/diacare.16.3.155.
    1. Kurtz AB, Nabarro JD. Circulating insulin-binding antibodies. Diabetologia. 1980;19:329–334. doi: 10.1007/BF00280515.
    1. Holmberg H, Mersebach H, Kanc K, Ludvigsson J. Antibody response to insulin in children and adolescents with newly diagnosed type 1 diabetes. Diabet Med. 2008;25:792–797. doi: 10.1111/j.1464-5491.2008.02468.x.
    1. Lindholm A, Jensen LB, Home PD, Raskin P, Boehm BO, Rastam J. Immune responses to insulin aspart and biphasic insulin aspart in people with type 1 and type 2 diabetes. Diabetes Care. 2002;25:876–882. doi: 10.2337/diacare.25.5.876.
    1. Radermecker RP, Scheen AJ. Allergy reactions to insulin: effects of continuous subcutaneous insulin infusion and insulin analogues. Diabetes Metab Res Rev. 2007;23:348–355. doi: 10.1002/dmrr.714.
    1. Radermecker RP, Pierard GE, Scheen AJ. Lipodystrophy reactions to insulin: effects of continuous insulin infusion and new insulin analogs. Am J Clin Dermatol. 2007;8:21–28. doi: 10.2165/00128071-200708010-00003.
    1. Davidson JK, DeBra DW. Immunologic insulin resistance. Diabetes. 1978;27:307–318. doi: 10.2337/diab.27.3.307.
    1. Hattori N, Duhita MR, Mukai A, Matsueda M, Shimatsu A. Development of insulin antibodies and changes in titers over a long-term period in patients with type 2 diabetes. Clin Chim Acta. 2014;433:135–138. doi: 10.1016/j.cca.2014.03.008.
    1. Havelund S, Plum A, Ribel U, et al. The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin. Pharm Res. 2004;21:1498–1504. doi: 10.1023/B:PHAM.0000036926.54824.37.
    1. Bartley PC, Bogoev M, Larsen J, Philotheou A. Long-term efficacy and safety of insulin detemir compared to neutral protamine Hagedorn insulin in patients with type 1 diabetes using a treat-to-target basal-bolus regimen with insulin aspart at meals: a 2-year, randomized, controlled trial. Diabet Med. 2008;25:442–449. doi: 10.1111/j.1464-5491.2007.02407.x.
    1. Brange J, Owens DR, Kang S, Volund A. Monomeric insulins and their experimental and clinical implications. Diabetes Care. 1990;13:923–954. doi: 10.2337/diacare.13.9.923.
    1. Thalange N, Bereket A, Larsen J, Hiort LC, Peterkova V. Treatment with insulin detemir or NPH insulin in children aged 2–5 year with type 1 diabetes mellitus. Pediatr Diabetes. 2011;12:632–641. doi: 10.1111/j.1399-5448.2010.00750.x.
    1. Thalange N, Bereket A, Larsen J, Hiort LC, Peterkova V. Insulin analogues in children with type 1 diabetes: a 52-week randomized clinical trial. Diabet Med. 2013;30:216–225. doi: 10.1111/dme.12041.
    1. International Conference on Harmonisation. ICH harmonised tripartite guideline. guideline for good clinical practice E6(R1). . Accessed Nov 2015.
    1. World Medical Association. WMA Declaration of Helsinki—Ethical principles for medical research involving human subjects. . Accessed Nov 2015.
    1. International Society for Pediatric and Adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 2009. . Accessed Nov 2015.
    1. Clarke W, Jones T, Rewers A, Dunger D, Klingensmith GJ. Assessment and management of hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes. 2008;9:165–174. doi: 10.1111/j.1399-5448.2008.00405.x.
    1. Cole TJ, Freeman JV, Preece MA. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Stat Med. 1998;17:407–429. doi: 10.1002/(SICI)1097-0258(19980228)17:4<407::AID-SIM742>;2-L.
    1. Russell-Jones D, Simpson R, Hylleberg B, Draeger E, Bolinder J. Effects of QD insulin detemir or neutral protamine Hagedorn on blood glucose control in patients with type 1 diabetes mellitus using a basal–bolus regimen. Clin Ther. 2004;26:724–736. doi: 10.1016/S0149-2918(04)90072-0.
    1. Standl E, Lang H, Roberts A. The 12-month efficacy and safety of insulin detemir and NPH insulin in basal–bolus therapy for the treatment of type 1 diabetes. Diabetes Technol Ther. 2004;6:579–588. doi: 10.1089/dia.2004.6.579.
    1. Fineberg SE, Kawabata TT, Finco-Kent D, et al. Immunological response to exogenous insulin. Endocr Rev. 2007;28:625–652. doi: 10.1210/er.2007-0002.
    1. Ilag LL, Deeg MA, Costigan T, et al. Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus® insulin glargine in patients with type 1 or type 2 diabetes mellitus. Diabetes Obes Metab. 2016;18:159–168. doi: 10.1111/dom.12584.
    1. Perantie DC, Lim A, Wu J, et al. Effects of prior hypoglycemia and hyperglycemia on cognition in children with type 1 diabetes mellitus. Pediatr Diabetes. 2008;9:87–95. doi: 10.1111/j.1399-5448.2007.00274.x.
    1. Wiegand S, Raile K, Reinehr T, et al. Daily insulin requirement of children and adolescents with type 1 diabetes: effect of age, gender, body mass index and mode of therapy. Eur J Endocrinol. 2008;158:543–549. doi: 10.1530/EJE-07-0904.
    1. Robertson KJ, Schoenle E, Gucev Z, Mordhorst L, Gall MA, Ludvigsson J. Insulin detemir compared with NPH insulin in children and adolescents with type 1 diabetes. Diabet Med. 2007;24:27–34. doi: 10.1111/j.1464-5491.2007.02024.x.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera