Insulin degludec does not increase antibody formation versus insulin glargine: an evaluation of phase IIIa trials

J Vora, J Seufert, H Solberg, O Kinduryte, T Johansen, P Hollander, J Vora, J Seufert, H Solberg, O Kinduryte, T Johansen, P Hollander

Abstract

We examined insulin antibody formation in patients with type 1 (T1D) or type 2 diabetes (T2D) treated with once-daily insulin degludec (IDeg) or insulin glargine (IGlar) to evaluate the impact of antibody formation on efficacy and safety. Insulin antibodies were measured using subtraction radioimmunoassays in six phase IIIa clinical trials using IDeg (n = 2250) and IGlar (n = 1184). Spearman's correlation coefficient was used to evaluate associations between cross-reacting antibodies and change from baseline glycated haemoglobin (HbA1c) and insulin dose. IDeg- and IGlar-specific antibodies remained low [<1% bound/total radioactivity (B/T)] and with low levels of antibodies cross-reacting with human insulin in patients with T1D (<20% B/T) and T2D (<6% B/T). Spearman's correlation coefficients between insulin antibody levels and change in HbA1c or insulin dose were low in both treatment groups. No clinically meaningful differences in adverse event (AE) rates were observed in patients with >10% B/T or without an absolute increase in antibodies cross-reacting with human insulin. IDeg treatment resulted in few immunogenic responses in patients with T1D and T2D; antibody formation was not associated with change in HbA1c, insulin dose or rates of AEs.

Keywords: insulin antibodies; insulin degludec; long-acting insulin; type 1 diabetes; type 2 diabetes.

© 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Cross‐reacting antibody levels to human insulin (HI) over time in patients with (A) type 1 diabetes (BEGIN Basal‐Bolus Type 1 Long [3583] 10) and (B) type 2 diabetes (BEGIN Once Long [3579] 12). Antibody levels were measured at week 0 (baseline), week 12, week 26, week 40, week 52 (end of trial, EOT) and week 53 (end of follow‐up, EOF) after a 1‐week washout period. Patients were treated with NPH insulin during the washout period to minimize interference of trial drugs with the antibody assay. Dark blue circles = insulin degludec (IDeg)‐treated patients; light blue diamonds = insulin glargine (IGlar)‐treated patients. Data are presented as mean ± standard error of the mean.

References

    1. Schernthaner G. Immunogenicity and allergenic potential of animal and human insulins. Diabetes Care 1993; 16(Suppl. 3): 155–165.
    1. Fineberg SE, Kawabata TT, Finco‐Kent D, Fountaine RJ, Finch GL, Krasner AS. Immunological responses to exogenous insulin. Endocr Rev 2007; 28: 625–652.
    1. Radermecker RP, Renard E, Scheen AJ. Circulating insulin antibodies: influence of continuous subcutaneous or intraperitoneal insulin infusion, and impact on glucose control. Diabetes Metab Res Rev 2009; 25: 491–501.
    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.
    1. Home PD, Rosskamp R, Forjanic‐Klapproth J, Dressler A. A randomized multicentre trial of insulin glargine compared with NPH insulin in people with type 1 diabetes. Diabetes Metab Res Rev 2005; 21: 545–553.
    1. Pieber TR, Eugene‐Jolchine I, Derobert E. Efficacy and safety of HOE 901 versus NPH insulin in patients with type 1 diabetes. The European Study Group of HOE 901 in type 1 diabetes. Diabetes Care 2000; 23: 157–162.
    1. Heise T, Nosek L, Bottcher SG, Hastrup H, Haahr H. Ultra‐long‐acting insulin degludec has a flat and stable glucose‐lowering effect in type 2 diabetes. Diabetes Obes Metab 2012; 14: 944–950.
    1. Jonassen I, Havelund S, Hoeg‐Jensen T, Steensgaard DB, Wahlund PO, Ribel U. Design of the novel protraction mechanism of insulin degludec, an ultra‐long‐acting basal insulin. Pharm Res 2012; 29: 2104–2114.
    1. Kurtzhals P, Heise T, Strauss HM et al. Multi‐hexamer formation is the underlying basis for the ultra‐long glucose‐lowering effect of insulin degludec. (Abstract). Diabetologia 2011; 54(Suppl. 1): S426.
    1. Heller S, Buse J, Fisher M et al. Insulin degludec, an ultra‐long acting basal insulin, versus insulin glargine in basal‐bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal‐Bolus Type 1): a phase 3, randomised, open‐label, treat‐to‐target non‐inferiority trial. Lancet 2012; 379: 1489–1497.
    1. Mathieu C, Hollander P, Miranda‐Palma B et al. Efficacy and safety of insulin degludec in a flexible dosing regimen vs insulin glargine in patients with type 1 diabetes (BEGIN: Flex T1): a 26‐week randomized, treat‐to‐target trial with a 26‐week extension. J Clin Endocrinol Metab 2013; 98: 1154–1162.
    1. Zinman B, Philis‐Tsimikas A, Cariou B et al. Insulin degludec versus insulin glargine in insulin‐naive patients with type 2 diabetes: a 1‐year, randomized, treat‐to‐target trial (BEGIN Once Long). Diabetes Care 2012; 35: 2464–2471.
    1. Onishi Y, Iwamoto Y, Yoo SJ, Clauson P, Tamer SC, Park S. Insulin degludec compared with insulin glargine in insulin‐naive patients with type 2 diabetes: a 26‐week, randomized, controlled, Pan‐Asian, treat‐to‐target trial. J Diabetes Invest 2013; 4: 605–612.
    1. Gough SC, Bhargava A, Jain R, Mersebach H, Rasmussen S, Bergenstal RM. Low‐volume insulin degludec 200 units/mL once daily improves glycemic control similarly to insulin glargine with a low risk of hypoglycemia in insulin‐naive patients with type 2 diabetes: a 26‐week, randomized, controlled, multinational, treat‐to‐target trial: the begin low volume trial. Diabetes Care 2013; 36: 2536–2542.
    1. Meneghini L, Atkin SL, Gough SC et al. The efficacy and safety of insulin degludec given in variable once‐daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26‐week, randomized, open‐label, parallel‐group, treat‐to‐target trial in individuals with type 2 diabetes. Diabetes Care 2013; 36: 858–864.
    1. Gough SC, Harris S, Woo V, Davies M. Insulin degludec: overview of a novel ultra long‐acting basal insulin. Diabetes Obes Metab 2013; 15: 301–309.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi