Interleukin-1 antagonism in new-onset type 1 diabetes
Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials.
Moran A, Bundy B, Becker DJ, et al; for the AIDA Study Group.
Lancet. 2013 Apr 4. doi:pii: S0140-6736(13)60023-9. 10.1016/S0140-6736(13)60023-9. [Epub]
BackgroundIn type 1 diabetes mellitus, interventions that stop or delay decline of β-cell function are desirable.[1,2] Recent research has focused on the role of the innate immune system in type 1 diabetes. Because of its direct β-cell proapoptotic action and mediatory effects on pancreatic β-cell glucotoxicity, interleukin-1β has been implicated in the pathogenesis of both type 1 and type 2 diabetes. In addition to its effects in the innate immune system, interleukin-1β might be important in the pathogenesis of type 1 diabetes via its role as a potent amplifier of the adaptive immune response. [3-5]
So far, there have been no randomised, placebo-controlled trials of interleukin-1 antagonism in patients with recent-onset type 1 diabetes. Therefore, it was hypothesised that interleukin-1β inhibition in new-onset type 1 diabetes would preserve β-cell function by blocking direct and hyperglycaemia-mediated β-cell toxicity, reducing overall inflammation and favouring regulatory T lymphocyte development and function. To assess this theory, in two trials it was tested whether canakinumab, a human mono clonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, maintained or enhanced β-cell function in recent-onset type 1 diabetes. These studies also assessed the feasibility and safety and tolerability of anti-interleukin-1 treatment.
Two randomised, placebo-controlled trials were performed in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0.2 nM.
Participants were randomly assigned to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial).
- The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0.01 nmol/L (95% CI –0.11 to 0.14; p=0.86)(fig. 1), and between the anakinra and the placebo groups at 9 months was 0.02 nmol/L (–0.09 to 0.15; p=0.71)(fig. 2).
- The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0.018), which was mainly because of a higher number of injection site reactions in the anakinra group.
Inhibition of interleukin-1β with either canakinumab or anakinra did not slow the reduction in β-cell function in new-onset type 1 diabetes. Interleukin-1β blockade might be more suitable for combination therapy protocols in new-onset type 1 diabetes or in prevention trials in individuals with pre-type 1 diabetes.
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- The Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial: a randomised, controlled trial. Ann Intern Med 1998; 128: 517–23.
- Steffes MW, Sibley S, Jackson M, Thomas W. Beta cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care 2003; 26: 832–36.
- Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012; 11: 633–52.
- Sanda S, Bollyky J, Standifer N, et al. Short-term IL-1beta blockade reduces monocyte CD11b integrin expression in an IL-8 dependent fashion in patients with type 1 diabetes. Clin Immunol 2010; 136: 170–73.
- Mandrup-Poulsen T, Pickersgill LMS, Donath MY. Blockade of interleukin 1 in type 1 diabetes mellitus. Nat Rev Endocrinol 2010; 6: 158–66.
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