The immunopathogenesis of type 1 diabetes mellitus (T1DM) is associated with T-lymphocyte autoimmunity. To be fully active, immune T-lymphocytes require a co-stimulatory signal in addition to the main antigen driven signal. Abatacept modulates co-stimulation andprevents full T-lymphocyte activation. We evaluated the effect of abatacept in recent-onset T1DM.
In this multicentre, double-masked, randomised controlled trial, 112 subjects (ages 6–36) recently diagnosed with T1DM; 77 received abatacept (10 mg/kg, maximum 1000 mg/dose) and 35 received placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over two years. Primary outcome was baseline-adjusted geometric mean 2-hour area under the curve (AUC) serum C-peptide following a mixed meal tolerance test at two years. Secondary outcomes include difference between groups in incidence of loss of peak C-peptide to < 0·2 pmol/ml, slope of C-peptide over time, changes in HbA1c and insulin dose, and safety. This trial is registered in ClinicalTrials.gov (NCT00505375).
Adjusted C-peptide AUC was 59% (95% CI: 6·1%, 112%) higher at two years with abatacept (0·378 pmol/ml) versus placebo (0·238 pmol/ml) (p=0·0029). The difference between groups was present throughout the trial, with an estimated 9·6 months’ delay in decline with abatacept. There was lower HbA1c (p<0·002) but similar insulin use. There were few, clinically not significant infusion related adverse events and minimal overall adverse events. There was no increase in infections or neutropenia.
Co-stimulation modulation with abatacept slowed decline of beta cell function over two years. The beneficial effect suggests that T-lymphocyte activation still occurs around the time of clinical diagnosis of T1DM. Yet, despite continued administration of abatacept over 24 months, the decline in beta cell function with abatacept was parallel to that with placebo after six months of treatment, causing us to speculate that T-lymphocyte activation may lessen with time. Further observation will determine whether the beneficial effect continues after cessation of abatacept infusions.
National Institutes of Health.