Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment

Abstract

OBJECTIVE We previously reported that 2 years of costimulation modulation with abatacept slowed decline of β-cell function in recent-onset type 1 diabetes (T1D). Subsequently, abatacept was discontinued and subjects were followed to determine whether there was persistence of effect. RESEARCH DESIGN AND METHODS Of 112 subjects (ages 6-36 years) with T1D, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over 2 years. The primary outcome-baseline-adjusted geometric mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 2 years-showed higher C-peptide with abatacept versus placebo. Subjects were followed an additional year, off treatment, with MMTTs performed at 30 and 36 months. RESULTS C-peptide AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.217 nmol/L (95% CI 0.168-0.268) and 0.141 nmol/L (95% CI 0.071-0.215) for abatacept and placebo groups, respectively (P = 0.046). The C-peptide decline from baseline remained parallel with an estimated 9.5 months' delay with abatacept. Moreover, HbA1c levels remained lower in the abatacept group than in the placebo group. The slightly lower (nonsignificant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years. CONCLUSIONS Costimulation modulation with abatacept slowed decline of β-cell function and improved HbA1c in recent-onset T1D. The beneficial effect was sustained for at least 1 year after cessation of abatacept infusions or 3 years from T1D diagnosis.

Figure 1

Enrollment, randomization, and follow-up of study participants.

Figure 2

A: Population mean of stimulated C-peptide 2-h AUC mean over time for each treatment group. The estimates are from the ANCOVA model adjusting for age, sex, baseline value of C-peptide, and treatment assignment. y-Axis is on a log(y + 1) scale. The significance level at 36 months is 0.046. Error bars show 95% CI. B: Predicted population mean of stimulated C-peptide 2-h AUC mean over time for each treatment group. Estimates are from the analysis of mixed-effects model adjusting for age, sex, baseline value of C-peptide, and treatment assignment and including a fixed effect for time as a linear line on the log(y + 1) scale. The significance level of the difference between the two parallel lines is 0.0011. C: The proportion of participants with 2-h peak C-peptide remaining ≥0.2 nmol/L over time for each treatment group.

Figure 3

The population mean of HbA_1c (significance levels are <0.005 for all 6-month interval group differences) (A) and insulin use over time (B) for each treatment group (only statistical significance for less use in the abatacept group was at 6 and 12 months). The estimates are from the ANCOVA model adjusting for age, sex, baseline value of HbA_1c, and treatment assignment. Insulin use is per kilogram of body weight at 3-month intervals. Error bars show 95% CIs.

Figure 4

The ratio (abatacept to placebo) of treatment effect on 3-year stimulated C-peptide (C-Pep.) AUC mean within categories of prespecified baseline factors. The estimates are from the ANCOVA modeling log of C-peptide adjusting for age, sex, baseline value of C-peptide, the indicated categorized factor, treatment assignment, and treatment interaction terms. Error bars show 95% CI.