Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial

Abstract

Objective: Previous studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses.

Research design and methods: We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests.

Results: A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline.

Conclusions: Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.

Graphical abstract

Figure 1

Consolidated Standards of Reporting Trials diagram. T1D, type 1 diabetes. *Consecutive confirmed abnormal OGTT.

Figure 2

Effects of abatacept on study outcomes. A: Effect of abatacept on the development of the primary end point of AGT/diabetes (HR 0.702; 95% CI 0.452, 1.09; P = 0.11). B: Effect of abatacept on the progression from AGT to type 1 diabetes (T1D) (HR 0.710; 95% CI 0.377, 1.34). C: C-peptide levels were higher in the abatacept-treated group at month 12 (P = 0.03). Rx, prescription.

Figure 3

Immune cell subsets in the treatment groups and effects of abatacept on T-cell phenotypes and proliferation. The frequency of ICOS⁺ of the total Tfh cells (A), ICOS⁺ Tfh cells in children (3, 6, 12, and 24 months: P = 0.0005, P = 0.003, P = 0.05, and P = 0.15, respectively) (B), and in adults (3, 6, 12, and 24 months: P < 0.0001, P < 0.0001, P = 0.008, and P = 0.93, respectively) (C). The baseline levels of ICOS⁺ Tfh cells was higher at the baseline in children (P < 0.0001), but there were similar effects of abatacept treatment in children and adults. D: Tph of CD4⁺ memory cells were reduced with abatacept treatment vs. control (3, 6, 12, and 24 months: P < 0.0001, P < 0.0001, P < 0.0001, and P = 0.67, respectively). Tconv, conventional T cell. E: CD4⁺ Tregs were also reduced (3, 6, 12, and 24 months: P < 0.0001, P < 0.0001, P < 0.0001, and P = 0.13, respectively). Gating strategy is shown in Supplementary Fig. 1. Naive CD4⁺ (3, 6, 12, and 24 months: P = 0.002, P = 0.25, P = 0.008, and P = 0.02, respectively) (F) and CD8⁺ T cells (3, 6,12, and 24 months: P < 0.0001, P < 0.0001, P < 0.0001, and P = 0.15, respectively) (G) in participants treated with abatacept or placebo. H: The percentage of Ki67⁺CD4⁺ T cells was reduced in participants treated with abatacept vs. placebo (3, 6, 12, and 24 months: P < 0.0001, P < 0.0001, P < 0.0001, and P = 0.95, respectively).