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

Abstract

<p> </p> <p><strong>Objective</strong></p> <p>Previous studies showed that inhibiting lymphocyte costimulation reduces declining beta 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 (NGT) to abnormal (AGT) glucose tolerance or to diabetes and the effects of treatment on immune and metabolic responses. </p> <p><strong>Research Design and Methods</strong></p> <p>We conducted a phase-2, randomized, placebo-controlled, double-masked trial of abatacept</p> <p>in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The endpoint was AGT or diabetes, assessed by oral glucose-tolerance tests. </p> <p><strong>Results</strong></p> <p>101 participants received abatacept and 111 placebo. Eighty-one (35 abatacept/46 placebo) met the endpoint of AGT or type 1 diabetes diagnosis (HR=0.702 (0.452, 1.09)(p=0.11) The C-peptide responses to OGTTs were higher in the abatacept arm (p<.03) . Abatacept reduced the frequency of ICOS+PD1+ T-follicular helper (Tfh) cells during treatment (p<0.0001), increased naïve CD4+ T cells, and also reduced the frequency of CD4+ Tregs from the baseline (p=0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naïve CD4+ T, and Treg cells returned to baseline. </p> <p><strong>Conclusions</strong></p> <p>Although abatacept treatment for one 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.</p>

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