Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial.
washington; spokane; pmrc; Humans; Abatacept; Diabetes Mellitus, Type 1; Immunosuppressive Agents; T-Lymphocytes, Regulatory; Glucose
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.
Kidney & Diabetes
Russell, William E; Bundy, Brian N; Anderson, Mark S; Cooney, Laura A; Gitelman, Stephen E; Goland, Robin S; Gottlieb, Peter A; Greenbaum, Carla J; Haller, Michael J; Krischer, Jeffrey P; Libman, Ingrid M; Linsley, Peter S; Long, S Alice; Lord, Sandra M; Moore, Daniel J; Moore, Wayne V; Moran, Antoinette M; Muir, Andrew B; Raskin, Philip; Skyler, Jay S; Wentworth, John M; Wherrett, Diane K; Wilson, Darrell M; Ziegler, Anette-Gabriele; and Herold, Kevan C, "Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial." (2023). Articles, Abstracts, and Reports. 7295.