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

• DOI: 10.2337/dc22-2200
• Publication Date: 2023-03-15T13:04:52Z
• Authors: William E. Russell; Brian N. Bundy; Mark S. Anderson; Laura A. Cooney; Stephen E. Gitelman; Robin S. Goland; Peter A. Gottlieb; Carla J. Greenbaum; Michael J. Haller; Jeffrey P. Krischer; Ingrid M. Libman; Peter S. Linsley; S. Alice Long; Sandra M. Lord; Daniel J. Moore; Wayne V. Moore; Antoinette M. Moran; Andrew B. Muir; Philip Raskin; Jay S. Skyler; John M. Wentworth; Diane K. Wherrett; Darrell M. Wilson; Anette-Gabriele Z...; Kevan C. Herold
• Keywords: Biomedical and clinical sciences; T-Lymphocytes; Clinical Sciences; Immunology; Clinical Trials and Supportive Activities; 610; Medical and Health Sciences; T-Lymphocytes, Regulatory; Abatacept; Endocrinology & Metabolism; Clinical Research; Diabetes Mellitus; Humans; Metabolic and endocrine; Nutrition; Biomedical and Clinical Sciences; Prevention; Diabetes; Type 1 Diabetes TrialNet Study Group; Health sciences; Regulatory; 3. Good health; Diabetes Mellitus, Type 1; Glucose; 6.1 Pharmaceuticals; Original Article; Immunosuppressive Agents; Type 1

OBJECTIVEPrevious 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 METHODSWe 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.RESULTSA 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.CONCLUSIONSAlthough 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.