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

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. SkylerJohn M. Wentworth, Diane K. Wherrett, Darrell M. Wilson, Anette Gabriele Ziegler, Kevan C. Herold

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

OBJECTIVE Previous studies showed that inhibiting lymphocyte costimulation reduces declining b-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from nor-mal 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.

Original languageEnglish (US)
Pages (from-to)1005-1013
Number of pages9
JournalDiabetes care
Volume46
Issue number5
DOIs
StatePublished - May 2023

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialized Nursing

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