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

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posted on 2023-03-15, 00:10 authored by 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, Phillip Raskin, Jay S. Skyler, John M Wentworth, Diane K. Wherrett, Darrell M. Wilson, Anette-Gabriele Ziegler, Kevan C. Herold, the Type 1 diabetes TrialNet Study Group

  

Objective

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. 

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 endpoint was AGT or diabetes, assessed by oral glucose-tolerance tests. 

Results

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. 

Conclusions

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.

Funding

Juvenile Diabetes Research Foundation International 1-SRA-2020-900-M-X 2-SRA-2018-609-Q-R 2-SRA-2020-900-S-B 3-SRA-2015-27-Q-R 82-2013-652

U.S. Department of Health and Human Services > National Institutes of Health > National Center for Research Resources M01 RR00400 UL1 RR024131 UL1 RR024139 UL1 RR024153 UL1 RR024975 UL1 RR024982 UL1 RR025744 UL1 RR025761 UL1 RR025780 UL1 RR029890 UL1 RR031986 UL1 TR001872

U.S. Department of Health and Human Services > National Institutes of Health > National Institute of Allergy and Infectious Diseases UM1AI109565

U.S. Department of Health and Human Services > National Institutes of Health > National Institute of Diabetes and Digestive and Kidney Diseases U01 DK060782 U01 DK060916 U01 DK060987 U01 DK061010 U01 DK061016 U01 DK061029 U01 DK061030 U01 DK061034 U01 DK061035 U01 DK061036 U01 DK061037 U01 DK061040 U01 DK061041 U01 DK061042 U01 DK061055 U01 DK061058 U01 DK084565 U01 DK085453 U01 DK085461 U01 DK085463 U01 DK085465 U01 DK085476 U01 DK085499 U01 DK085504 U01 DK085505 U01 DK085509 U01 DK097835 U01 DK103153 U01 DK103180 U01 DK103266 U01 DK103282 U01 DK106984 U01 DK106994 U01 DK107013 U01 DK107014 UC4 DK085466 UC4 DK106993

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