Baseline insulin secretion determines the response to abatacept in Stage 1 type 1 diabetes
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posted on 2025-11-14, 19:59 authored by Alfonso Galderisi, Alice L J Carr, Peter Taylor, Jacopo Bonet, David Cuthbertson, Jay Sosenko, Emily K Sims, Carmella Evans-Molina, Chiara Dalla Man, Heba M Ismail, Brandon Nathan, Alessandra Petrelli, Peter Senior, Jennifer L Sherr, Kevan Herold, William E Russell, Antoinette Moran, Colin Dayan<p dir="ltr">Abatacept, a CTLA-4 immunoglobulin that inhibits T cell costimulation, was evaluated for 12 months in Stage 1 type 1 diabetes to delay disease progression. Despite modest preservation of AUC C-peptide at 12 months, the primary endpoint was not met. Herein, we adopt the oral minimal model (OMM) to assess beta cell function over 48 months and explore how baseline insulin secretion (Phitot) modifies treatment response. Phitot was computed using the OMM from the oral glucose tolerance test at baseline and every 6 months. Participants were stratified into high- or low-secretors depending on baseline Phitot 33rd or <33rd centile, respectively. A sensitivity analysis was performed to validate threshold choice. Among 203 participants (96 abatacept and 107 placebo), 39% on abatacept and 47% on placebo progressed to Stage 2 or 3 within 96 months. High-secretors on abatacept gained 15.8 progression-free months ([95%CI 4.85, 26.68] p=0.005) and had 54% lower hazard of progression vs placebo (HR 0.46 [95%CI 0.25, 0.84] p=0.012). Treatment effect differed significantly by secretor status (interaction HR 2.92[95%CI 1.23, 6.96] p=0.015). Phitot identifies a responder subgroup to 12-months of abatacept, with delayed disease progression, providing the first evidence that an immune intervention in Stage 1 may delay disease progression.</p>
Funding
AG is supported by Breakthrough T1D (3-SRA-2022-1186-S-B and 3-SRA-2023-1422-S-B). ALJC is supported by the Charles A Allard Chair in Diabetes Research, the Blanch Family, the Alberta Diabetes Institute and the Chan Family. PT is supported by Breakthrough T1D 3-SRA-2023-1422-S-B. EKS is supported by funding from R01DK121929, R01DK133881 and a Ralph W. and Grace M. Showalter trust and Grant 2021258 from the Doris Duke Charitable Foundation through the COVID-19 Fund to Retain Clinical Scientists collaborative grant program, made possible through the support of Grant 62288 from the John Templeton Foundation. CEM is supported by the National Institute of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health under Award Number R01-DK-093954, UC4-DK-127786, R21-DK119800, R01DK127308-01, and P30DK097512 (to C.E.M.); VA Merit Award I01BX001733 HMI is supported by the National Institute of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health under Award Number K23DK129799. AP is supported by Breakthrough T1D Transition Award (1-FAC-2025-1632- A-N). PS is supported by the Charles A Allard Chair in Diabetes Research and the Academic Medicine and Health Services Program KCH received support from NIH grants DK057846, and AI66387, and DK106993 (Type 1 diabetes TrialNet). WER received support for this project from NIH DK106993 (Type 1 Diabetes TrialNet) and from the JP Fletcher Foundation. AM received support for this project from NIH DK106993 (Type 1 Diabetes TrialNet). CD is supported by Breakthrough T1D (3-SRA-2023-1422-S-B). Funding Acknowledgement. The Type 1 Diabetes TrialNet Study Group is a clinical trials network currently funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (
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- 1. DOI - Is supplement to Baseline Insulin Secretion Determines Response to Abatacept in Stage 1 Type 1 Diabetes
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