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Cited by 615Diabetes and associated disordersT-cell and B-cell ImmunologyDiabetes Management and Research

Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial

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Orban, Tihamer, Bundy, Brian, Becker, Dorothy J, DiMeglio, Linda A, Gitelman, Stephen E, Goland, Robin, Gottlieb, Peter A, Greenbaum, Carla J +11 more·2011·The Lancet
DOI 10.1016/s0140-6736(11)60886-6PMC PMC3462593
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Abstract

Background The immunopathogenesis of type 1 diabetes mellitus is associated with T-cell autoimmunity. To be fully active, immune T cells need a co-stimulatory signal in addition to the main antigen-driven signal. Abatacept modulates co-stimulation and prevents full T-cell activation. We evaluated the effect of abatacept in recent-onset type 1 diabetes. Methods In this multicentre, double-blind, randomised controlled trial, patients aged 6-45 years recently diagnosed with type 1 diabetes were randomly assigned (2:1) to receive abatacept (10 mg/kg, maximum 1000 mg per dose) or placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over 2 years. Computer-generated permuted block randomisation was used, with a block size of 3 and stratified by participating site. Neither patients nor research personnel were aware of treatment assignments. The primary outcome was baseline-adjusted geometric mean 2-h area-under-the-curve (AUC) serum C-peptide concentration after a mixed-meal tolerance test at 2 years' follow-up. Analysis was by intention to treat for all patients for whom data were available. This trial is registered at ClinicalTrials.gov, NCT00505375. Findings 112 patients were assigned to treatment groups (77 abatacept, 35 placebo). Adjusted C-peptide AUC was 59% (95% CI 6·1-112) higher at 2 years with abatacept (n=73, 0·378 nmol/L) than with placebo (n=30, 0·238 nmol/L; p=0·0029). The difference between groups was present throughout the trial, with an estimated 9·6 months' delay (95% CI 3·47-15·6) in C-peptide reduction with abatacept. There were few infusion-related adverse events (36 reactions occurred in 17 [22%] patients on abatacept and 11 reactions in six [17%] on placebo). There was no increase in infections (32 [42%] patients on abatacept vs 15 [43%] on placebo) or neutropenia (seven [9%] vs five [14%]). Interpretation Co-stimulation modulation with abatacept slowed reduction in β-cell function over 2 years. The beneficial effect suggests that T-cell activation still occurs around the time of clinical diagnosis of type 1 diabetes. Yet, despite continued administration of abatacept over 24 months, the decrease in β-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing us to speculate that T-cell activation lessens with time. Further observation will establish whether the beneficial effect continues after cessation of abatacept infusions. Funding US National Institutes of Health.

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  • The fusion protein CTLA4-Ig (abatacept) preserved stimulated C-peptide concentration for only 9 months despite continuous intravenous administration for 2 years.

    “For example, the fusion protein CTLA4-Ig (abatacept) preserved stimulated C-peptide concentration for only 9 months despite continuous intravenous administration for 2 years.138”

    From Type 1 diabetes (2014) · cites this paper as [138]

    The Results report an estimated 9.6-month delay in C-peptide decline, not preservation lasting only nine months. The Discussion says the difference from placebo was maintained throughout the two years of abatacept administration, despite a subsequent parallel decline in both groups. The supplied passages do not give page numbers. (LLM, conf=0.90)

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  • After promising phase 1-2 trials in patients with recent-onset type 1 diabetes and detectable endogenous insulin production, phase 3 trials of anti-CD3 antibodies (otelixizumab and teplizumab), and the Diamyd vaccine (GAD-alum immunotherapy) did not meet primary endpoints.

    “Disappointingly, after promising phase 1–2 trials in patients with recent-onset type 1 diabetes and detectable endogenous insulin production, phase 3 trials of anti-CD3 antibodies (otelixizumab and teplizumab), and the Diamyd vaccine (GAD-alum immunotherapy) did not meet primary endpoints.135–141”

    From Type 1 diabetes (2014) · cites this paper as [138]

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  • Abatacept has been shown to preserve C-peptide when administered soon after the onset of clinical type 1 diabetes.

    “Abatacept has also been shown to preserve Cpeptide when administered soon after the onset of clinical type 1 diabetes, 19”

    From The future of type 1 diabetes therapy (2025) · cites this paper as [19]

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Authors
Orban, T., Bundy, B., Becker, D. J., DiMeglio, L. A., Gitelman, S. E., Goland, R., Gottlieb, P. A., Greenbaum, C. J., Marks, J. B., Monzavi, R., Moran, A., Raskin, P., Rodriguez, H., Russell, W. E., Schatz, D., Wherrett, D., Wilson, D. M., Krischer, J. P., & Skyler, J. S.
Affiliations
  • Joslin Diabetes Center (US)
  • University of South Florida (US)
  • University of Pittsburgh (US)
  • Indiana University School of Medicine (US)
  • University of California, San Francisco (US)
  • Columbia University (US)
  • Benaroya Research Institute (US)
  • University of Miami (US)
  • Children's Hospital Los Angeles (US)
  • University of Minnesota (US)
  • The University of Texas Southwestern Medical Center (US)
  • Vanderbilt University (US)
  • University of Florida (US)
  • University of Toronto (CA)
  • Stanford University (US)
Corresponding author
Skyler, Jay S
ORCID
Venue
The Lancet
Publisher
Elsevier BV
Published
2011-07
Volume
378
Issue
9789
Pages
412-419
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(11)60886-6
PMC
PMC3462593
OpenAlex
W2154694193
Cited by
612
References
31
Citations by year
2026: 26 · 2025: 40 · 2024: 52 · 2023: 30 · 2022: 33 · 2021: 34 · 2020: 43 · 2019: 32 · 2018: 41 · 2017: 31 · 2016: 43 · 2015: 45 · 2014: 46 · 2013: 57 · 2012: 45
FWCI
31.92
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • The Lancet (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
Funders
  • Sanofi
  • University of Florida
  • University of Washington
  • MacroGenics
  • Novo Nordisk
  • National Institutes of Health (5ul1rr031986-02)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U01-DK-084565, U01DK061040, U01DK085461, U01DK085505, U01DK085499, U01DK061055, U01DK061036, U01DK061010, U01DK061058, U01DK061034, U01DK085504, U01DK061042, U01DK085463, U01DK085453, UC4DK117009, U01DK061041, U01DK085466, U01DK085509, U01 DK-061016)
  • U.S. National Library of Medicine (HHSN267200800019C)
  • National Center for Research Resources (UL1RR029890, UL1RR024131, M01RR000400, UL1-RR031986, UL1RR025744, UL1RR024153, UL1RR024982, UL1RR025761, M01-RR00400, UL1RR024975, UL1RR024139, UL1RR025780)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords
abatacept, type 1 diabetes, recent-onset type 1 diabetes, T cell costimulation, T cell-mediated autoimmunity, C-peptide, beta-cell function, immunomodulation, mixed meal tolerance test, infusion-related adverse events, infection, neutropenia, children and adolescents, disease progression, HLA-DR
MeSH terms
Abatacept, Adolescent, Adult, Child, Diabetes Mellitus, Type 1, Double-Blind Method, Female, Humans, Immunosuppressive Agents, Male, T-Lymphocytes, Autoimmunity, Randomized Controlled Trials as Topic, Immunoconjugates, Insulin-Secreting Cells, Young Adult

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