1962-LB: Baseline Insulin Secretion Determines the Response to Abatacept In Stage 1 Type 1 Diabetes
Bibliographic record
Abstract
Introduction and Objective: The TrialNet Abatacept Prevention study of 12 months use of the CTLA-4 immunoglobulin to delay disease progression in Stage 1 type 1 diabetes (T1D) did not meet its primary endpoint. We adopted the oral minimal model (OMM) to quantify insulin secretion and assess if high vs low baseline secretion determined treatment response. Methods: Beta cell responsivity to glucose (Phitotal ) was computed from oral glucose tolerance test at baseline and every 6 months up to 48 months in placebo and abatacept arms. Baseline secretor groups were defined as high-secretors (Phitotal >33rd centile) and low-secretors (Phitotal ≤33rd centile). Risk regression analyses compared time to Stage 2 or 3 T1D between arms, by baseline secretor group. Age-adjusted ANCOVA compared Phitotal at pre-specified discretized visits. Results: In high-secretors, abatacept delayed progression by ~12 months (48 (IQR 26, 48) vs 35 (IQR 17, 48), p=0.009) with 51% lower hazard for progression among abatacept high secretors (HR 0.51, (95% CI 0.29, 0.89), p=0.018). High-secretors on abatacept maintained Phitotal after treatment suspension for up to 48 months, unlike placebo high-secretors (0.3% (95% CI -3.8, 4.5) vs -9% (95% CI -13.2, -4.8), p=0.002). Conclusion: The OMM reveals heterogeneity within Stage 1 T1D and identifies abatacept responders with high baseline beta cell function. This is consistent with the observation in murine models that abatacept is most effective in early disease. Disclosure A.L. Carr: None. A. Galderisi: None. P. Taylor: None. J. Bonet: None. D.D. Cuthbertson: None. J. Sosenko: None. E.K. Sims: Consultant; Sanofi. Speaker's Bureau; Med Learning Group. Other Relationship; American Diabetes Association. C. Evans-Molina: Advisory Panel; DiogenX. Research Support; Bristol-Myers Squibb Company, Lilly Diabetes. Advisory Panel; Isla Technologies, Neurodon. Research Support; Neurodon. C. Dalla Man: None. P.A. Senior: Consultant; Abbott. Research Support; Canadian Institutes of Health Research, Eli Lilly and Company. Consultant; GlaxoSmithKline plc. Speaker's Bureau; GlaxoSmithKline plc. Consultant; Insulet Corporation, Novo Nordisk. Speaker's Bureau; Novo Nordisk. Consultant; Ypsomed AG, Vertex Pharmaceuticals Incorporated. H.M. Ismail: Consultant; Rise Therapeutics. B.M. Nathan: None. A. Petrelli: None. J.L. Sherr: Consultant; Abbott. Advisory Panel; StartUp Health T1D Moonshot. Research Support; Dexcom, Inc. Advisory Panel; Cecelia Health, MannKind Corporation. Consultant; Insulet Corporation, Vertex Pharmaceuticals Incorporated, Ypsomed AG. Advisory Panel; Medtronic, Vertex Pharmaceuticals Incorporated. K.C. Herold: Consultant; Sanofi, Dompé, Vertex Pharmaceuticals Incorporated, Sonoma, NexImmune. W.E. Russell: None. A. Moran: Research Support; Abbott. Consultant; Abata Therapeutics. Other Relationship; Novo Nordisk. C. Dayan: Advisory Panel; Provention Bio, Inc, Provention Bio, Inc, Microbion, Microbion, Sanofi. Speaker's Bureau; Sanofi. Advisory Panel; SAB Biotherapeutics, Inc. Consultant; SAB Biotherapeutics, Inc, Sanofi, AstraZeneca, Immunocore, Ltd. Advisory Panel; Amarna, Shoreline Bio, Vertex Pharmaceuticals Incorporated. Funding National Institutes of Health via National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085453, U01 DK085461, U01 DK085465, U01 DK085466, U01 DK085476, U01 DK085499, U01 DK085504, U01 DK085509, U01 DK103153, U01 DK103180, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106994, U01 DK107013, U01 DK107014, UC4 DK097835, U01 DK106993,R01DK121929, R01DK133881,DK057846,AI66387, DK106993,DK106993); National Center for Research Resources (UL1TR000142, UL1TR002366, UL1TR000445, UL1TR000064, UL1TR002537, UL1TR001082, UL1TR000114, UL1TR001857, UL1TR002529, UL1TR001872), Immune Tolerance Network (UM1 AI09565).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".