Abatacept (CTLA4-Ig) to delay type 1 diabetes in at-risk relatives

What was tested and why it matters

Type 1 diabetes doesn't appear overnight. Years before any symptoms, the immune system begins attacking the insulin-producing cells in the pancreas, and that attack can be detected as autoantibodies in the blood while blood sugar is still completely normal — a phase researchers call "stage 1."¹ This TrialNet study asked a simple but important question: if you intervene at that early stage, can you slow or stop the slide toward diabetes?²

The drug tested was abatacept (brand name Orencia), a medicine already used for rheumatoid arthritis. It works by blunting one of the "go" signals that immune T-cells need to switch on, a mechanism called costimulation blockade.² Earlier work had shown abatacept slowed the loss of insulin-making capacity in people newly diagnosed with type 1 diabetes, so the team wanted to know whether starting even earlier — before blood sugar ever became abnormal — could prevent progression altogether.²

Who it was for

The trial enrolled relatives of people with type 1 diabetes who carried two or more islet autoantibodies but still had normal glucose tolerance.² Enrolled participants ranged from about 6 to 45 years old.³

How it was designed

This was a Phase 2 randomized, double-masked, placebo-controlled trial.² In total, 212 participants were randomized — 101 to abatacept and 111 to placebo — and received monthly intravenous infusions of either abatacept or saline placebo for 12 months.² They were then followed with periodic oral glucose tolerance tests to see who progressed. The main outcome was the time from randomization until blood sugar became abnormal or until clinical (stage 3) diabetes was diagnosed.² The study was run across TrialNet sites in the United States, Canada, Australia, and Germany, and ran from 2013 to its completion in 2022.³

The key results

The trial missed its primary endpoint. Overall, 81 participants progressed — 35 on abatacept versus 46 on placebo — which corresponds to a hazard ratio of 0.702 (95% CI 0.452 to 1.09; P=0.11).² That is a trend toward benefit, but it did not reach statistical significance, so the result could be due to chance.²

There were encouraging signals, though. People who received abatacept preserved more C-peptide, a direct marker of the body's own insulin production (P<0.03).² Abatacept also clearly altered immune cells during treatment — it reduced inflammatory "T-follicular helper" cells (P<0.0001) and shifted other T-cell populations — but those changes reversed within a year of stopping the drug.²

What it means and what's next

The authors concluded that one year of abatacept did not significantly delay progression, but that costimulation blockade does measurably modify the disease process and helps preserve insulin secretion.² The reversal of immune effects after stopping treatment hints that longer or continued dosing, or combining abatacept with other agents, might be needed to translate these biological effects into a durable clinical benefit — a key open question for future prevention trials.²

References

1. JDRF / TrialNet. Type 1 Diabetes TrialNet — Pathway to Prevention and disease staging. Type 1 Diabetes TrialNet. https://www.trialnet.org/ ↩

2. Russell WE, Bundy BN, Anderson MS, et al. Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial. Diabetes Care (2023);46(5):1005-1013. https://doi.org/10.2337/dc22-2200 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹² ↩¹³

3. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) / Type 1 Diabetes TrialNet. CTLA4-Ig (Abatacept) for Prevention of Abnormal Glucose Tolerance and Diabetes in Relatives At-Risk for Type 1 Diabetes (NCT01773707). ClinicalTrials.gov (2013-2022). https://clinicaltrials.gov/study/NCT01773707 ↩ ↩²