Baseline Insulin Secretion Determines Response to Abatacept in Stage 1 Type 1 Diabetes.

Abatacept, a cytotoxic T lymphocyte–associated protein 4 immunoglobulin that inhibits T-cell costimulation, was evaluated for 12 months in stage 1 type 1 diabetes (T1D) to delay disease progression. Despite modest preservation of area under the curve C-peptide at 12 months, the primary end point was not met. We adopted the oral minimal model (OMM) to assess β-cell function over 48 months and explored how baseline insulin secretion (ϕtotal) modified treatment response. Using the OMM, ϕtotal was computed from oral glucose tolerance tests conducted at baseline and every 6 months. Participants were stratified into high- and low-secretor groups depending on baseline ϕtotal ≥33rd or <33rd centile, respectively. A sensitivity analysis was performed to validate threshold choice. Among 203 participants (abatacept n = 96; 107 placebo n = 107), 39% receiving abatacept and 47% receiving placebo experienced progression to stage 2 or 3 within 96 months. High secretors receiving abatacept gained 15.8 progression-free months (95% CI 4.85, 26.68; P = 0.005) and had a 54% lower hazard of progression versus those receiving placebo (hazard ratio [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). A subgroup of responders to 12 months of abatacept was identified by ϕtotal, providing the first evidence that an immune intervention in stage 1 T1D may delay disease progression. ARTICLE HIGHLIGHTS: We sought to investigate whether baseline insulin secretion (ϕtotal), quantified using the oral minimal model assessing β-cell function, could identify a subgroup of responders to abatacept (a cytotoxic T lymphocyte-associated protein 4 immunoglobulin that inhibits T-cell costimulation) among those with stage 1 type 1 diabetes (T1D). Abatacept preserved ϕtotal during and up to 1 year after treatment cessation; high baseline secretors treated with abatacept gained ∼16 months of progression-free survival and had a 54% lower hazard of progression versus those receiving placebo, whereas no benefit was observed in low secretors. This is the first evidence of an immune intervention delaying disease progression in those with stage 1 T1D. Continued treatment may result in a greater delay in progression.