Progression to type 1 diabetes across the autoimmunity and glycaemia continuum: Insights from real-world paediatric and adult cohorts.

Background

Type 1 diabetes (T1D) follows a staged autoimmune natural history, yet most evidence describing progression derives from highly selected, genetically at-risk cohorts.

Methods

Using the TriNetX Network, we identified eight cohorts of autoantibody-positive individuals without prior T1D. Four cohorts had preserved glycaemia (HbA1c ≤5.6%) and four parallel cohorts had dysglycaemia (HbA1c 5.7%-6.4%). Cohorts were sub-defined by autoantibody burden (single vs. two autoantibodies) and age (≤18 vs. >18 years). Follow-up was 3 years, with incident clinically coded T1D as the primary outcome.

Results

Among 7000 individuals, progression risk varied substantially by age, glycaemia and autoantibody burden. In those with HbA1c ≤38 mmol/mol (≤5.6%; n = 4536), children had higher risk than adults with both single (HR 4.13, 95% CI 2.92-5.85) and two autoantibody burden (HR 7.03, 95% CI 3.63-13.62). In the dysglycaemia group (39-46 mmol/mol [5.7%-6.4%]; n = 2464), the paediatric-adult gradient persisted for both single (HR 2.01, 95% CI 1.45-2.78) and two autoantibodies (HR 4.22, 95% CI 2.29-7.75). Elevated HbA1c increased progression risk in single-antibody individuals (children HR 1.44, 95% CI 1.05-1.97; adults HR 2.94, 95% CI 2.05-4.20) but not significantly in individuals who already had two antibodies.

Conclusions

Real-world progression from islet autoimmunity to T1D is strongly modified by age, HbA1c and autoantibody burden. Mild dysglycaemia and single-antibody positivity, not captured by current staging criteria, identify individuals at increased risk.