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 (HbA 1c ≤5.6%) and four parallel cohorts had dysglycaemia (HbA 1c 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 HbA 1c ≤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 HbA 1c 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, HbA 1c and autoantibody burden. Mild dysglycaemia and single‐antibody positivity, not captured by current staging criteria, identify individuals at increased risk.