Accounting for Age-Related Increases in HbA1c More Accurately Quantifies Risk of Type 1 Diabetes Progression in Islet Autoantibody-Positive Adults

OBJECTIVE: HbA1c thresholds used to define dysglycemia in autoantibody-positive individuals at risk for type 1 diabetes do not account for age-related increases in HbA1c and may overestimate progression risk in adults. We evaluated whether age-adjusted HbA1c or a higher HbA1c threshold improves risk stratification across age-groups. RESEARCH DESIGN AND METHODS: We analyzed 5,024 autoantibody-positive relatives (3,720 children and 1,304 adults) participating in the TrialNet Pathway to Prevention study. Age-related HbA1c effects were modeled using 6,273 adults from the population-based Exeter 10000 cohort. Progression risk was compared using the standard dysglycemia threshold (HbA1c ≥5.7% [39 mmol/mol]), age-adjusted HbA1c, and an alternative threshold of HbA1c ≥6.0% (42 mmol/mol). RESULTS: Using HbA1c ≥5.7% (39 mmol/mol), children had higher 1-year progression risk than adults among single autoantibody-positive participants (38% [95% CI 28, 47] vs. 13% [7.2, 19]) and multiple autoantibody-positive participants (55% [49, 60] vs. 38% [27, 47]) (both P < 0.001). Age adjustment reduced these differences; progression risk was similar among single autoantibody-positive participants (38% [28, 47] vs. 27% [13, 39]; P = 0.32), with attenuated differences among multiple autoantibody-positive participants. An HbA1c threshold ≥6.0% (42 mmol/mol) yielded comparable progression risk between adults and children across autoantibody subgroups. In post hoc analyses, adults aged <30 years had progression risk similar to children (P = 0.1). CONCLUSIONS: Age-related variation in HbA1c influences dysglycemia classification in adults at risk for type 1 diabetes. Age-adjusted HbA1c or a higher HbA1c threshold (≥6.0% [42 mmol/mol]) in adults aged ≥30 years identifies individuals with progression risk comparable to children and may improve age-specific risk stratification in prevention settings.