Rising Hemoglobin A1c in the Nondiabetic Range Predicts Progression of Type 1 Diabetes As Well As Oral Glucose Tolerance Tests

OBJECTIVE Biomarkers predicting risk of type 1 diabetes (stage 3) among children with islet autoantibodies are greatly needed to prevent diabetic ketoacidosis and facilitate prevention therapies. RESEARCH DESIGN AND METHODS Children in the prospective The Environmental Determinants of Diabetes in the Young (TEDDY) study (n = 707) with confirmed diabetes-associated autoantibodies (GAD antibody, IA-2A, and/or insulin autoantibody) and two or more HbA(1c) measurements were followed to diabetes or median age 11.1 years. Once confirmed autoantibody positive, HbA(1c) was measured quarterly. Cox models and receiver operative characteristic curve analyses revealed the prognostic utility for risk of stage 3 on a relative HbA(1c) increase from the baseline visit or an oral glucose tolerance test (OGTT) 2-h plasma glucose (2-hPG). This HbA(1c) approach was then validated in the Type 1 Diabetes TrialNet Pathway to Prevention Study (TrialNet) (n = 1,190). RESULTS A 10% relative HbA(1c) increase from baseline best marked the increased risk of stage 3 in TEDDY (74% sensitive; 88% specific). Significant predictors of risk for HbA(1c) change were age and HbA(1c) at the baseline test, genetic sex, maximum number of autoantibodies, and maximum rate of HbA(1c) increase by time of change. The multivariable model featuring a HbA(1c) >= 10% increase and these additional factors revealed increased risk of stage 3 in TEDDY (hazard ratio [HR] 12.74, 95% CI 8.7-18.6, P < 0.0001) and TrialNet (HR 5.09, 95% CI 3.3-7.9, P < 0.0001). Furthermore, the composite model using HbA(1c) >= 10% increase performed similarly to an OGTT 2-hPG composite model (TEDDY area under the curve [AUC] 0.88 and 0.85, respectively) and to the HbA(1c) model in TrialNet (AUC 0.82). CONCLUSIONS An increase of >= 10% in HbA(1c) from baseline is as informative as OGTT 2-hPG in predicting risk of stage 3 in youth with genetic risk and diabetes-associated autoantibodies.

Automated summary

This study suggests that an increase of >= 10% in HbA(1c) from baseline is as informative as OGTT 2-hPG in predicting the risk of stage 3 in children with diabetes-associated autoantibodies.