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

Abstract

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 HbA1c measurements were followed to diabetes or median age 11.1 years. Once confirmed autoantibody positive, HbA1c was measured quarterly. Cox models and receiver operative characteristic curve analyses revealed the prognostic utility for risk of stage 3 on a relative HbA1c increase from the baseline visit or an oral glucose tolerance test (OGTT) 2-h plasma glucose (2-hPG). This HbA1c approach was then validated in the Type 1 Diabetes TrialNet Pathway to Prevention Study (TrialNet) (n = 1,190).

Results: A 10% relative HbA1c increase from baseline best marked the increased risk of stage 3 in TEDDY (74% sensitive; 88% specific). Significant predictors of risk for HbA1c change were age and HbA1c at the baseline test, genetic sex, maximum number of autoantibodies, and maximum rate of HbA1c increase by time of change. The multivariable model featuring a HbA1c ≥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 HbA1c ≥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 HbA1c model in TrialNet (AUC 0.82).

Conclusions: An increase of ≥10% in HbA1c from baseline is as informative as OGTT 2-hPG in predicting risk of stage 3 in youth with genetic risk and diabetes-associated autoantibodies.

Figure 1

Identification of optimal thresholds and evaluation of percent HbA_1c increase from baseline HbA_1c (A) and OGTT 2-hPG (B) optimal thresholds as a prognostic for progression to type 1 diabetes in the TEDDY children. For the HbA_1c, n = 707 and for the OGTT n = 426. NPV, negative predicative value.

Figure 2

Multivariable Cox proportional hazards models evaluating ≥10% HbA_1c increase in TEDDY and TrialNet on progression to type 1 diabetes from time at ≥10% increase in HbA_1c. Reference is <10% HbA_1c increase. Models adjusted for age at HbA_1c baseline, HbA_1c baseline measure, number of autoantibodies at time of HbA_1c change, maximum rate of change from baseline, and genetic sex. A ≥10% increase in HbA_1c increases the risk of progression to type 1 diabetes in both the TEDDY (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) studies.

Figure 3

Evaluating the utility of percent HbA_1c increase and OGTT 2-HPG as prognostic measures on predicting progression of type 1 diabetes in a subset of TEDDY children with both percent HbA_1c change and OGTT data available (n = 426) (A) and composite score performance over increasing follow-up horizons (B). The composite score for HbA_1c ≥10% included whether or not the 10% increase in HbA_1c was achieved, the baseline HbA_1c value, the age at baseline HbA_1c, the maximum number of autoantibodies by time of the HbA_1c change, and maximum rate of change through the time of the HbA_1c ≥10% increase. Composite score for OGTT ≥8 mmol/L included whether or not the threshold was met, OGTT 2-hPG value at baseline, family history of type 1 diabetes, and genetic sex. Only significant covariates are included in the composite score models.

Figure 4

Venn diagram of the TEDDY children who met the HbA_1c ≥10% threshold and/or OGTT 2-hPG ≥8 mmol/L threshold (n = 286/426) and progressed to stage 3 (n = 204).