American Diabetes Association
3 files

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

posted on 2022-08-30, 18:28 authored by Kendra Vehik, David Boulware, Michael Killian, Marian Rewers, Richard McIndoe, Jorma Toppari, Ake Lernmark, Beena Akolkar, Anette-Gabriele Ziegler, Henry Rodriguez, Desmond A Schatz, Jeffrey P. Krischer, William A. Hagopian, TrialNet Study Group, TEDDY Study Group


Objective: Biomarkers predicting risk of type 1 diabetes (Stage 3) among children with islet autoantibodies are greatly needed to prevent DKA and facilitate prevention therapies. 

Research Design and Methods: Children in the prospective TEDDY study (n=707) with confirmed diabetes-associated autoantibodies (GADA, IA-2A and/or IAA) and ≥2 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 (ROC) analyses revealed the prognostic utility for risk of Stage 3 on a relative HbA1c increase from the baseline visit or an OGTT 2-hr plasma glucose (2-hPG). This HbA1c approach was then validated in the TrialNet Pathway to Prevention study (n=1190).

Results: A 10% relative HbA1c increase from baseline best marked increased risk of Stage 3 in TEDDY (74% sensitive; 88% specific). Significant predictors of risk for HbA1c change were age and HbA1c at 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 (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 AUC=0.88 and 0.85, respectively) and to the HbA1c model in TrialNet (AUC=0.82).

Conclusion: 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.


Centers for Disease Control and Prevention (CDC)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)


National Institute of Allergy and Infectious Diseases (NIAID)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) HHSN267200700014C U01 DK106993 U01 DK124166 U01 DK128847 U01 DK63790 U01 DK63821 U01 DK63829 U01 DK63836 U01 DK63861 U01 DK63863 U01 DK63865 UC4 DK100238 UC4 DK106955 UC4 DK112243 UC4 DK117483 UC4 DK63821 UC4 DK63829 UC4 DK63836 UC4 DK63861 UC4 DK63863 UC4 DK63865 UC4 DK95300

National Institute of Environmental Health Sciences (NIEHS)

U.S. Department of Health and Human Services > National Institutes of Health


University of Colorado UL1 TR002535