Definition of Dysglycemia in Pre-symptomatic Type 1 Diabetes: A Guide to the Timing of Interventional Therapies
The clinical onset of type 1 diabetes is preceded by presymptomatic stages, that are marked by the presence of two or more islet autoantibodies. Stage 1 is characterized by normal blood glucose levels, while stage 2 is marked by dysglycemia. However, the criteria for defining stage 2 vary among leading authorities. Originally, stage 2 was defined by TrialNet, demonstrating the efficacy of teplizumab* as an immunotherapy in delaying progression to symptomatic stage 3 for individuals meeting this definition. Subsequently, the American Diabetes Association (ADA) and an expert consensus committee revised these definitions. Researchers from the Institute of Diabetes Research at Helmholtz Munich were able to assess for the first time the significance of these differing criteria for progression to symptomatic type 1 diabetes providing guidance on the timing of interventional therapies in children with presymptomatic type 1 diabetes. Their analysis is published in the Lancet Diabetes & Endocrinology.
Early Detection of Type 1 Diabetes Through Screening
Type 1 diabetes (T1D) is an autoimmune disease with three defined stages. While T1D is often first diagnosed in the symptomatic stage 3, screening programs like the Fr1da Study enable earlier diagnosis in the presymptomatic stages. The diagnosis of these early stages, characterized by the presence of two or more islet autoantibodies and normoglycemia (stage 1) or dysglycemia (stage 2), is crucial to identify individuals eligible for interventional therapies, such as the anti-CD3 monoclonal antibody teplizumab, which can slow down the progression from stage 2 to the clinical onset (stage 3) T1D.
The Role of Dysglycemia in Defining Stage 2 T1D
While the three stages of T1D are widely accepted, the criteria for dysglycaemia used to define stage 2 T1D remain inconsistent. Researchers at the Institute of Diabetes Research at Helmholtz Munich analyzed two-year progression rates in Fr1da-children diagnosed with stage 2 T1D using different dysglycemia criteria. These include elevated blood glucose levels during an oral glucose tolerance test, impaired HbA1c levels or longitudinal >10% increase in HbA1c. They aimed to determine the significance of different dysglycaemia criteria for progression to clinical T1D.
This study highlights that there are clear differences in the two-year progression rates of children from the Fr1da study based on different dysglycemia criteria. The highest progression rate (80.1%) was observed in children with impaired HbA1c concurrent with at least one abnormal glucose level during an oral glucose tolerance test. A two-year progression rate of 66.6% was noted in children meeting at least two of the dysglycemia criteria, compared to 31.4% in those with any dysglycemia, including children with only a single abnormality. In contrast, children who showed a longitudinal >10% increase in HbA1c but maintained normal blood glucose levels had a two-year progression rate of 23.3%
While these observations support the use of two or more dysglycemia abnormalities simultaneously for identifying children in a more advanced presymptomatic stage, where treatment with teplizumab is assumed to be most effective, they also provide guidance for the timing of interventional therapies intended to be applied earlier in the presymptomatic stage.
Original publication
Hummel et. al (2024): Dysglycaemia definitions and progression to clinical type 1 diabetes in youth with multiple islet autoantibodies. The Lancet Diabetes & Endocrinology. DOI: https://doi.org/10.1016/S2213-8587(24)00337-1
Further Information
*What is teplizumab?
Teplizumab is an immunotherapy drug that delays the onset of symptomatic (stage 3) type 1 diabetes in individuals at high risk. The monoclonal antibody targets CD3, which is a receptor on the surface of immune cells. The drug was first approved by the Food and Drug Administration (FDA) in the USA in 2022 and is now accessible in Germany through the Paul-Ehrlich-Institute's “Härtefallprogramm”.
