146-OR: Clustering Pediatric Type 2 Diabetes Patients Exposes Differential Responses to Therapeutic Interventions

Introduction & Objective: Diabetes is a heterogeneous disease, with patients displaying varying degrees of adiposity, beta-cell dysfunction, and insulin resistance. Ahlqvist et al. established five distinct sub-types of adult-onset diabetes, with differing disease progression and risk for complications, based on clustering of six clinical variables. These clusters were developed and validated in adult populations, but their reproducibility in pediatric diabetes remains unknown. We sought to determine if pediatric patients can be sub-classified into clusters based on the same variables, and if these clusters had differing responses to treatment.

Methods: We analyzed Progress in Diabetes Genetics in Youth (ProDiGY), a multi-ethnic resource that brings together youth with clinician-diagnosed type 2 diabetes (T2D) before age 20 years from SEARCH (n=428) and the Treatment Options for T2D in Adolescents and Youth (TODAY) study (n=455). In participants with negative autoantibodies, we used a k-means (k=3) clustering method, with variables BMI, HOMA2_B, HOMA2_IR, and HbA1c; we excluded age of diagnosis given its limited range in a pediatric population.

Results: We identified three distinct pediatric clusters in each cohort-sex group. Cluster 1 had high HbA1c and low HOMA2_B, denoting low beta-cell function. Cluster 2 had the highest BMI, HOMA2_IR, and HOMA2_B, denoting insulin resistance. Cluster 3 had intermediate levels of HOMA2_IR and HOMA2_B but the lowest HbA1c, denoting milder diabetes. In TODAY, participants in cluster 1 had the highest rates of treatment failure (76% versus 46% overall, p<0.0001). Metformin alone was most likely to be successful in cluster 3 (failure rate 19%) and had the highest rates of failure in cluster 1 (failure rate 86%, p<0.0001).

Conclusion: Clustering pediatric T2D by clinical measures reveals distinct sub-types with differing responses to treatment. Clustering might be used to inform treatment choices in pediatric T2D patients.