Type 2 Diabetes Clusters Indicate Diabetes Duration Key in Fracture Risk

Introduction: Individuals with type 2 diabetes mellitus (T2DM) are at an increased risk of developing fractures, despite higher mean BMI and BMD. Recently, clinically-relevant sub-groups of T2DM have been characterised using biomarkers of glycemic metabolism. Aim: Characterise T2DM sub-groups in a population-based setting and test for differences in fracture risk. Methods: A total of 10019 Rotterdam Study participants were available with glycemic and (incident) fracture follow-up. Participants with T2DM (n=1678) were partitioned in subgroups using K-means clustering based on: HOMA-B, HOMA-IR, age of diabetes onset, BMI and waist circumference measurements. Non-vertebral fracture risk was estimated across T2D subgroups using Cox proportional hazard models, adjusted for sex, age, BMI, collection cohort and prevalent T2DM. Results: Four T2D clusters were defined each with relatively-unique clinical characteristics namely, 1) advanced age of onset; 2) decreased insulin sensitivity; 3) beta-cell disfunction; 4) Obesity/high BMI. Individuals with prevalent and incident T2DM (independent of cluster) had lower risk of fracture than non-diabetics (see Forest plot). In contrast, individuals with prevalent T2DM (n=1152) had increased risk of non-vertebral fracture (HR: 2.1, 95%CI: 1.65–2.76), than individuals without T2DM. Conclusion: Despite that partitioning the heterogeneity of T2DM in clinically-meaningful clusters opens the road to tailored prevention and care, our findings with prevalent T2DM indicate that disease duration (likely with inadequate glycemic control) is the main determinant of fracture risk. In line with this contention, the association between T2DM and fracture risk is not causal, as causality requires association with incident cases, as also confirmed by earlier Mendelian randomization studies. Future work, using genetically-determined disease definitions and biomarkers will help unveil clusters of individuals with T2DM at increased risk of fracture.