Fasting Plasma Glucose Levels within the High Normal Range are Associated with a Significantly Increased Risk of Future Dysglycemia in Transfusion-Dependent β Thalassemia: A Decade-Long Multicenter Retrospective Analysis.

Objectives: The primary objective was to evaluate the risk of developing glucose dysregulation and diabetes mellitus over 10 years among transfusion-dependent β-thalassemia (β-TDT) patients with varying levels of fasting plasma glucose (FPG) within the normoglycemic range. The secondary objective was to identify which baseline variables were associated with a higher risk of developing abnormal fasting glucose levels in the future. Setting: This retrospective observational study included β-TDT patients followed from January 2014 to January 2025 in three thalassemia centers: Tehran and Shiraz in Iran, and Ferrara in Italy. Patients and results: A total of 238 β-TDT patients (age range: 10-41.9 years; 96 males and 142 females) were included in the study. Patients were categorized into three subgroups according to their fasting glycemic status during the 10 year follow-up [Group A: 93/238 β-TDT patients (39.1%) with persistent normal FPG according to the American Diabetes Association (ADA) criteria; Group B: 67/238 patients (28.1%) developed persistent impaired fasting glucose (IFG), and Group C: 78/238 patients (32.8%) developed thalassemia-related diabetes mellitus (Th-RDM)]. To determine the optimal cutoff for the risk of progressing to impaired fasting glucose (IFG) and Th-RDM at 10-year follow-up, ROC curve analyses and respective areas under the curve were analyzed. The FPG cutoff value for optimal specificity and sensitivity was established at 87.5 mg/dL. Almost all (76/78) patients who developed Th-RDM (97.4%) were diagnosed in Shiraz. At the diagnosis of Th-RDM, the multivariate linear regression model documented an association of FPG with serum ferritin level (t-stat: 2.9873; P: 0.0041) but not with the other investigated variables: age, gender, body mass index, pre-transfusional hemoglobin level, oral iron chelating agents, serum ferritin, history of splenectomy and positive family history for T1 DM and T2 DM reported at baseline. These results reinforce the main role of chronic iron burden in the etiopathogenesis of Th-RDM in β-TDT patients. Conclusions: FPG levels at the upper end of the normal range (defined as < 100 mg/dL) in β-TDT patients with severe iron overload are associated with a significantly increased risk for developing either IFG or Th-RDM over a 10-year observational period. The identification of an FPG cutoff (87.5 mg/dL), above which the risk for future dysglycemia increases significantly, could be useful in the routine practice, urging clinicians to intensify iron chelation and monitor these patients more closely.