Erythrocytosis and thromboembolic risks associated with SGLT2 inhibitors in type 2 diabetes

This study aimed to determine if sodium-glucose co-transporter-2 inhibitors (SGLT2i) use in diabetic patients leads to erythrocytosis and increases the incidence of arterial and venous thrombosis events. This is a retrospective cohort study using records from over 50 U.S. healthcare organizations. Adults with type 2 diabetes who received SGLT2i therapy were compared to those on glucagon-like peptide-1 receptor agonists (GLP1RA) or dipeptidyl peptidase-4 inhibitors (DPP4i). The primary outcome was the risk of erythrocytosis, defined by elevated hemoglobin and hematocrit levels. Secondary outcomes included arterial and venous thromboembolic events. Propensity score matching was applied to balance baseline characteristics, and Cox proportional hazards regression models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Results demonstrated that compared to SGLT2i use, DPP4i use was associated with a significantly higher risk of erythrocytosis in both male (hemoglobin > 16.5 g/dL: HR 1.954 [1.909-2.001]) and female (hemoglobin > 16 g/dL: HR 1.873 [1.803-1.947]) patients with type 2 diabetes. Similarly, GLP1RA use was associated with a significantly higher risk of erythrocytosis in both male (HR 1.605 [1.573, 1.636] and female (HR 1.697 [1.640, 1.755]) patients compared to SGLT2i use. Compared with DPP4i users, SGLT2i users had less cardiovascular events, except for increased stroke/TIA in females (HR 1.744 [1.654-1.839]). Compared with GLP1RA, SGLT2i use was associated with a decrease risk of MACE in both men and women, but higher risk for other cardiovascular and peripheral vascular events. Among SGLT2i users, those who developed erythrocytosis had increased incidence of thromboembolic events compared to those without erythrocytosis. Lastly, among SGLT2i patients treated for their erythrocytosis, the men who discontinued SGLT2i had increased risks of stroke/TIA, MI, and limb ischemia, while women had increased risk of stroke/TIA, MI, and venous thrombosis. Those who received anti-platelet therapy were associated with elevated risks of stroke/TIA, MI, venous thrombosis, and limb ischemia. In contrast, patients who receive phlebotomy had no significant difference in the outcomes. Therefore, regular monitoring of hematologic parameters is recommended for early detection and modified therapeutic strategies should be considered to reduce complication risks. Further studies are needed to establish effective strategies to reduce complications in this population.