Impact of SGLT2 inhibitors on clinical outcomes in diabetic patients with CLL receiving BTK inhibitors: A global propensity-matched study.

7051 Background: Diabetic patients with chronic lymphocytic leukemia (CLL) receiving Bruton’s tyrosine kinase inhibitors (BTKi) face intersecting challenges of metabolic dysfunction, immune dysregulation, and treatment-related toxicities, including cardiovascular complications and increased susceptibility to infections. Sodium–glucose cotransporter 2 inhibitors (SGLT2i), have emerged as a pleiotropic cardio-renal-metabolic therapeutic class with benefits extending beyond glycemic control. We hypothesize that early initiation of SGLT2i in diabetic patients with CLL may mitigate BTKi–associated toxicities and improve long-term treatment tolerability and clinical outcomes. Methods: We used the TriNetX Global Collaborative Network to identify patients with CLL (C91.1, C83.00) and diabetes (E08–E13) treated with BTK inhibitors (ibrutinib, acalabrutinib, or zanubrutinib), comparing those with and without SGLT2 inhibitor exposure. Propensity score matching adjusted for demographic, metabolic, cardiovascular, and renal confounders, as well as hypoglycemic and cardiovascular medications. After matching, 1,102 patients (551 per cohort) were included. Outcomes were assessed within 3 years of the index event, and hazard ratios (HRs) with 95% confidence intervals were estimated. Results: The 3-year all-cause mortality was significantly lower with concurrent BTKi and SGLT2i compared with BTKi alone (HR 0.50, 0.38–0.66), corresponding to a 3-year overall survival of 77% versus 62% (p < 0.0001). Hematologic toxicity was also significantly lower in the SGLT2i cohort, including grade 3 thrombocytopenia (HR 0.632, 0.461–0.866), grade 3 anemia (HR 0.532, 0.422–0.671), and neutropenia (HR 0.618, 0.419–0.911). Infectious complications were less frequent in the SGLT2i group, with a significant decrease in neutropenic fever (HR 0.393, 0.221–0.698), sepsis (HR 0.686, 0.504–0.934), and pneumonia (HR 0.65, 0.506–0.835). Likewise, a lower incidence of Deep vein thrombosis and pulmonary embolism was found in the SGLT2i cohort (0.555, 0.35–0.879). Surprisingly, cardiovascular outcomes were not significantly different between groups, including hypertension (HR 1.10, 0.961–1.278), atrial fibrillation (HR 1.073, 0.86–1.339), and heart failure (HR 1.128, 0.919–1.385). Conclusions: SGLT2i use was associated with significantly longer 3-year overall survival and lower hazards of severe cytopenias and serious infections in diabetic patients with CLL receiving BTK inhibitors, with no meaningful differences in major cardiovascular outcomes. The mechanisms underlying these associations is unclear; however, emerging evidence suggests that SGLT2i may exert immunomodulatory effects and have been shown to reduce tumor cell proliferation in breast cancer models. Further studies are warranted to confirm the role of SGLT2i in diabetic CLL patients.