Hematologic and cardiovascular outcomes of SGLT2 inhibitors in patients with chronic lymphocytic leukemia and type 2 diabetes: A real-world TriNetX analysis.

7050 Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) exhibit biologically plausible metabolic and immunomodulatory effects beyond glycemic control that may be relevant in chronic lymphocytic leukemia (CLL), by reducing insulin resistance, activating AMPK signaling, suppressing downstream PI3K/AKT/mTOR activity, and improving cellular metabolic homeostasis. SGLT2i also decrease systemic and adipose-derived inflammation by inhibiting the NLRP3 inflammasome, reducing IL-6 and TNF-α levels, and mitigating oxidative stress. Improved mitochondrial efficiency and modulation of HIF-1α signaling may influence leukemic cell survival and immune exhaustion, suggesting a plausible role for SGLT2i in reducing infection risk, cardiovascular events, and survival outcomes in patients with CLL. However, real-world clinical evidence remains limited. Methods: We conducted a retrospective cohort study using the TriNetX Analytics Network to evaluate outcomes associated with SGLT-2i use in adults with CLL and type 2 diabetes mellitus. SGLT-2-exposed and non-exposed cohorts were compared for infectious complications, hematological outcomes like cytopenias, cardiovascular (CV), and all-cause mortality. Propensity score matching minimized confounding due to contemporary CLL therapies, baseline demographics, comorbidities, and treatment-related outcomes. Time-to-event outcomes were analyzed using Kaplan-Meier and Cox models. Results: After propensity score matching, with comparable mean short and long term follow durations (60-821 days), SGLT2 inhibitor use was associated with a significantly lower risk of pneumonia (5.4% vs 8.0%; HR 0.70, 95% CI 0.56-0.89) and CV mortality (13.9%, vs 21.9%) with improved survival on KM analysis (p<0.001; HR-0.70, 95% CI 0.59-0.83). A modest reduction in sepsis was observed in SGLT2i users (4.7% vs 6.0%), but did not reach statistical significance (HR 0.82, 95% CI 0.65-1.05). All-cause mortality was numerically lower in the SGLT2 cohort (7.4% vs 8.5%), but no significant difference in survival was observed (HR 0.91, 95% CI 0.76-1.10). The SGLT2i group showed lower thrombocytopenia risk and a similar rare risk of AIHA between the two cohorts, with no significant difference in time-to-event analysis, suggesting that SGLT2 inhibitors may preferentially reduce selective infectious complications and CV mortality without significant improvement in overall mortality. Conclusions: SGLTI might have biologically plausible cardioprotective, metabolic, and immunomodulatory effects that may improve outcomes related to inflammation and infection, and reduce CV mortality in CLL, without a demonstrable short-term overall mortality benefit. Longer follow-up and prospective studies are needed to define the durability of these effects and their impact on survival.