Association of GLP-1 receptor agonist exposure with mortality, infectious, and hematologic outcomes in chronic lymphocytic leukemia: A real-world retrospective TriNetX study.

e18591 Background: Emerging studies show that Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) might have antineoplastic and immune-mediated effects beyond glycemic control by inhibiting PI3K/AKT/mTOR and ERK/MAPK pathways, modulating inflammatory cytokines, and altering the tumor microenvironment, which are key drivers of chronic lymphocytic leukemia (CLL) progression and immune dysfunction. GLP-1 RAs also improve insulin sensitivity and decrease adipose-mediated systemic inflammation, which relate to infectious risk and mortality in CLL, but their impact on clinical outcomes and survival in patients with CLL remains poorly defined. Methods: We conducted a retrospective cohort study using the TriNetX Network to evaluate outcomes associated with GLP-1 RA use in adults with CLL and type 2 diabetes mellitus. GLP-1-exposed and non-exposed cohorts were compared for infectious complications, hematologic events like cytopenias, ICU admissions, adverse events, cardiovascular (CV), and all-cause mortality, while accounting for exposure to contemporary CLL therapies to assess potential confounding and analyzing time-to-event outcomes using Kaplan-Meier and Cox models after excluding pre-existing events. Results: After propensity score matching, follow-up was well balanced between cohorts, with comparable mean short-term (~326 days) and long-term (758-824 days) durations. GLP-1 use was associated with significantly lower risks of sepsis (3.1% vs 6.1%; HR 0.51, 95% CI 0.37-0.69), pneumonia (4.3% vs 8.0%; HR 0.53, 95% CI 0.40-0.70), thrombocytopenia (3.7% vs 5.9%; HR 0.63, 95% CI 0.46-0.86), and all-cause mortality (2.5% vs 8.1%; HR 0.30, 95% CI 0.22-0.41) when compared to the non-GLP1 cohort, with early and sustained separation of Kaplan-Meier curves. CV mortality and ICU admission rates were significantly lower in the GLP-1 cohort with HRs of 0.69 (95% CI 0.57-0.83) and 0.61 (95% CI 0.49–0.77), respectively. Autoimmune Hemolytic Anemia (AIHA) was rare and similar between groups, with no significant difference in time-to-event. Within the GLP-1 CLL cohort, absolute rates of acute pancreatitis (1.2%) and hypoglycemia (3.0%) were low. Exposure to contemporary CLL therapies was uncommon, including BTK inhibitors (3.3%), BCL2 inhibitors (4.4%), anti-CD20 antibodies (rituximab 3.1%, obinutuzumab 2.8%), and ibrutinib specifically (1.9%), with high treatment-free survival rates across CLL therapy exposure (80-95%), indicating that observed outcomes were unlikely due to treatment-related toxicity or differential therapy exposure. Conclusions: GLP-1 receptor agonists have biologically plausible antineoplastic, metabolic, and immunomodulatory effects that may improve inflammation-related infection and survival outcomes in diabetic patients with CLL, warranting further research.