Association between gliflozins use and outcomes in adults with sepsis: A multicenter retrospective cohort study among Veterans

Abstract: Background: Sodium-glucose-cotransporter-2 inhibitors (SGLT2i) improve cardiorenal outcomes in patients with diabetes, chronic heart failure or kidney disease, but their effects in acute settings are unknown. This study evaluated the impact of SGLT2i use on 90-day mortality, major adverse cardiovascular events (MACE), and acute kidney injury (AKI) in patients with sepsis. Methods: A propensity-matched, multicenter retrospective cohort study was conducted using the Veterans Affairs Healthcare System (VAHCS) National Registry from January 1, 2017, to December 31, 2023. Adult veterans with sepsis using SGLT2i in the year prior to admission were compared to a 1:4 matched control group, adjusting for demographics, comorbidities, medications, and sepsis characteristics. We conducted a sensitivity analysis using SuperLearner to estimate the propensity score and perform matching. Chronic SGLT2i use was defined as >= 3 outpatient fills or <180-day gap from the last fill according to the VAHCS pharmacy registries. Primary outcome was 90-day mortality; secondary outcomes included MACE within 90 days, AKI, MAKE-30, EDKA, and hospital length of stay. Results: Among 197,879 eligible patients, 5.15% were SGLT2i prior users and 94.85% were non-users. After propensity-matching, 10,200 SGLT2i users (mean [SD] age: 70.0 [9.1]; 97.5% male, and 72.4% white) were compared to 37,785 controls (mean [SD] age: 70.2 [9.4]; 97.3% male, and 72.5% white). SGLT2i prior use was associated with a significantly reduced risk of 90-day mortality (OR = 0.591, 95% CI: 0.557-0.628), AKI (OR = 0.862, 95% CI: 0.809-0.918), and MAKE-30 (OR = 0.725, 95% CI: 0.683-0.771). There was no association between SGLT2i use and MACE (OR = 0.986, 95% CI: 0.931-1.044). SGLT2i users had shorter hospital stays (13.4 vs. 18.1 days). However, SGLT2i use was associated with a significantly increased risk of EDKA (OR = 2.371, 95% CI: 2.106-2.671). Conclusion: SGLT2i users prior to hospitalization for sepsis had reduced risk of 90-day mortality and AKI, suggesting chronic organ protection decreases the risk of organ failure when sepsis develops.