Association of SGLT2 inhibitors with suicidality, all-cause mortality, and hospitalization in bipolar disorder: A cohort study of 1.23 million adults

Background Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated promising neuropsychiatric properties in animal research. Aims We aimed to examine whether SGLT2i exposure is associated with reduced incidence of suicidality, all-cause mortality, and hospitalization in bipolar disorder (BD). Method This cohort study utilized the TriNetX network (2008–2025) to identify 1,230,821 adults with BD, including 36,092 SGLT2i users and 1,194,729 non-users. The outcomes were incident suicidality, all-cause mortality, and hospitalization over 5-years of follow-up. Adjusted hazard ratios (aHRs) were estimated using Cox proportional hazards models, with additional 1:1 propensity score matching (PSM) for survival analysis conducted to control for confounding. Subgroup analyses stratified results by sex, race/ethnicity, concurrent mood stabilizer use, and somatic comorbidities. Results SGLT2i exposure was associated with significantly reduced risk of suicidality (aHR 0.75, 95% CI 0.71–0.79), all-cause mortality (aHR 0.55, 95% CI 0.52–0.57), and hospitalization (aHR 0.71, 95% CI 0.69–0.72). Protective associations remained consistent across subgroups, including patients receiving lithium, lamotrigine, or valproate. After PSM (31,001 matched pairs), five-year outcomes favored SGLT2i users: suicidality-free survival 94.51% versus 93.56%, overall survival 88.99% versus 79.57%, and hospitalization-free survival 72.39% versus 66.72% (all p < 0.001). Conclusions In this large cohort of over 1.23 million adults with BD, SGLT2i therapy was associated with substantially lower risks of suicidality, hospitalization, and all-cause mortality, with consistent benefits across demographic and clinical subgroups. These novel findings suggest SGLT2is may represent a promising therapeutic strategy to improve psychiatric and survival outcomes in BD. Prospective RCTs are warranted to evaluate long-term safety and efficacy.