Association of SGLT2 inhibitors and New-Onset Dementia in Non-Diabetic Patients with Heart Failure

Abstract Background Patients with heart failure (HF) are at increased risk of developing dementia, an outcome that substantially worsens clinical prognosis and quality of life. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are well-established in cardiovascular protection, but their association with incident dementia remains poorly documented, particularly in non-diabetic populations. Methods We conducted a retrospective cohort study using the TriNetX Research Network (2016–2025), including adults with HF and no prior history of dementia or diabetes. Patients initiating SGLT2i (n=46,049) were compared with non-users (n=205,010). After 1:1 propensity score matching, 39,979 pairs were analyzed. The primary outcome was new-onset dementia. Secondary outcomes were Alzheimer’s disease, vascular dementia, and all-cause mortality. Additional cardiovascular outcomes included ischemic stroke, myocardial infarction, and end-stage kidney disease (ESKD). Outcomes were assessed using Kaplan–Meier survival analysis and Cox proportional hazards models. Results Over a relatively short median follow-up of 1.2 years in a population with a mean age of 64 years, SGLT2i use was associated with a significantly lower risk of new-onset dementia (HR 0.77, 95% CI 0.68–0.87; p0.001). Risks were also reduced for Alzheimer’s disease (HR 0.58, 95% CI 0.45–0.74; p0.001), vascular dementia (HR 0.41, 95% CI 0.27–0.62; p0.001), and all-cause mortality (HR 0.63, 95% CI 0.61–0.66; p0.001). SGLT2i therapy was further associated with lower risks of ischemic stroke (HR 0.67, 95% CI 0.60–0.75; p0.001) and ESKD (HR 0.75, 95% CI 0.63–0.89; p=0.001). Conclusion In this large, real-world patient with HF without diabetes, SGLT2i therapy was associated with a significantly lower risk of new-onset dementia and all-cause mortality.