Aims: 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 analysed. The primary outcome was new-onset dementia. Secondary outcomes were Alzheimer's disease, vascular dementia, and all-cause mortality. Additional cardiovascular outcomes included ischaemic 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 [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.68-0.87; P < .001]. Risks were also reduced for Alzheimer's disease (HR 0.58, 95% CI 0.45-0.74; P < .001), vascular dementia (HR 0.41, 95% CI 0.27-0.62; P < .001), and all-cause mortality (HR 0.63, 95% CI 0.61-0.66; P < .001). SGLT2i therapy was further associated with lower risks of ischaemic stroke (HR 0.67, 95% CI 0.60-0.75; P < .001) and ESKD (HR 0.75, 95% CI 0.63-0.89; P = .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.
Keywords: Alzheimer's disease; Cardiovascular outcomes; Heart failure; Incident dementia; SGLT2 inhibitors; Vascular dementia.
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