Association of SGLT2 inhibitors and new-onset dementia in non-diabetic patients with heart failure
A Hacil, O H HanonAbstract
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 median follow-up of 1.2 years, SGLT2i use was associated with a significantly lower risk of new-onset dementia (HR 0.77, 95% CI 0.68–0.87; p<0.001). Risks were also reduced for Alzheimer’s disease (HR 0.58, 95% CI 0.45–0.74; p<0.001), vascular dementia (HR 0.41, 95% CI 0.27–0.62; p<0.001), and all-cause mortality (HR 0.63, 95% CI 0.61–0.66; p<0.001). SGLT2i therapy was further associated with lower risks of ischemic stroke (HR 0.67, 95% CI 0.60–0.75; p<0.001) and ESKD (HR 0.75, 95% CI 0.63–0.89; p=0.001).
Conclusions
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. These findings suggest potential neuroprotective benefits of SGLT2 inhibitors and highlight the importance of incorporating cognitive outcomes into future heart failure trials.