Lower Risk of Incident Dementia with SGLT2 Inhibitor Versus DPP-4 Inhibitor Initiation in Patients with Type 2 Diabetes and Prior Traumatic Brain Injury: A Retrospective Cohort Study.

Purpose: SGLT2 inhibitors have been associated with reduced dementia risk in patients with type 2 diabetes mellitus (T2DM); however, whether this association extends to patients with traumatic brain injury (TBI) remains unknown. Patients and Methods: We conducted a new-user, active-comparator, retrospective cohort study using the TriNetX Research Network. Adults aged ≥50 years with T2DM and a history of TBI who newly initiated an SGLT2 inhibitor were compared with new users of a DPP-4 inhibitor as the active-comparator group between 2014 and 2023. A 1-year landmark period was applied before the outcome was ascertained. The primary outcome was incident dementia during an analytic window extending from day 365 to up to 10 years after the index date. Secondary outcomes included dementia subtypes (ie, vascular dementia or Alzheimer's disease) and all-cause mortality. Propensity score matching, sensitivity analyses, and multivariable Cox regression were performed. Results: After matching, 3,877 patients were included in each group. Incident dementia occurred in 129 patients (3.33%) in the SGLT2 inhibitor group and 243 patients (6.27%) in the DPP-4 inhibitor group (HR, 0.71; 95% CI, 0.57-0.88; p = 0.002). In exploratory secondary analyses, associations were observed for vascular dementia (HR, 0.49; p = 0.005) and all-cause mortality (HR, 0.76; p < 0.001), but not for Alzheimer's disease (HR, 0.90; p = 0.654). A similar exploratory association was observed in the code-defined non-concussion intracranial injury subgroup (HR, 0.65; p = 0.004). Conclusion: In this retrospective cohort study, SGLT2 inhibitor use was associated with a lower risk of incident dementia in patients with T2DM and TBI. These hypothesis-generating findings warrant further prospective validation.