Background: - Type 2 diabetes (T2D) increases the risk of dementia by 1.5 to 2.5 times. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and metformin, widely used antidiabetic therapies, have demonstrated potential neuroprotective effects. Their comparative effectiveness in dementia prevention remains unknown.
Methods: - This retrospective cohort study used the TriNetX global federated network, analyzing de-identified records from over 98 healthcare organizations. Adults with T2D initiating SGLT2i or metformin as first-line therapy were propensity score-matched (1:1). The primary outcome was overall dementia incidence, including vascular dementia, Alzheimer's disease, and other subtypes. Secondary outcomes included all-cause mortality. Time-to-event outcomes were assessed using Kaplan-Meier curves and Cox models.
Results: - Among 74,975 matched patients in each cohort, SGLT2i use was associated with a lower incidence of overall dementia: 2.7 % vs. 6.9 %: adjusted hazard ratio (aHR) 0.80 [95 % CI 0.76;0.84]. Reductions were observed in vascular dementia (0.8 % vs. 2.0 %; aHR 0.87), Alzheimer's dementia (1.1 % vs. 3.2 %; aHR, 0.76), and all-cause mortality (6.8 % vs. 15.4 %; aHR, 0.92). Benefits were pronounced in older adults, particularly those aged ≥80 years.
Conclusions: - SGLT2is significantly reduced dementia risk and mortality compared to metformin in T2D patients. These findings suggest SGLT2is may offer superior neuroprotective benefits, underscoring their potential as a first-line therapy for T2D. Further randomized trials are needed to confirm these results.
Keywords: Comparative effectiveness; Dementia prevention; Metformin; Sodium-glucose cotransporter 2 inhibitors; Type 2 diabetes mellitus.
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