Baseline HbA1c and dementia risk at SGLT2i initiation in type 2 diabetes.

Abstract

Aim: Type 2 diabetes (T2DM) is a major modifiable risk factor for dementia, yet the optimal timing of sodium-glucose cotransporter-2 inhibitor (SGLT2i) initiation for cognitive protection remains unclear. HbA1c is routinely measured, but its role in predicting dementia risk at the time of SGLT2i initiation is unknown.

Methods: We performed a retrospective cohort study using the Global Collaborative Network (>150 health systems worldwide). Adults with T2DM initiating SGLT2i between 2005 and 2025 were included, applying a 456-day washout to reduce protopathic and immortal time bias. Patients were stratified by baseline HbA1c (<7.0%, 7.0%-8.9%, ≥9.0%) and matched 1:1 by propensity scores for demographics, comorbidities, medications and utilization. The primary outcome was incident all-cause dementia; secondary endpoints included dementia subtypes, major adverse cardiovascular events (MACE), major adverse kidney events (MAKE) and osteoporotic fracture as a negative control.

Results: Among matched cohorts (median follow-up 4.2 years), dementia risk increased with higher HbA1c: HR 1.32 (7.0%-8.9%) and HR 1.68 (≥9.0%) versus <7.0%. These associations were consistent but attenuated in propensity-score-matched models (HR 1.08 and 1.28). Associations were strongest for vascular dementia and consistent across sensitivity analyses and cause-specific competing-risk Cox models.

Conclusions: Baseline HbA1c at SGLT2i initiation predicts dementia risk. Delaying therapy until HbA1c ≥9% may forfeit protection, whereas earlier use may safeguard brain, heart and kidney health.