OBJECTIVES: Previous biological evidence suggested that both sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1-RA) use might be associated with a neuroprotective potential in the context of type 2 diabetes mellitus (T2DM). Therefore, we performed a population-based cohort study to investigate associations of SGLT2i and GLP-1-RA with the risk of developing dementia in people with T2DM, respectively.

METHODS: Using the real-world primary care-based database THIN®UK, two independent cohort studies employing a new user design were performed to compare the risk of all-cause dementia, Alzheimer’s disease, and vascular dementia between (i) SGLT2i and (ii) GLP-1-RA against Dipeptidyl peptidase-4 inhibitors (DPP-4i) among people with T2DM (≥40 years).

RESULTS: For the primary outcome of all-cause dementia, 11,679 SGLT2i users were compared with 21,329 DPP-4i users and 9,037 GLP-1-RA users were compared with 37,317 DPP-4i users, respectively. With a median follow-up period of 1.3 (interquartile range: 0.5 – 2.4) years, the initiation of SGLT2i vs DPP-4i was potentially associated with a reduction in the risk of all-cause dementia (adjusted HR, 0.77; 95% CI, 0.57-1.05) and vascular dementia (adjusted HR, 0.87; 95% CI, 0.50-1.51), and unchanged risk of Alzheimer’s disease (adjusted HR, 0.97; 95% CI, 0.54-1.73). Over a median follow-up of 1.8 (interquartile range: 0.8 – 3.8) years, compared to DPP-4i users, GLP-1-RA users may have a lower risk of Alzheimer’s disease (adjusted HR, 0.87; 95% CI, 0.52-1.45), but not all-cause dementia (adjusted HR, 0.92; 95% CI, 0.74-1.14) and vascular dementia (adjusted HR, 1.00; 95% CI, 0.68-1.46).

CONCLUSIONS: This study suggests that the initiation of SGLT2i might be associated with reduced risks of vascular dementia, while the initiation of GLP-1-RA might be associated with a lower risk of Alzheimer’s disease, compared to DPP-4i initiators. However larger and diverse data is required to assert the significance of the findings.