Dapagliflozin restores odour-induced functional integration of primary olfactory cortex circuit but not olfactory-related regional brain activation in patients with type 2 diabetes: A 16-week randomised comparative study.

AIMS: Although some hypoglycaemic agents have been suggested to possess neuroprotective effects, their mechanisms and efficacy remain controversial. We aimed to investigate the effects of dapagliflozin, liraglutide or acarbose treatment on the directed functional connectivity (FC) of the primary olfactory cortex (POC) circuit and regional activation under odour stimulation in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: The 16-week randomised, prospective, parallel-group, and open-label trial included 36 patients with T2D inadequately controlled with metformin, who were randomised (1:1:1) to receive dapagliflozin, liraglutide or acarbose. Meanwhile, 36 healthy controls were recruited. All participants underwent olfactory task functional magnetic resonance imaging, along with a battery of olfactory and cognitive tests, both at baseline and postintervention. RESULTS: After 16 weeks, dapagliflozin restored odour-induced functional integration of the POC-sensorimotor cortex-middle temporal cortex circuit (Gaussian random field correction applied), whereas liraglutide and acarbose did not. Dapagliflozin also tended to improve attention (p = 0.071). In contrast, liraglutide enhanced odour-induced activation in the left hippocampus, which was not observed with dapagliflozin and acarbose. The decreased odour-induced directed FC was associated with changes in lipid levels, olfactory threshold, executive function and memory performance (all p < 0.05). CONCLUSIONS: These results suggest that dapagliflozin and liraglutide exhibit distinct neuroprotective effects. While liraglutide enhances activation in local olfactory-related regions, dapagliflozin facilitates functional integration within neural circuits. This highlights the importance of targeting both metabolic and neural pathways to manage diabetes-related cognitive decline.