Association between different sodium-glucose co-transporter 2 inhibitors and the risk of dementia: a network...

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), as key therapeutic agents for type 2 diabetes, have in recent years been recognized as potentially exerting neuroprotective effects on the central nervous system. However, systematic comparative evidence remains lacking regarding whether different SGLT2i exhibit differential effects on dementia risk. By conducting a network meta-analysis to compare the association between different SGLT2i and the risk of dementia onset, the relative efficacy of each drug in reducing dementia risk is determined.

A systematic search was conducted across databases including PubMed, Embase, Web of Science, and the Cochrane Library, from their inception to the search cutoff date of 1 December 2025. Randomized controlled trials and observational studies comparing SGLT2i with other antidiabetic medications or placebo, and reporting dementia outcomes, were included. A network meta-analysis employing a random-effects model was conducted. Pooled effect sizes were expressed as hazard ratios with 95% confidence intervals. Relative efficacy among different drugs was ranked using the probability of ranking, whilst heterogeneity and consistency were assessed.

Six cohort studies involving 845,433 patients were included in this analysis. The results of the network meta-analysis indicated that canagliflozin (HR = 0.75, 95% CrI: 0.59, 0.98), Dapagliflozin (HR = 0.75, 95% CrI: 0.59, 0.98), and Empagliflozin (HR = 0.69, 95% CrI: 0.55, 0.85) significantly reduced the risk of dementia onset. Empagliflozin had the highest probability of being ranked as the most effective treatment (81.2%). However, no statistically significant differences were observed between empagliflozin and dapagliflozin or canagliflozin in the network comparisons. For Alzheimer's disease, Dapagliflozin (HR = 0.68, 95% CrI: 0.48, 0.96) and Empagliflozin (HR = 0.62, 95% CrI: 0.45, 0.87) also demonstrated significant risk reduction, whilst direct comparisons between Empagliflozin and other agents showed no significant differences. For vascular dementia, Empagliflozin (HR = 0.63, 95% CrI: 0.46, 0.87) and Canagliflozin (HR = 0.71, 95% CrI: 0.48, 0.98) also demonstrated favorable outcomes.

The findings of this study indicate that dapagliflozin, empagliflozin, and canagliflozin, particularly empagliflozin, demonstrate significant potential in reducing the incidence of dementia and related cognitive impairments. Compared with DPP-4 inhibitors, these agents effectively lower the risk of dementia, Alzheimer's disease, and vascular dementia, offering an effective therapeutic option for diabetic patients, particularly the elderly.