To compare the efficacy and long term safety of Glucagon-like peptide-1 receptor agonists (GLP-1RAs) to sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in reducing Alzheimer’s and related dementia (ADRD) in patients with Type 2 Diabetes.

T2DM is a well-established risk factor for ADRD, potentially through mechanisms involving insulin resistance, vascular dysfunction, and neuroinflammation. Both GLP-1RAs and SGLT2i have demonstrated individual neuroprotective and cognitive benefits in preclinical and observational studies. However, direct head-to-head comparative evidence on their relative impact on ADRD incidence remains limited.

A systematic search of PubMed, ScienceDirect, and ClinicalTrials.gov was conducted following PRISMA guidelines. Observational cohort studies comparing the risk of clinically diagnosed ADRD between GLP-1RA and SGLT2i users were included. Study quality, effect estimates, and heterogeneity were assessed using standardized criteria.

Four studies filled the necessary criteria and were included in the systematic review. The pooled meta-analysis yielded a Hazard Ratio (HR) of 1.09 (95% CI: 1.00-1.19) Showing no statically significantDifference in the risk of ADRD between GLP1RA and SGLT2i (p=0.06). However, the Leave One Out Sensitivity Analysis revealed that omitting Tang.et.als study resulted in a HR of 1.10 (95% CI: 1.00-1.21), demonstrating that SGLT2i is associated with a marginally but significantly lower risk of ADRD.

The safety profiles were consistent with established data, characterized by transient gastrointestinal events for GLP-1RAs and genitourinary infections for SGLT2i.

SGLT2 inhibitors offer a marginally greater reduction in the risk of Alzheimer's Disease and Related Dementias compared to GLP-1 Receptor Agonists. Implications of the study, highlight the need for further research with extended follow-up period.