Associations of metformin-based antidiabetic combinations and Alzheimer’s disease onset: a retrospective EHR cohort study

Abstract Background Type 2 Diabetes (T2D) is an established risk factor for dementia and Alzheimer’s Disease (AD). Previous literature primarily examines the neuroprotective benefits of antidiabetic medications (metformin, SGLT2 inhibitors, and GLP-1 receptor agonists) in isolation. This study evaluates the association between individual and combined effects of metformin, SGLT2 inhibitors, and GLP-1 receptor agonists on AD incidence within a T2D population. Methods We stratified a cohort of 69,208 drug-exposed T2D individuals (including 444 AD patients) into six mutually exclusive medication groups consisting of five exposure groups and one active-comparator reference group. The five drug exposure groups are metformin Only ( n = 182), GLP-1 Only ( n = 8), SGLT2 Only ( n = 8), metformin+SGLT2 ( n = 30), metformin + GLP-1 ( n = 42). These groups were matched 1:1 to an Other Medications ( n = 236) reference group based on age, sex, race, and ethnicity to control for demographic confounders. For statistical analysis, cox hazards, cumulative incidence, and density and box plots were utilized to analyze the correlation between these medications and Alzheimer’s onset. Results The metformin + GLP-1 receptor agonist group (HR 0.41) was associated with the greatest reduction in AD hazard (HR 0.41), representing a 59% lower hazard compared to alternative therapies. Metformin+SGLT2 (HR 0.56) and metformin Only (HR 0.75) also showed significant associations with lower AD risk, corresponding to 44% and 25% lower hazards, respectively. Monotherapies for GLP-1 and SGLT2 did not reach statistical significance, potentially due to smaller sample sizes. Conclusions Our findings indicate that the use of metformin alone and in combination with GLP-1 or SGLT2 agents are associated with a significant delay in AD onset. These findings warrant further investigation through prospective clinical trials to evaluate clinical efficacy and mechanistic studies to elucidate the underlying biological pathways, as definitive clinical efficacy cannot be established from observational data alone.