GLP-1 Receptor Agonists vs SGLT2 Inhibitors for Alzheimer Disease Risk in Type 2 Diabetes: A Systematic Review and Meta-Analysis

Purpose: People with type 2 diabetes mellitus (DM2) have an increased risk of Alzheimer's Disease (AD). GLP1 receptor agonists (GLP1RAs) and SGLT2 inhibitors (SGLT2i) have emerged as potential interventions to prevent AD and dementia and may provide insights into disease mechanisms. Methods: PubMed, Embase, and Cochrane were searched for randomized controlled trials (RCTs), cohort, and case control studies between January 1, 2006, and April 15, 2025, comparing GLP1RAs and/or SGLT2i in adults with DM2 without cognitive impairment at baseline. A total of 12 studies met the inclusion criteria (1 RCT and 11 cohort studies). The primary outcome was incident AD and dementia, assessed primarily through adjusted hazard ratio (HR). Secondary outcomes were HbA1C levels and their relation to cognitive protection. A regression analysis was performed to assess the variables that could explain the result obtained. Results: GLP1RAs and SGLT2i consistently demonstrated a reduced risk of AD (HR = 0.72; 95% CI, 0.59 to 0.87) and dementia (HR = 0.84; 95% CI, 0.76 to 0.92) compared to other glucose-lowering therapies, with moderate/high heterogeneity and moderate certainty. Also, SGLT2i showed a modest benefit over GLP1RAs in protecting against AD (HR: = 1.07; 95% CI, 1.00 to 1.14; p = 0.0496), and baseline HbA1c was associated with AD risk estimates among SGLT2i users but not among GLP-1RAs users. Conclusion: These findings reinforce the potential of GLP1RAs and SGLT2i as therapeutic options to slow cognitive decline in DM2, possibly depending on glycemic control and central modulation.