MON-653 - GLP-1 Receptor Agonists and Dementia-Related Outcomes in Adults With Obesity and/or Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis of Real World Evidence

Background. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been proposed as potential neuroprotective agents; however, evidence from real-world clinical practice settings regarding their association with dementia-related outcomes in high-risk metabolic populations remains inconsistent and difficult to interpret.
Objective. To evaluate the association between GLP-1 receptor agonist use and the risk of dementia-related outcomes, including Alzheimer’s disease, in adults with cardiometabolic conditions.
Methods. We conducted a systematic review and meta-analysis of large-scale observational cohort studies following PRISMA guidelines. PubMed/MEDLINE, Embase, and Scopus were searched from inception to March 2026. Studies utilizing target trial emulation frameworks and evaluating GLP-1 RA use and dementia-related outcomes were included. Study selection, data extraction, and risk of bias assessment were performed independently by multiple reviewers. Adjusted effect estimates were prioritized for quantitative synthesis. Random-effects models were used to pool hazard ratios (HRs) with 95% confidence intervals (CIs). Subgroup analyses were performed according to comparator class. Clinical relevance was assessed using predefined thresholds for meaningful risk reduction (HR 0.7–0.8). Certainty of evidence was evaluated using the GRADE approach.
Results. Eleven studies comprising 5,959,941 participants were included. GLP-1 RA use was associated with a reduced risk of all-cause dementia (HR 0.78, 95% CI 0.62–0.99; I2 =86%) and Alzheimer’s disease (HR 0.77, 95% CI 0.63–0.95; I2 > 80%). In comparator-specific analyses, a stronger association was observed versus DPP-4 inhibitors (HR 0.70, 95% CI 0.51–0.95), whereas the effect was attenuated and of borderline significance versus SGLT2 inhibitors (HR 0.83, 95% CI 0.68–1.00). Confidence intervals for all outcomes included effects below clinically meaningful thresholds. The certainty of evidence was rated as very low across all outcomes.
Conclusions. GLP-1 receptor agonist use was associated with a lower risk of dementia-related outcomes in observational studies; however, the magnitude of this association is modest, heterogeneous, and uncertain in terms of clinical relevance. Differences across comparator therapies and methodological variability further limit interpretation. These findings should be considered exploratory, highlighting the need for more robust
and methodologically consistent research.

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