SGLT-2 Inhibitors versus GLP-1 Receptor Agonists for Dementia and Depression in Type 2 Diabetes Mellitus: A Meta-Analysis

Background: The comparative effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) on dementia and depression risk in patients with type 2 diabetes mellitus (T2DM) remain unclear. We conducted a meta-analysis to directly compare the incidence of dementia and depression-related outcomes between users of these two drug classes. Methods: A systematic literature search was conducted across PubMed, Embase, Cochrane Library, and Web of Science from inception to June 1, 2026. Observational studies reporting quantifiable data on dementia or depression-related events in adults with T2DM were included. Detailed information on study design, age, demographic characteristics, eligibility criteria, outcome definitions, and outcome incidence was extracted. Data were pooled using a random-effects model to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Sensitivity analyses involved sequential exclusion of individual studies. Prespecified subgroup analyses examined effect modifiers including geographic region, study design, age, and follow-up duration. Study quality was assessed using the Newcastle-Ottawa Scale, and the overall certainty of evidence and methodological rigor of this meta-analysis were evaluated using the AMSTAR 2 checklist. Results: Thirteen observational studies comprising 1,055,315 participants were included. Compared with GLP-1RA users, SGLT-2i users had lower rates of all-cause dementia (OR 0.85, 95% CI 0.77– 0.94; P = 0.001), vascular dementia (OR 0.75, 95% CI 0.71– 0.80; P < 0.001), Alzheimer’s disease (OR 0.76, 95% CI 0.72– 0.79; P < 0.001), and composite depression-related outcomes (OR 0.76, 95% CI 0.67– 0.88; P = 0.001), including suicide/self-harm (OR 0.69, 95% CI 0.60– 0.80; P < 0.001) and depression/anxiety (OR 0.78, 95% CI 0.65– 0.93; P = 0.006). Subgroup analyses revealed more pronounced differences in Asian populations (dementia: OR 0.86, 95% CI 0.75– 0.99; I 2 = 0%), European cohorts (depression: OR 0.67, 95% CI 0.54– 0.84; I 2 = 83%), and in studies that enrolled younger adults (minimum age 18 years, without an upper age restriction) (dementia: OR 0.79, 95% CI 0.76– 0.81; I 2 = 0%; depression: OR 0.67, 95% CI 0.54– 0.84; I 2 = 83%). Conclusions: In this meta-analysis of observational studies, SGLT-2i use was associated with lower rates of dementia and depression-related outcomes compared with GLP-1RA use in patients with T2DM. Age and geographic region may influence the observed associations. Future randomized controlled trials and studies reporting outcomes stratified by sex, socioeconomic status, and educational level are warranted.