Diabetes Obes MetabBrain & NeurologicalCohortDecember 22, 2025

Association between glucagon-like peptide-1 receptor agonists and risk of dementia in older adults with type 2 diabetes: A target trial emulation.

Zhou T, Tang H, Zhang B, Zhang D, Lu Y, Li L, Chen J, Chen Y, Asch DA, Chen Y

Key Finding

In older adults with type 2 diabetes, GLP-1 medications reduced dementia risk by 24% compared to DPP4 inhibitors but increased risk by 53% compared to SGLT2 inhibitors over 2-3 years of follow-up.

What This Study Found

Think of this study as a horse race where researchers wanted to see which diabetes medication helps the brain stay sharpest longest. They followed over 15,000 older adults with type 2 diabetes who started one of three different medication types: GLP-1 receptor agonists (like Ozempic), DPP4 inhibitors, or SGLT2 inhibitors. Like matching runners by fitness level before a race, they used statistical matching to ensure fair comparisons between groups. The results were surprising - GLP-1 medications weren't universally protective. Compared to DPP4 inhibitors, GLP-1s were like having better brain armor, reducing dementia cases from 148 to 109 people (a 24% lower risk). But when racing against SGLT2 inhibitors, GLP-1s actually fell behind, with 127 dementia cases versus only 64 in the SGLT2 group (53% higher risk). This suggests SGLT2 inhibitors might be the unexpected champion for brain protection, not the heavily marketed GLP-1s.

Statistics Decoded

HR 0.76 (95% CI 0.59-0.97) for GLP-1s vs DPP4 inhibitors means GLP-1 users had about 24% lower dementia risk - like reducing your chances from 100 to 76. The confidence interval (0.59-0.97) means we're 95% confident the true protection is somewhere between 41% and 3% - this barely crossed the 'probably not luck' threshold. HR 1.53 (95% CI 1.13-2.07) for GLP-1s vs SGLT2 inhibitors means 53% higher dementia risk - like increasing chances from 100 to 153. This confidence interval (1.13-2.07) is more robust, suggesting the increased risk is between 13% and 107%. The actual event numbers (109 vs 148, and 127 vs 64) show the absolute differences weren't huge, but the patterns were consistent.

Why This Matters

This challenges the assumption that newer, popular diabetes drugs are automatically better for brain health - SGLT2 inhibitors, not GLP-1s, appear most protective against dementia in older diabetic adults. Doctors may need to weigh brain protection alongside weight loss and blood sugar control when choosing diabetes medications for older patients.

Original Abstract

Type 2 diabetes (T2D) is associated with increased dementia risk, but comparative data across newer glucose-lowering therapies remain limited. We examined whether the initiation of GLP-1 receptor agonists (GLP-1 RAs) was associated with incident dementia compared with DPP4 inhibitors (DPP4is) and SGLT2 inhibitors (SGLT2is) in older adults with T2D. We conducted a retrospective cohort study emulating a target trial using electronic health records from the University of Pennsylvania Health System (2019-2024), with external validation in the TriNetX U.S. Collaborative Network. Adults aged ≥50 with T2D, no prior dementia, and no GLP-1 RA, DPP4i, or SGLT2i use in the previous year were eligible. New GLP-1 RA users were propensity-score matched (1:1) to DPP4i users (n = 6677 pairs) and SGLT2i users (n = 8434 pairs). The outcome was incident dementia, defined by ICD-10-CM codes. Cox proportional hazards models estimated hazard ratios (HRs), with multiple sensitivity and subgroup analyses performed. Over a median follow-up of 3.0 years (GLP-1 RA vs. DPP4i) and 2.4 years (GLP-1 RA vs. SGLT2i), GLP-1 RA use was associated with a lower dementia risk versus DPP4is (109 vs. 148 events; HR 0.76, 95% CI 0.59-0.97), but a higher risk versus SGLT2is (127 vs. 64 events; HR 1.53, 95% CI 1.13-2.07). Findings were consistent across sensitivity and subgroup analyses. External validation confirmed reduced dementia risk versus DPP4is but not versus SGLT2is. In this large real-world cohort, GLP-1 RAs were associated with lower dementia risk than DPP4is but higher risk than SGLT2is. Prospective, biomarker-informed studies are needed to clarify mechanisms and inform treatment choices in older adults with T2D.