Key result
GLP-1 RAs linked to ~33% higher Alzheimer's disease risk versus SGLT2 inhibitors.
Why the study?
Comparative long-term data on dementia, cardiovascular events, and mortality in older adults with T2DM treated with GLP-1 RAs versus SGLT2is are limited.
Do SGLT2 inhibitors reduce the risk of dementia, cardiovascular events, and all-cause mortality compared with GLP-1 receptor agonists in older adults with type 2 diabetes on metformin?
Cohort (n=112,422)
Yes
Do SGLT2 inhibitors reduce the risk of dementia, cardiovascular events, and all-cause mortality compared with GLP-1 receptor agonists in older adults with type 2 diabetes on metformin?
Relative Risk: 1.33 (95% CI 1.18–1.48)
In older adults with type 2 diabetes on metformin, SGLT2 inhibitors may be associated with a lower risk of incident dementia and all-cause mortality compared with GLP-1 receptor agonists.
GLP-1 RA use was associated with higher Alzheimer's risk versus SGLT2is; should not yet change practice and leaves open class-specific effects.
BackgroundType 2 diabetes mellitus (T2DM) increases the risk of cardiovascular and neurocognitive complications. GLP-1 receptor agonists (GLP-1 RAs) and SGLT2 inhibitors (SGLT2is) have pleiotropic effects beyond glycemic control, but comparative long-term data on dementia, cardiovascular events, and mortality in older adults are limited.MethodsThis retrospective cohort study used the TriNetX US Collaborative Network. Adults ≥60 years with T2DM on metformin plus either GLP-1 RAs or SGLT2is (n=56,211 per cohort after matching, 2014-2020) were propensity-score matched on demographic and clinical characteristics. Five-year outcomes included incident Alzheimer's disease, vascular dementia, other dementia, dementia-related medication use, NSTEMI, STEMI, and all-cause mortality.ResultsAfter propensity-score matching, GLP-1 RA use was associated with higher risks of Alzheimer's disease (RR 1.33, 95% CI 1.18-1.48), vascular dementia (RR 1.56, 95% CI 1.39-1.76), other dementia (RR 1.33, 95% CI 1.21-1.47), dementia-related medication initiation, and all-cause mortality (RR 1.11, 95% CI 1.08-1.15) compared with SGLT2is. NSTEMI and STEMI risks did not differ significantly between groups.ConclusionsIn older adults with T2DM, SGLT2is were associated with lower risks of dementia, dementia-related medication use, and all-cause mortality compared with GLP-1 RAs in propensity-score matched cohorts. These observational findings are hypothesis-generating and should be confirmed in prospective studies.
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Mortada et al. (2026) conducted a cohort in Type 2 diabetes mellitus (n=112,422). GLP-1 receptor agonists vs. SGLT2 inhibitors was evaluated on Incident Alzheimer's disease (RR 1.33, 95% CI 1.18-1.48). GLP-1 RA exposure was associated with a higher risk of incident Alzheimer's disease (RR 1.33; 95% CI 1.18-1.48) and all-cause mortality compared with SGLT2 inhibitors in older adults.
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