Glucagon-like peptide-1 receptor agonist initiation and risk of clinically recorded Alzheimer’s disease–type dementia in older adults with type 2 diabetes: a target trial emulation using causal machine learning

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Abstract Background Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose cotransporter-2 (SGLT2) inhibitors are increasingly used for type 2 diabetes. Despite established metabolic, cardiovascular, and renal benefits, it remains uncertain whether GLP-1 receptor agonists are associated with longer clinically recorded Alzheimer’s disease (AD)-type dementia-free survival than sulfonylureas (SU) or SGLT2 inhibitors. Methods Using All of Us electronic health records, we emulated target trials among adults aged ≥ 55 years with type 2 diabetes, a 12-month washout, and no prior dementia. We compared GLP1 receptor agonists with SU and SGLT2 inhibitors. Propensity score weighting and doubly robust estimation addressed confounding. Causal survival forests estimated individualized treatment effects on 48-month RMST free from clinically recorded AD-type dementia. Findings In the GLP-1 receptor agonist versus SU comparison (6,328 individuals; 48-month NNT ≈ 202), initiation was associated with a small but statistically significant increase in AD-type dementia-free survival (ATE 0 · 21 months; 95% CI: 0 · 07–0 · 35). The highest-benefit stratum gained 0 · 45 months (95% CI: 0 · 28–0 · 62). In the SGLT2 inhibitor comparison (3,070 individuals; 48-month NNT ≈ 245), the average effect was not statistically significant (ATE 0 · 06 months; 95% CI: − 0 · 18–0 · 31), but treatment effects were heterogeneous. The highest-benefit stratum gained 0 · 83 months (95% CI: 0 · 49– 1 · 17). Predicted benefit was associated with older age, insulin use, lower HbA1c, and lower BMI. Interpretation GLP-1 receptor agonists may delay clinically recorded AD-type dementia compared with SU. Comparative effectiveness versus SGLT2 inhibitors may vary, supporting study. Given hypothesis-generating findings, diabetes treatment selection should remain guided by glycemic, cardiovascular, renal, and patient-centered considerations. Funding German Federal Ministry of Research, Technology and Space (03LWH0181B).

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