Long‐term delirium and survival outcomes in patients treated with GLP‐1 receptor agonists versus metformin in type 2 diabetes: A population‐based cohort study

Abstract Aim Type 2 diabetes mellitus (T2DM) is associated with an increased risk of delirium and mortality. While glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) provide metabolic and neuroprotective benefits, their long‐term impact on delirium risk remains uncertain. This study compares GLP‐1 RAs and metformin in relation to delirium and mortality in T2DM patients using real‐world data. Methods A retrospective cohort study was conducted using the TriNetX global federated research network, which primarily comprises U.S.‐based healthcare organisations (approximately 85%), with additional sites in Europe, Asia‐Pacific and the Middle East. Adults (≥18 years) with T2DM who initiated GLP‐1 RAs or metformin were included. Propensity score matching (PSM) balances baseline characteristics. The primary outcome was incident delirium; the secondary outcome was all‐cause mortality. Kaplan–Meier survival curves and time‐dependent Cox models assessed associations. Results After 1:1 PSM ( N = 63 096 per group), GLP‐1 RAs showed no overall reduction in delirium risk (AHR: 0.98, 95% CI: 0.94–1.02, p = 0.3628). However, they were protective in the first 5 years (AHR: 0.89, 95% CI: 0.86–0.92, p < 0.0001) but increased delirium risk between 5 and 10 years (AHR: 1.15, 95% CI: 1.04–1.26, p = 0.0046). Subgroup analysis revealed lower delirium risk with GLP‐1 RAs in middle‐aged patients (40–79 years) and those with HbA1c <7.5%. Higher risk was observed in Asian and Native Hawaiian/Pacific Islander populations. However, these findings should be interpreted with caution due to the relatively small subgroup sizes and the limited representativeness of these groups within the predominantly U.S.‐based database, in which Asian and Native Hawaiian/Pacific Islander patients together accounted for less than 5% of the overall cohort. Mortality risk was lower in absolute terms for GLP‐1 RAs (6.28% vs. 9.95%) but higher in long‐term hazard (AHR: 1.16, 95% CI: 1.12–1.21, p < 0.001). Conclusions GLP‐1 RA use was initially associated with a lower risk of delirium, but this association reversed over time. Subgroup variations suggest individualised treatment considerations. Metformin remains a preferred option given its stable cognitive and survival benefits.