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.