Metformin vs. second-line therapy for delirium prevention in type 2 diabetes: A multinational study

Type 2 diabetes mellitus (T2DM) is a major risk factor for neurocognitive impairment, with delirium predicting dementia. While metformin may offer neuroprotection, prior studies face selection bias. This study examines the association between metformin use and delirium risk compared to dipeptidyl peptidase-4 inhibitors (DPP-4i).

This multinational cohort study analyzed 860,388 T2DM patients using the TriNetX network. After propensity score matching, 84,221 metformin users were compared to 84,221 DPP-4i users. The primary outcome was delirium incidence, with secondary outcomes including all-cause mortality. Cox proportional hazards models estimated adjusted hazard ratios (AHRs), and sensitivity analyses addressed competing risks.

Metformin use was linked to a lower risk of delirium (AHR, 0.86; 95% CI, 0.83-0.89) and mortality (AHR, 0.76; 95% CI, 0.74-0.78). Subgroup analyses confirmed consistent delirium risk reduction across age, sex, and glycemic control. Sensitivity analyses upheld this effect, mitigating survival bias concerns.

In this large-scale study, metformin use was associated with reduced delirium and mortality risk compared to DPP-4i, reinforcing its role as the preferred first-line T2DM therapy, especially in patients at risk for neurocognitive decline.