SGLT2i vs. Metformin for Delirium Prevention in Type 2 Diabetes: A Real-World, Head-to-Head Comparative Study

Objective:

To compare the effectiveness of sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus metformin in preventing delirium among patients with type 2 diabetes (T2D), using real-world data.

Research Design and Methods:

We conducted a retrospective cohort study using the TriNetX global health research network, including 857,171 adults with T2D who initiated either SGLT2i (n=88,012) or metformin (n=769,159) from 2005 to 2025. Propensity score matching (1:1) was used to balance covariates between groups. The primary outcome was incident delirium; secondary outcomes included all-cause mortality. Absolute risk reduction (ARR), adjusted hazard ratios (aHRs), and Kaplan-Meier survival analyses were used to assess outcomes.

Results:

After matching, SGLT2i use was associated with a significantly lower risk of delirium compared to metformin (ARR: 5.03%, 3.97% vs. 9.0%; aHR 0.91, 95% CI: 0.87–0.95, p<0.001). All-cause mortality was also lower in the SGLT2i group (ARR: 9.23%, aHR 0.85, 95% CI: 0.87–0.88, p<0.001). The most pronounced benefits were seen in adults aged ≥80 years (aHR 0.83, p<0.0001), males, and high-risk subgroups using insulin or sedatives.

Conclusions:

This first head-to-head real-world study suggests that SGLT2i may offer superior protection against delirium compared to metformin in T2D patients, especially in high-risk populations. These findings support the inclusion of cognitive outcomes in diabetes treatment decisions and suggest a potential shift in first-line therapy strategies.