Association of sodium‐glucose cotransporter 2 inhibitors with risk of incident dementia and all‐cause mortality in older patients with type 2 diabetes: A retrospective cohort study using the TriNetX US collaborative networks

Abstract Background Limited evidence exists to support any specific medication over others to prevent dementia in older patients with type 2 diabetes (T2D). We investigated whether treatment with sodium‐glucose cotransporter 2 (SGLT‐2) inhibitors is associated with a lower risk of incident dementia and all‐cause mortality, relative to dipeptidyl peptidase‐4 (DPP‐4) inhibitors and glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA). Methods In this retrospective, active‐comparator cohort study, we used data from the TriNetX electronic health records network. Our primary cohort comprised patients with T2D aged ≥50 years, registered between January 2012 and December 2022. Patients with a history of dementia were excluded. We used Kaplan–Meier survival analysis to estimate the incidence of dementia and all‐cause mortality in our cohort after they had used glucose‐lowering drugs for at least 12 months. Propensity score matching was performed to balance the SGLT‐2 inhibitor, DPP‐4 inhibitor and GLP‐1 RA cohorts. Subgroup analyses for sex and age were also conducted. Results Our first cohort comprised 193 948 patients treated with metformin and SGLT‐2 inhibitors and an equal number of patients treated with metformin and DPP‐4 inhibitors. In this cohort, the risk of dementia and all‐cause mortality was lower in patients treated with SGLT‐2 inhibitors than in those treated with DPP‐4 inhibitors (hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.59–0.65, for dementia; HR: 0.54, 95% CI: 0.52–0.56, for all‐cause mortality). Our second cohort comprised 165 566 patients treated with metformin and SGLT‐2 inhibitors and an equal number of patients treated with metformin and GLP‐1 RAs. In this cohort, the risk of dementia and all‐cause mortality was lower in those treated with SGLT‐2 inhibitors than in those treated with GLP‐1 RAs (HR: 0.92, 95% CI: 0.87–0.98, for dementia; HR: 0.88, 95% CI: 0.85–0.91, for all‐cause mortality). Conclusions The use of SGLT‐2 inhibitor was associated with a lower risk of incident dementia and all‐cause mortality in older adults with T2D compared to DPP‐4 inhibitor and GLP‐1 RA.