Cognitive impairment risk in adults aged ?60 years treated with SGLT 2 versus DPP 4 inhibitors

Background: Age is the strongest non-modifiable risk factor for dementia, with incidence increasing sharply after 60 years of age. However, most pharmaco-epidemiologic studies evaluate broad adult populations, potentially obscuring treatment-specific effects in older adults. Concurrently, interest has grown in repurposing antidiabetic agents for dementia prevention. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used second-line therapies for type 2 diabetes, yet current guidelines do not provide class-specific recommendations regarding their comparative impact on dementia risk.

Objective: This meta-analysis is the first to directly compare SGLT-2 inhibitors versus DPP-4 inhibitors in reducing dementia risk, with analyses restricted to adults aged ≥60 years to better characterize effects in this high-risk population.

Methods: A systematic literature search of PubMed, Scopus, and Web of Science was conducted on September 19, 2025, to identify comparative studies evaluating dementia outcomes among older adults treated with SGLT-2 or DPP-4 inhibitors. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Certainty of evidence was assessed using the GRADE approach.

Results: Seven studies published between 2023 and 2025 were included, encompassing 743,641 participants. Pooled analysis demonstrated a significantly lower risk of incident all-cause dementia among SGLT-2 inhibitor users compared with DPP-4 inhibitor users (RR 0.72; 95% CI 0.59–0.86; p = 0.0005), with moderate certainty of evidence. Subgroup analyses of three studies further revealed that SGLT-2 inhibitors were associated with a significantly reduced risk of Alzheimer’s disease (RR 0.60; 95% CI 0.56–0.65; p < 0.00001) and vascular dementia (RR 0.54; 95% CI 0.48–0.60; p < 0.00001).

Conclusion: Among adults aged ≥60 years, SGLT-2 inhibitor therapy is associated with a significantly lower risk of all-cause dementia, Alzheimer’s disease, and vascular dementia compared with DPP-4 inhibitors, suggesting potential neuroprotective benefits in older populations with diabetes.

Keywords: SGLT-2 inhibitors; DPP-4 inhibitors; dementia; Alzheimer’s disease; vascular dementia

Nawris Alhassan is a nurse based in the United States with clinical experience in surgical-trauma, step-down ICU, and maternal–newborn nursing. She currently volunteers as a triage nurse at a free health clinic, where she has observed significant gaps in care for older adults with diabetes. These experiences inspired her research on the risk of cognitive impairment in adults aged 60 and older treated with SGLT-2 inhibitors versus DPP-4 inhibitors. She finds healthcare deeply rewarding and plans to pursue further medical training with a focus on clinical research and advancing community health equity.