Frontiers in Pharmacology · Oct 15, 2026

Exploring the impact of GLP-1 analogues and DPP-4 inhibitors on cognitive decline in elderly patients with type 2 diabetes: a competing risks analysis from a real-world cohort

By Battini V, Biganzoli G, Di Pierro F et al.

BACKGROUND: Older adults with type 2 diabetes (T2DM) face an increased risk of cognitive decline. While glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown neuroprotective effects, comparative evidence versus dipeptidyl peptidase-4 inhibitors (DPP-4i) in real-world older populations is limited. METHODS: We conducted a retrospective cohort study using health administrative data, including individuals aged ≥65 initiating GLP-1RAs or DPP-4i therapy between 2010 and 2018. Patients with prior cognitive disorders were excluded. The primary outcome was a composite of incident cognitive disorders or death. Analyses were adjusted for clinical and demographic characteristics. Marginal structural models and competing risks methods were used to estimate treatment effects. Both an 'As treated' (AT) and an 'Intention to Treat' (ITT) designs were employed. RESULTS: A total of 2,579 individuals were included (GLP-1RAs: 393; DPP-4i: 2,186), with a median follow-up of 44 months in the AT analysis. GLP-1RAs users had a lower risk of the composite outcome, especially in the early follow-up (HR at 2 years: 0.5 [95% CI: 0.26-0.93]). Competing-risk analysis showed a lower early risk of death without prior cognitive disorders among GLP-1RA initiators. The point estimate of sub-distribution HR was 0.4 also for cognitive disorders, yet not statistically significant because of the small number of events. CONCLUSION: GLP-1RAs use was associated with a lower early risk of the composite outcome of cognitive disorders or death compared with DPP-4i in older adults with T2DM. The observed association with cognitive disorders alone was directionally consistent with a potentially lower risk, but the very small number of events precludes firm conclusions regarding a protective effect on cognitive outcomes. Longer follow-up and cognitive-specific evaluations are needed to confirm these associations.

doi.org/10.3389/fphar.2026.1822158 Open access PubMed 42959192 Populations