TYPE 2 diabetes (T2D) is not only a metabolic disorder but is increasingly recognised as a risk factor for cognitive decline and dementia. As newer classes of glucose-lowering drugs become more widely used, their potential benefits beyond glycaemic control have come under scrutiny. A recent study investigated whether glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are associated with a reduced risk of Alzheimer’s disease and related dementias (ADRD) in people with T2D. A key finding revealed that both drug classes were linked to a statistically significant reduction in dementia risk compared to other second-line therapies.
The researchers conducted a target trial emulation using real-world data from the OneFlorida+ Clinical Research Consortium, covering patient records from January 2014 to June 2023. Eligible participants were aged 50 and over, had a diagnosis of tT2D, and no prior history of dementia or use of dementia-specific treatments. Patients were grouped into three cohorts: GLP-1RA vs other glucose-lowering drugs (GLDs), SGLT2i vs other GLDs, and GLP-1RA vs SGLT2i. The study used Cox proportional hazards models with inverse probability of treatment weighting to minimise confounding variables and better simulate a randomised trial.
In total, the study analysed data from 92,160 individuals across the three comparison groups. Initiation of GLP-1RAs was associated with a 33% reduced risk of developing ADRD compared to other GLDs (hazard ratio [HR] 0.67; 95% CI: 0.47–0.96), with an incidence rate difference of −2.26 per 1,000 person-years. Similarly, SGLT2i users experienced a 43% lower risk (HR 0.57; 95% CI: 0.43–0.75), corresponding to an incidence rate difference of −3.05 per 1,000 person-years. However, there was no statistically significant difference between the two newer drug classes (HR 0.97; 95% CI: 0.72–1.32).
These findings suggest that both GLP-1RAs and SGLT2is may offer neuroprotective benefits in addition to managing blood glucose levels, an insight that could influence prescribing practices for patients with type 2 diabetes at risk of cognitive decline. However, this observational study has limitations, including potential residual confounding and reliance on clinical coding for dementia diagnosis. Randomised controlled trials are needed to confirm causality and better understand underlying mechanisms.
Reference
Tang H et al. GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias. JAMA Neurol. 2025;DOI: 10.1001/jamaneurol.2025.0353.
