Patients with type 2 diabetes who received glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors, had a lower risk of developing Alzheimer's disease and related dementias compared with those receiving other glucose-lowering drugs, according to a new study.
In the target-trial emulation study, published in JAMA Neurology, investigators from the University of Florida found that both glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduced the risk of Alzheimer's disease and related dementias (ADRD) compared with other second-line glucose-lowering drugs, with no statistically significant difference in efficacy between the two.
"We found about 33% to 43% lower risk," said senior study author Jingchuan Guo, MD, of the University of Florida College of Pharmacy, in an interview with Conexiant News. "These findings may have implications for aging-related health outcomes."
Using electronic health record data from the OneFlorida+ Clinical Research Consortium covering January 2014 to June 2023, investigators recruited 33,858 patients in the GLP-1 RA versus other GLD cohort, 34,185 in the SGLT2i vs other GLD cohort, and 24,117 in the GLP-1 RA versus SGLT2i cohort. All of the participants were 50 years or older with type 2 diabetes and no prior diagnosis of ADRD or antidementia treatment.
After adjusting for potential confounders using inverse probability of treatment weighting, the investigators found the incidence rate of ADRD was lower in GLP-1 RA initiators compared with other GLD initiators (rate difference = −2.26 per 1,000 person-years).
SGLT2i initiators demonstrated a stronger protective association, with a lower incidence compared with other GLD initiators (rate difference = −3.05 per 1,000 person-years).
Notably, when comparing the two medication classes directly, there was no statistically significant difference between GLP-1 RAs and SGLT2is.
The findings remained consistent across multiple sensitivity and subgroup analyses, strengthening the robustness of the results. The investigators noted that among individual GLP-1 RAs, semaglutide specifically was associated with a significantly decreased risk of ADRD compared with SGLT2is (HR = 0.54).
While the exact mechanisms remain unclear, the investigators suggested several potential explanations for the observed neuroprotective effects. GLP-1 RAs have been shown to reduce neuroinflammation, improve insulin signaling in the brain, and promote neurogenesis. They may also enhance synaptic plasticity and reduce amyloid-beta and tau pathology, hallmarks of Alzheimer's disease.
Similarly, SGLT2is may exert neuroprotection through improved cerebral blood flow, reduced oxidative stress, and enhanced mitochondrial function. Additionally, both medication classes have demonstrated improved metabolic control and vascular outcomes, which may contribute to better cognitive outcomes given the established link between vascular health and cognitive function.
The investigators acknowledged several limitations, including the potential for residual confounding despite extensive covariate adjustment, relatively short follow-up periods (mean = 1.95–3.76 years), and reliance on diagnosis codes to identify ADRD cases. They also noted that although associations were found, causality has not been established.
"I see our study as an initial point. It provides the initial evidence of the promising feature of GLP-1 [RAs] in lowering the risk of neurodegenerative conditions," said Dr. Guo. "[However], our study used a regional-based population, so future studies are definitely needed to further confirm and validate the results to see whether the benefits are consistent across different populations."
These findings add to growing evidence supporting the potential cognitive benefits of newer diabetes medications and suggest possible expanded clinical applications beyond glycemic control.
Disclosures can be found in the study.
