Neuroprotective effects of GLP-1 receptor agonists in neurodegenerative Disorders: A Large-Scale Propensity-Matched cohort study

Background: GLP-1 receptor agonists, traditionally used for treating type 2 diabetes mellitus and obesity, have demonstrated anti-inflammatory properties. However, their potential neuroprotective effects in neurodegenerative disorders remain unclear. Objective: To evaluate the impact of GLP-1 receptor agonists on the risk of developing various neurodegenerative conditions in obese patients. Methods: This comprehensive retrospective cohort study analyzed data from 5,307,845 obese adult patients across 73 healthcare organizations in 17 countries. Propensity score matching was performed, resulting in 102,935 patients in each cohort. We compared the risk of developing neurodegenerative disorders between obese patients receiving GLP-1 receptor agonist therapy and those who were not. Results: Obese patients treated with GLP-1 receptor agonists showed significantly lower risks of developing Alzheimer's disease (RR = 0.627, 95 %CI = 0.481-0.817), Lewy body dementia (RR = 0.590, 95 %CI = 0.462-0.753), and vascular dementia (RR = 0.438, 95 %CI = 0.327-0.588). The risk reduction for Parkinson's disease was not statistically significant overall (RR = 0.784, 95 %CI = 0.580-1.058) but was significant for semaglutide users (RR = 0.574, 95 %CI = 0.369-0.893). Semaglutide consistently showed the most pronounced protective effects across all disorders. Additionally, a significant reduction in all-cause mortality was observed (HR = 0.525, 95 %CI = 0.493-0.558). Conclusion: This study provides evidence that the effects of GLP-1 receptor agonists may extend beyond their known metabolic and cardioprotective benefits to include neuroprotection, associated with a decreased risk of developing various neurodegenerative disorders. These findings suggest the potential for expanding the therapeutic applications of GLP-1 receptor agonists to improve neurocognitive outcomes. Further research is warranted to elucidate the mechanisms underlying these neuroprotective effects and to explore their clinical applications in neurodegenerative disease prevention and treatment.