Semaglutide, a GLP-1 receptor agonist, is associated with a reduced risk of Alzheimer's disease diagnosis in individuals with type 2 diabetes, according to observational data. The study, which emulated target trials involving over 1 million diabetes patients, compared semaglutide to seven other diabetes medication classes.
The findings, published in Alzheimer's and Dementia, revealed a significant reduction in the risk of a first-time Alzheimer's diagnosis with semaglutide. The most notable risk reduction was observed in comparison to insulin (HR 0.33, 95% CI 0.21-0.51). Even when compared to other GLP-1 receptor agonists, semaglutide showed a risk reduction (HR 0.59, 95% CI 0.37-0.95). The results remained consistent across different obesity, gender, and age groups.
Potential Mechanisms and Clinical Implications
Rong Xu, PhD, of Case Western Reserve University School of Medicine, highlighted the real-world evidence supporting semaglutide's impact on Alzheimer's disease. Preclinical research has suggested that semaglutide may protect against neurodegeneration and neuroinflammation. "Our results indicate that further research into semaglutide's use will need to be further investigated through randomized clinical trials so alternative drugs can be tested as potential treatment for this debilitating illness," Xu stated.
Paul Edison, MD, PhD, of Imperial College London, noted that GLP-1 agonists have demonstrated multiple mechanisms of action in animal models, including reducing neuroinflammation, tau formation, and insulin resistance, as well as improving synaptic function and memory. "Alzheimer's is a multifactorial disease. To have an effective treatment, we should target multiple pathological processes like amyloid, tau, neuroinflammation, insulin resistance, and neuronal loss," Edison explained.
Ongoing Clinical Trials
Several clinical trials are underway to further investigate the potential of semaglutide in Alzheimer's disease. The phase III EVOKE and EVOKE Plus trials are evaluating the effects of semaglutide in early Alzheimer's disease. Additionally, a study is assessing semaglutide's impact on tau accumulation in individuals with or without diabetes who are amyloid-positive and have no or mild cognitive impairment. Another trial is examining how semaglutide affects the immune system and other biological processes in people with Alzheimer's.
Study Details
The emulation target trials utilized electronic health records of 1,094,761 type 2 diabetes patients without a prior Alzheimer's diagnosis. Participants were new users of semaglutide or one of the comparator medications and had at least one condition listed in semaglutide's prescription guidelines, such as obesity, hypertension, hypercholesterolemia, heart diseases, stroke, or HbA1C of 8.5% or greater. The primary outcome was a first-time Alzheimer's diagnosis, with Alzheimer's-related medication prescriptions as a secondary outcome. Patients were followed for up to 3 years.
Semaglutide was associated with a lower risk of both first-time Alzheimer's diagnosis and Alzheimer's-related drug prescriptions compared with other agents. "Cumulative incidence curves began to diverge within 30 days and continued to separate thereafter, indicating semaglutide's potential to delay or slow Alzheimer's disease development with sustained effects," the authors noted.
Limitations
The researchers acknowledged that the study is observational and does not establish a causal relationship. The follow-up period was limited to 3 years due to semaglutide's recent approval for treating type 2 diabetes.
