A new study published in Alzheimer’s and Dementia indicates that semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), may offer a protective effect against Alzheimer’s disease (AD) in patients with type 2 diabetes mellitus (T2DM). The research, leveraging real-world data from a large U.S. database, suggests a significant reduction in the risk of first-time AD diagnosis among semaglutide users compared to those using other antidiabetic medications.
Semaglutide's Potential in Alzheimer's Prevention
With the prevalence of AD expected to reach 13.8 million Americans by 2060, identifying modifiable risk factors and potential preventative measures is crucial. Semaglutide, already FDA-approved for T2DM and obesity, has shown promise in managing conditions like cardiovascular disease and depression, which are also AD risk factors. This has prompted investigation into its potential role in delaying or preventing AD.
Study Design and Methodology
The study, an emulation target trial, utilized the TriNetX Analytics platform, analyzing electronic health records (EHRs) of 1,094,761 T2DM patients without prior AD diagnosis. The study compared new users of semaglutide (n=17,104) with new users of other antidiabetic medications (n=1,077,657), including SGLT2 inhibitors, insulins, metformin, sulfonylureas, thiazolidinediones, and DPP-4 inhibitors. The primary outcome was the first-time diagnosis of AD, with AD-related medication prescriptions as secondary outcomes. All participants were 60 years or older and considered 'new users' of antidiabetic medications.
Key Findings: Reduced Alzheimer's Risk
The results indicated that T2DM patients prescribed semaglutide were significantly less likely to be diagnosed with AD during a three-year follow-up, irrespective of sex, gender, and obesity status. The three-year cumulative incidence curves showed a divergence within 30 days, suggesting a persistent effect of semaglutide in delaying AD development. Subpopulation analysis confirmed that semaglutide reduced the risk of first-time AD diagnosis compared to other antidiabetic medication groups. The secondary outcomes analysis also showed that semaglutide decreased AD-related medication prescriptions in diabetic patients, with or without obesity.
Proposed Mechanisms of Action
Existing evidence suggests that GLP-1RAs like semaglutide may protect cognitive function by increasing autophagy and brain glucose uptake. Preclinical studies have demonstrated that semaglutide can reduce neurotoxicity by preventing the proliferation of amyloid β (Aβ) plaques and tau tangles. Clinical studies have shown that GLP-1RAs reduce cognitive impairment in T2DM patients, with one study reporting a 53% reduced risk of all-cause dementia in T2DM patients prescribed GLP-1RAs.
Study Limitations and Future Directions
The study acknowledges several limitations, including its retrospective observational design using EHR data, which may be subject to biases from overdiagnoses, underdiagnoses, misdiagnoses, and unmeasured confounders. The relatively recent FDA approval of semaglutide limited the follow-up period to three years. Data was obtained from the TriNetX Analytics platform, requiring further validation in other platforms. The EHRs lacked data on medication adherence and cognitive impairment tracking, which may influence study outcomes.
Despite these limitations, the study suggests a potential protective effect of semaglutide against AD in older populations with T2DM and other comorbidities. Future studies are needed to investigate the effectiveness of semaglutide in other populations and its effect on mild cognitive impairment and other neurodegenerative diseases.
