Alzheimer’s disease (AD) is expected to affect 6.9 million Americans aged 65 years and above in 2024 and the figure is expected to rise to 13.8 million by the year 2060. AD treatment is difficult in that there is no known cure for it and about 40% of the cases are related to risk factors that can be modified.
However, due to its increase in prevalence and severity of suffering and economic burden to the society as well as the unavailability of cure for the disease, it is very important to focus on these modifiable risk factors so that the onset of AD and related dementia can be postponed or even prevented.
Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), was firstly approved by the US Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus (T2DM) in 2017 and later for weight loss in the year 2021.
Both T2DM and obesity are important modifiable risk factors for age-related cognitive decline, that is AD. In addition, semaglutide has also been shown to help with a host of other conditions, including some risk factors that are also related to AD such as cardiovascular ones, alcohol abuse, smoking, and depression.
Current trends in preclinical research indicate that semaglutide and obesity medication a glucagon-like peptide receptor agonist (GLP-1RA) prescribed for type 2 diabetes, contributes to the protection from neurodegeneration and neuroinflammation. Nevertheless, the evidence from the observational studies on its potential for the prevention of Alzheimer’s disease remains scanty.
We conducted emulation target trials based on a nationwide database of electronic health records (EHRs) of 116 million US patients. Seven target trials were emulated among 1,094,761 eligible patients with T2DM who had no prior AD diagnosis by comparing semaglutide with seven other antidiabetic medications. First ever diagnosis of AD occurred within a 3-year follow-up period and was examined using Cox proportional hazards and Kaplan–Meier survival analyses.
The inclusion criteria for all target trials included patients with type 2 diabetes mellitus (T2DM) with health care visits from December 2017 to May 2021, who had not been exposed to any anti-diabetic therapy for the last 6 months (new user), and who had at least one of the conditions for which semaglutide is usually prescribed (such as obesity, hypertension, hyper-cholesterolemia, cardiovascular diseases, stroke or A1C being over 8.5%).
Exclusions also applied to patients who had previously suffered from AD, patients who were treated with both semaglutide and active comparator drugs, and patients with conditions that fall under the indication, precautions, and restricted use of semaglutide (pancreatitis, type 1 diabetes, thyroid neoplasms, and gastroparesis).
Semaglutide was attached with significantly lowered or reduced risk for first-time AD diagnosis, most strongly compared with insulin (hazard ratio, 0.33 [95% CI: 0.21to 0.51]) and most weakly compared with other GLP-1RAs (HR, 0.59 [95% CI: 0.37 to0.95]). Similar results were seen across obesity status, gender, and age groups.
Authors mentioned in this study, actual populations suffering from T2DM, who as well are at high chances of developing AD, semaglutide was associated with minimal incidences of first AD diagnosis or use of AD medications compared to insulin or others non-insulin non-GLP1RAs and GLP1RAs.
These findings were consistent across older patients, both sexes, and those with and without obesity. Cumulative incidence curves started to diverge by 30 days and remained separated after that point, suggesting that there is a potential for semaglutide to not only prolong the time to the onset of Alzheimer’s disease but also to have long-lasting effects in slowing down the progression of the disease.
These findings support further studies to assess semaglutide’s potential in preventing AD. Semaglutide was associated with 40% to 70% reduced risks of first-time AD diagnosis in T2DM patients compared to other antidiabetic medications, including otherGLP-1RAs.∙ Semaglutide was associated with significantly lower AD-related medication prescriptions.
Similar reductions were seen across obesity status, gender, and age groups.∙ Our findings provide real-world evidence supporting the potential clinical benefits of semaglutide in mitigating AD initiation and development in patients with T2DM.
