Semaglutide Linked with Reduced Risk of Alzheimer Disease in Large Observational Study

Semaglutide, when compared to 7 other antihyperglycemic medications, significantly reduced the risk for a first-time diagnosis of Alzheimer disease (AD) by 40% to 70% in adults with type 2 diabetes (T2D), according to findings from a research team at the Case Western Reserve School of Medicine.

Rong Xu, PhD
Courtesy Case Western Reserve University

In results from the real-world study that included records for 1 million individuals, the researchers reported consistent results for reduced risk across study subgroups, classified by age, gender, and obesity status. Comparator drugs included other glucagon-like peptide-1 receptor agonists (GLP-1RAs), the class to which semaglutide belongs.

The research was published on October 24 in the journal Alzheimer’s & Dementia.

“Preclinical research has suggested that semaglutide may protect against neurodegeneration and neuroinflammation,” lead researcher Rong Xu, PhD, professor of biomedical informatics and director of the Center for AI in Drug Discovery at CWUSM, and colleagues wrote. “Antidiabetic medications have shown promise in improving cognition, Aβ clearance, tau phosphorylation, neurotransmitter turnover…vascular function, inflammation, and lipid metabolism in AD,” the team wrote. “Our study shows that semaglutide significantly reduces first-time AD diagnoses compared to other antidiabetic medications, suggesting potential benefits beyond insulin resistance improvement.”

Patients with T2DM who were prescribed semaglutide had a significantly decreased risk of receiving a first-time diagnosis of AD during a 3-year follow-up compared with those prescribed other antidiabetic medications. The largest reduction in risk was seen in comparison with insulin (HR 0.33, 95% CI 0.21-0.51) and the smallest was against other GLP-RAs (HR 0.59, 95% CI 0.37-0.95), according to the study findings

Age. Among participants aged 60 years and older at the first recorded prescription, the overall 3-year risk of first-time diagnosis of AD was twice as high as in the general population (0.33% vs 0.16%). However, the decrease in risk of a first-time diagnoses of AD was similar to the decrease observed in the overall cohort, according to Xu et al. A notable finding showed that separation among the 3-year cumulative incidence curves comparing semaglutide with each of the 7 comparator drugs began with the first 30 days and the divergence continued, according to the study results. The continued separation indicates “the potential sustained benefits of semaglutide in delaying or slowing AD development,” authors wrote.

Gender. After propensity score matching, each balanced semaglutide vs insulin group include 8881 women (mean age 56.8 years) and 6895 men (mean age 59.5 years). Among women, semaglutide was associated with the largest decreased risk for first-time AD diagnosis in comparison with insulin of approximately 78% (HR 0.22) and the lowest (47%) in comparison with other GLP-1 RAs (HR 0.53). The trends were similar among men with T2D and no prior AD diagnosis, although the associations were somewhat weaker, but with overlapping confidence intervals, authors reported.

Obesity status. Obesity was defined for the study as having had a medical encounter for obesity diagnosis in the past 2 years. Among adults filling the criteria, the observed decrease in risk of a first-time AD diagnosis in semaglutide-treated adults compared with groups treated with comparator antidiabetes medications was similarly compared with insulin (HR 0.29) compared to when compared with other GLP-1RAs.

AD-related prescriptions. The findings were also consistent when Xu et al assessed prescriptions for AD-related medication as an alternative outcome in this population with T2D and no prior AD diagnosis, with semaglutide again associated with a decreased risk of the secondary outcome compared with other antidiabetic medications, regardless of obesity status.

To simulate a randomized clinical trial, investigators conducted 7 emulation target trials based on a national database of electronic health records (EHR) of 116 million individuals. The researchers identified 1 094 761 adults with T2D without a diagnosis of AD, including 17 104 new users of semaglutide and 1 077 657 new users of 7 other antidiabetic medication classes: other GLP-1 RAs, insulin, metformin, dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, sulfonylureas, and thiazolidinediones.

The primary study outcome was an EHR-documented first-time diagnosis of AD with AD-related medication prescriptions used as secondary outcomes. All eligible participants were followed from index event until the occurrence of the outcome, death, loss to follow-up, or 3 years after the index event, whichever occurred first. The 6 populations assessed were all patients, older patients (≥60), women, men, patients with obesity, and patients without obesity.

Individuals who were eligible had T2D and medical encounters between December 2017 and May 2021, had no use of any antidiabetic medications within the past 6 months (ie, new users), and had been diagnosed with at least 1 condition included in the labeling for semaglutide (eg, obesity, hypertension, hypercholesterolemia, heart diseases, stroke, or HbA1C ≥8.5%)

Although their findings potentially support the idea that semaglutide could prevent Alzheimer’s disease, the study’s limitations restrict the researchers from making firm causal conclusions. “Our results indicate that further research into [the use of semaglutide] will need to be further investigated through randomized clinical trials so alternative drugs can be tested as potential treatment for this debilitating illness,” researchers concluded.

Source: Wang W, Want QQ, Qi X, et al. Associations of semaglutide with first-time diagnosis of Alzheimer’s disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US. 2024;1-12. Alzheimer's & Dementia. doi:10.1002/alz.14313