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Semaglutide (Ozempic) was tied to a reduced risk of Alzheimer's disease diagnoses in people with type 2 diabetes, observational data showed.

In emulation target trials involving more than 1 million eligible diabetes patients, the GLP-1 receptor agonist was associated with a significantly reduced risk for a first-time Alzheimer's diagnosis compared with seven other diabetes medication classes, reported Rong Xu, PhD, of Case Western Reserve University School of Medicine in Cleveland, and co-authors.

The largest risk reduction was in comparison with insulin (HR 0.33, 95% CI 0.21-0.51), Xu and co-authors reported in . The smallest risk reduction was against other GLP-1 receptor agonists (HR 0.59, 95% CI 0.37-0.95). Results were consistent across obesity, gender, and age groups.

"This new study provides real-world evidence for its impact on Alzheimer's disease, even though preclinical research has suggested that semaglutide may protect against neurodegeneration and neuroinflammation," Xu said in a statement. "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."

In , GLP-1 agonists have been shown to reduce neuroinflammation, tau formation, and insulin resistance and improve synaptic function and memory, observed Paul Edison, MD, PhD, of Imperial College London, who wasn't part of the study.

"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 told MedPage Today.

"GLP-1 analogs are a class of compounds which have demonstrated multiple mechanisms of action influencing Alzheimer's pathogenesis," he said. They also reduce cardiovascular and cardiometabolic risk, which in itself is a risk factor for Alzheimer's disease, he added.

In the phase IIb ELAD trial, the GLP-1 receptor agonist liraglutide (Saxenda, Victoza) had some beneficial effects in people with Alzheimer's disease, Edison noted.

Two phase III trials -- and -- are testing the effects of semaglutide in early Alzheimer's disease. Another study is assessing whether in people with or without diabetes who are amyloid-positive and have no or mild cognitive impairment. A trial also is underway to evaluate how semaglutide and other biological processes in people with Alzheimer's.

Xu and colleagues conducted seven emulation target trials using the electronic health records of 1,094,761 type 2 diabetes patients without a prior Alzheimer's diagnosis. The target trials separately compared semaglutide with insulins, metformin, DPP-4 inhibitors, SGLT2 inhibitors, sulfonylureas, thiazolidinediones, and other GLP-1 receptor agonists.

Eligible participants had medical encounters between December 2017 and May 2021, had not used any other antidiabetic medications within the past 6 months (were "new users"), and were diagnosed with at least one condition listed in semaglutide's prescription guidelines (obesity, hypertension, hypercholesterolemia, heart diseases, stroke, or HbA1C of 8.5% or greater).

The main outcome was a first-time Alzheimer's diagnosis; a secondary outcome was Alzheimer's-related medication prescriptions. Patients were followed for up to 3 years.

Most participants were treated with insulin (708,989 new users) or metformin (550,105 new users). A total of 17,104 were treated with semaglutide.

Before propensity-score matching, the insulin and semaglutide groups differed by age, sex, ethnicity, obesity, some cardiovascular conditions, Alzheimer's-related risk factors, and medical encounters including outpatient visits. After propensity-score matching, comparison groups were balanced. Mean baseline age was 58, and about 40% were men.

Semaglutide showed a lower risk of both first-time Alzheimer's diagnosis and Alzheimer-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," Xu and co-authors noted.

The study is observational and does not show a causal relationship, the researchers acknowledged. Due to semaglutide's recent approval for treating type 2 diabetes, the follow-up period was limited to 3 years.

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