Semaglutide, Tirzepatide, and the Brain–Vascular Axis in Patients with Diabetes and Obesity

Type 2 diabetes and obesity are major global health problems that often occur together. In the United States, between 2017 and 2020, 62.8% of adults with diabetes also had obesity, affecting about 17 million people. Both conditions contribute to insulin resistance, oxidative stress, and chronic inflammation, increasing the risk of neurodegeneration. 

The 2024 Lancet Commission on Dementia identified diabetes and obesity as important modifiable risk factors for dementia, with relative risks of 1.7 and 1.3, respectively. Patients with both disorders face higher rates of dementia, Parkinson's disease, and stroke.

Glucagon-like peptide one receptor agonists (GLP-1RAs), such as semaglutide and tirzepatide, are widely used for type 2 diabetes and obesity. While their cardiometabolic benefits are established, their effects on brain and vascular outcomes are less clear.

This retrospective cohort study used TriNetX US electronic health records from December 2017 to June 2024 to compare semaglutide and tirzepatide with other antidiabetic drugs in adults aged 40 or older with type 2 diabetes and obesity. After excluding those with prior neurodegenerative or cerebrovascular disease, 60,860 patients were included and matched into two equal groups of 30,430. During seven years of follow-up, GLP-1RA users showed lower risks of dementia (HR 0.63), stroke (HR 0.81), and all-cause mortality (HR 0.70), but no significant reduction in Parkinson's disease or intracerebral hemorrhage. Benefits were more substantial in older adults, women, and those with a body mass index of 30–40.

These findings suggest semaglutide and tirzepatide may protect neurodegenerative and cerebrovascular outcomes beyond glucose control.

Reference: 

1. Lin H, Tsai Y, Liao P, Wei JC. Neurodegeneration and stroke after semaglutide and tirzepatide in patients with diabetes and obesity. JAMA Netw Open. 2025;8(7):e2521016. doi:10.1001/jamanetworkopen.2025.21016, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2836412?widget=personalizedcontent&previousarticle=0)