GLP-1s Lower Mortality, Neurodegeneration Risks

The use of tirzepatide and semaglutide among adults with type 2 diabetes (T2D) and obesity was associated with a significant risk reduction in all-cause mortality, dementia, and ischemic stroke, according to a study published in JAMA Network Open.¹

The findings show that the benefits of glucagon-like peptide-1 (GLP-1) receptor agonists reach beyond glycemic control. These findings support the researchers’ suggestion to conduct further trials on GLP-1s and their neuroprotective and cerebrovascular benefits.

“Large cohort studies investigating the neuroprotective properties of antidiabetic drugs have suggested that [GLP-1] receptor agonists (GLP-1RAs) are among the most promising antidiabetic drugs in reducing dementia risk,” wrote authors of the study. “First approved for [T2D] treatment in 2005, GLP-1RAs have transformed diabetes and obesity management by improving glycemic control, weight loss, and cardiovascular outcomes.”

Using EHR data, researchers gathered patients 40 or older with T2D and obesity to explore their neuroprotective and cerebrovascular outcomes. | image credit: Edugrafo / stock.adobe.com

READ MORE: Q&A: How Advancements in GLP-1s, CGM Impact Insulin Management

Since the approval of liraglutide (Saxenda) for weight-loss in 2014,² the demand for GLP-1s among patients with either diabetes or obesity has skyrocketed. With 10% of the US population having diabetes and 2 in 5 US adults reporting obesity today,^3-4 it’s not out of the ordinary to refer to these drugs as “life-changing,” like many diabetes and weight-loss experts have asserted.

Between 2017 and 2021, GLP-1 use increased 40-fold, as Indiana University School of Medicine statistics show an estimated 6 million US patients are now on semaglutide (Ozempic) or tirzepatide (Mounjaro).⁵ Now, however, researchers are uncovering even further benefits of GLP-1RAs that reach beyond improved cardiometabolic outcomes.

“Preclinical studies have shown that GLP-1RAs exert neurocognitive protection by reducing amyloid-β deposition, tau hyperphosphorylation, neuroinflammation, and oxidative stress, while also improving cognitive function in murine Alzheimer disease and human brain organoid models,” they continued.¹ “Semaglutide and tirzepatide have longer half-lives and enhanced pharmacokinetics, with emerging evidence suggesting greater neuroprotective potential than earlier GLP-1RAs.”

Amid the minimal research previously conducted on neurocognitive GLP-1RA outcomes, there are no large-scale clinical trials exploring them. In their attempt to add to the literature, researchers conducted this study to assess the incidence of dementia, Parkinson disease, ischemic stroke, intracerebral hemorrhage, and all-cause mortality on patients with T2D and obesity treated with semaglutide or tirzepatide compared with other antidiabetic drugs.

Using electronic health record data between December 1, 2017, and June 30, 2024, researchers gathered patients 40 or older with T2D and obesity. Participants were included if they initiated semaglutide, tirzepatide, or other antidiabetic drugs. Patients were excluded if they previously reported neurodegenerative or cerebrovascular diseases.

“The primary outcomes were new-onset neurodegenerative diseases, including dementia (Alzheimer disease, vascular dementia, and other dementia), mild cognitive impairment, and Parkinson disease, and cerebrovascular diseases, including ischemic stroke and intracerebral hemorrhage,” wrote the authors.¹ “The secondary outcome was all-cause mortality, identified from death records in the TriNetX database during the study period.”

The final analysis included a total of 60,860 adults (mean age, 58 years; 50.8% women) with T2D and obesity. Participants were then separated equally, with 30,430 patients split into both the GLP-1RA and other antidiabetic drugs groups.

Throughout the 7-year study period, patients in the GLP-1RA group taking either semaglutide or tirzepatide experienced significant reductions in stroke, dementia, and all-cause mortality risk compared with those taking other antidiabetic drugs. There were no significant changes in patients’ risk of Parkinson disease or intracerebral hemorrhage.

“Our findings show that initiating GLP-1RA treatment was associated with a reduced incidence of dementia, stroke, and all-cause mortality in patients with [T2D] and obesity, with more pronounced associations observed in older adults; women, who are known to have higher baseline risks of dementia; and individuals with a BMI of 30 to 40, possibly due to their more modifiable metabolic status,” they wrote.¹

Findings from this study were distinctly focused on a variety of specific outcomes, showing benefits for some and no significant risk reductions for others. For example, previous studies have reported positive effects of GLP-1RAs on all outcomes explored, but only 3 of the 5 outcomes showed significant reductions in this study.

Another notable detail from this study was that tirzepatide wasn’t FDA-approved until 2022, midway through the study period, possibly owing much of the GLP-1 benefits to semaglutide rather than tirzepatide.

Despite significantly positive outcomes among a large cohort of patients with T2D and obesity, the aforementioned discrepancies in results and previous studies support the need for further research in this area. Researchers suggest future studies focus on GLP-1s compared with other antidiabetic drugs without cotreatments.

“In this cohort study, we found electronic health record–based evidence that the use of GLP-1RAs, particularly semaglutide and tirzepatide, is associated with a lower incidence of dementia, stroke, and all-cause mortality in patients with both [T2D] and obesity, suggesting potential neuroprotective and cerebrovascular benefits,” concluded the authors.¹ “These findings highlight the possible role of GLP-1RAs in mitigating neurodegenerative and cerebrovascular risks in this high-risk population.”

READ MORE: Diabetes Resource Center

Ready to impress your pharmacy colleagues with the latest drug information, industry trends, and patient care tips? Sign up today for our free Drug Topics newsletter.

References

1. Lin H, Tsai Y, Liao P, et al. 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

2. Phelan M. Innovators who fought to unlock GLP-1 drugs for obesity awarded Mani L. Bhaumik Breakthrough of the Year Award. American Association for the Advancement of Science. April 4, 2024. Accessed July 25, 2025. https://www.aaas.org/news/innovators-glp-1-obesity-bhaumik-breakthrough

3. Type 2 diabetes. CDC. May 15, 2024. Accessed July 25, 2025. https://www.cdc.gov/diabetes/about/about-type-2-diabetes.html

4. Adult obesity facts. CDC. May 14, 2024. Accessed July 25, 2025. https://www.cdc.gov/obesity/adult-obesity-facts/index.html

5. Logan P. On the increase in use of GLP-1s. Indiana University School of Medicine. June 12, 2024. Accessed July 25, 2025. https://medicine.iu.edu/blogs/bioethics/on-the-increase-in-use-of-glp-1s