How Do GLP-1 Agonists Fit Into Stroke Care?

Glucagon-like peptide-1 (GLP-1) receptor agonists—best known for treating diabetes and driving weight loss—may also hold promise as tools for protecting the brain prior to and after stroke and slowing neurodegeneration, experts discussed at the International Stroke Conference (ISC) 2026. From mechanistic effects on inflammation and cerebral blood flow to emerging clinical data on stroke prevention, presenters outlined how these therapies could reshape cerebrovascular care.

GLP-1 agonists remain largely untested in this at-risk patient population and warrant further research, experts said. | Image credit: mingnimit - stock.adobe.com

Samarth Shah, PharmD, BCPS, clinical pharmacy specialist at the Hospital of the University of Pennsylvania, first gave an overview of GLP-1s, from their mechanism of action to clinical uses.

GLP-1, an endogenous hormone, is produced in response to glucose and stimulates insulin secretion to decrease glucagon production. GLP-1 agonists increase GLP-1’s resistance to dipeptidyl peptidase-4—which degrades endogenous GLP-1—and extend its half-life. For patients with diabetes, the stimulation of insulin production and decrease in glucagon, along with increased satiety and slowed gastric emptying, have a clear impact on outcomes.

In cardiovascular and cerebrovascular disease, GLP-1s have been linked in a reduction in atherosclerosis, blood pressure reduction through vasodilation, improvements in lipid panels, and cardiac and renal protection, Shah said.

But the question at hand for the audience at ISC 2026 was how GLP-1 receptor agonists might help patients with cerebrovascular disease specifically.

“One key component here is that GLP-1 receptors are widely distributed throughout the nervous system,” Shah said. “…One big thing that GLP-1s have shown is that they inhibit apoptosis and decrease inflammation.1,2 That could be something we think about when we’re thinking about how these drugs are going to help mechanistically.”

When patients have an acute ischemic stroke, there may be increased expression of GLP-1 receptors, Shah explained. If that is the case, giving a patient a GLP-1 agonist after a stroke could theoretically allow the mechanistic effects to happen as the drug binds to an increased number of receptors.

GLP-1s could potentially play a role in protecting against cerebral ischemia, Shah said, noting that the vasodilation seen with GLP-1 agonist use can lead to a reduction in blood pressure and increased cerebral blood flow, which brings an increase in cyclic adenosine monophosphate and vascular endothelial growth factor. In closing, Shah highlighted the potential for GLP-1s in promoting neurogenesis and modulating neurotransmitters.

“[GLP-1 agonists] increase insulin signal transduction—we know that for sure,” Shah said. “But they can also increase neurogenic and synaptic plasticity, as well as have direct central effects such as causing that vasodilation.”

Do GLP-1–Targeted Therapies Have a Role in Bolstering Brain Health?

With the groundwork laid, Alireza Atri, MD, director of Banner Sun Health Research Institute, began his talk with a primer on Alzheimer disease (AD), which has complex pathophysiology and copathology with conditions including vascular cognitive impairment. AD’s contribution to neurodegeneration and dementia has yet to be completely understood, he added, but noted that in neurodegenerative diseases overall, the immune system plays a significant role. Further, Atri emphasized that copathology is the rule, not the exception, in brain autopsies of individuals with AD dementia.

“By the time people come to autopsy in their 70s or 80s, it’s one of the rarest things to have just Alheimer disease changes in the brain,” Atri said.

Some of the definitions used for AD were updated in 2024 with the ATX(N) framework,4 separating AD symptoms from the disease itself, Atri explained. Notably, vascular brain injury is included as a category of biomarkers, defined as infarction on MRI, CT, or White matter hyperintensities. And throughout the AD disease trajectory from preclinical to clinical manifestation, there is inflammation present—a well-known stroke risk factor.

Research on GLP-1 itself in the field of neurology has been ongoing since the early 1990s, with both murine and human studies pointing to a possible role in stroke treatment, Atri said, citing evidence from various mouse studies and several human studies.

In a post-hoc analysis of the randomized SUSTAIN 6 and PIONEER 6 studies, GLP-1 receptor agonists reduced the incidence of any type of first stroke with treatment vs placebo in patients with type 2 diabetes and high cardiovascular risk regardless of prior stroke at baseline.4 This was mostly driven by small-vessel occlusion prevention.

Still, GLP-1 agonists remain largely untested in this patient population and warrant further research, Atri said.

Now, this only brings us to the beginning, because we’ve been pushing the door but we haven’t pulled it open yet,” Atri said, “But it gives us some suggestions about where to go in the next few decades. Given GLP-1s have multiple effects on pathways in the brain—including on systemic inflammation, vascular health, and neuroinflammation… We should take more shots on goal, I think. And I think there is hope, and the glass is more than half full.”

How Stroke Neurologists Can Leverage GLP-1 Agonists in Practice

In the field of stroke neurology, GLP-1 receptor agonists may most obviously fit into the preventive space.

“To me, this is a clear-cut issue: the prevention of major cardiovascular events—be it cardiac or stroke—with GLP-1s,” Howard Feldman, a professor of neurosciences at the University of California San Diego, said. “What is the level of evidence and what do we have to draw, and how do they roll up to clinical practice guidelines?” A number of meta-analyses have been done on trials mainly geared toward cardiovascular outcomes, he added.

Feldman cited a meta-analysis published in The International Journal of Stroke in 2024 aiming to characterize the role of GLP-1s in stroke.5 Nine of the 11 cardiovascular outcome trials included in the analysis centered on patients with diabetes, 1 included patients with obesity, and 1 was specific to GLP-1 receptor agonist use, including 7 GLP-1s. With GLP-1s, total stroke and nonfatal stroke rates were lower.

With follow-up of 5.7 to 66 months and 247,596 patient-years, treatment with GLP-1s was associated with a lower total stroke rate (risk ratio [RR], 0.85; 95% CI, 0.77-0.93), a lower nonfatal stroke rate (RR, 0.87; 95% CI, 0.79-0.95). To a nonsignificant degree, GLP-1 agonist use was associated with lower fatal stroke and hemorrhagic stroke rates.

“Recommendations that come out of this type of meta-analysis are that GLP-1s are supported for use by stroke specialists in people with stroke, and with concurrent comorbid conditions or diabetes or obesity,” Feldman said. “Secondary stroke prevention can include adding a GLP-1 to metformin with diabetes, independent of hemoglobin A1c.”

A 2025 publication on secondary prevention of stroke with liraglutide vs placebo in 636 participants with type 2 diabetes control also showed a 44% lower cumulative incidence of stroke with GLP-1 inhibition vs placebo (HR, 0.56; 95% CI, 0.34-0.91; P = .02).6 Notably, the study enrollment was terminated early and therefore it was underpowered, so these results should be cautiously interpreted, Feldman noted.

Additionally, the 2024 Guidelines for the Primary Prevention of Stroke consider GLP-1s effective for type 2 diabetes and weight loss, therefore lowering the risk of stroke and cardiovascular disease.6 They recommend using GLP-1 agonists in patients with diabetes and cardiovascular disease or at a high risk of cardiovascular disease. However, there is not currently evidence to suggest that GLP-1 receptor agonists reduce the risk of first-ever stroke when used for weight loss alone in the absence of diabetes or high cardiovascular risk.

The potential role of GLP-1s in acute stroke is another area to be explored. A member of the audience, Chris Bladin, MBBS, FRACP, clinical telestroke lead at the Australian Stroke Alliance, highlighted the TEXAIS randomized controlled trial on exenatide that he was principal investigator on. Although the trial was not positive overall, there were positive signals,8 Bladin said.

Together, the existing and emerging data suggest there may be a role for GLP-1 agonists in stroke care. The question that remains is what their role is and how they might impact the stroke treatment algorithm in the future.

References

1. Yang X, Qiang Q, Li N, Feng P, Wei W, Hölscher C. Neuroprotective mechanisms of glucagon-like peptide-1-based therapies in ischemic stroke: an update based on preclinical research. Front Neurol. 2022;13:844697. doi:10.3389/fneur.2022.844697

2. Vergès B, Aboyans V, Angoulvant D, et al. Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms. Cardiovasc Diabetol. 2022;21(1):242.doi:10.1186/s12933-022-01686-3

3 Jack CR Jr, Andrews JS, Beach TG, et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement. 2024;20(8):5143-5169. doi:10.1002/alz.13859

4. Strain WD, Frenkel O, James MA, et al. Effects of semaglutide on stroke subtypes in type 2 diabetes: post hoc analysis of the randomized SUSTAIN 6 and PIONEER 6. Stroke. 2022;53(9):2749-2757. doi:10.1161/STROKEAHA.121.037775

5. Adamou A, Barkas F, Milionis H, Ntaios G. Glucagon-like peptide-1 receptor agonists and stroke: A systematic review and meta-analysis of cardiovascular outcome trials. Int J Stroke. 2024;19(8):876-887. doi:10.1177/17474930241253988
6. Zhu H, Yang B, Lu L, et al; LAMP Investigators. Liraglutide in acute minor ischemic stroke or high-risk transient ischemic attack with type 2 diabetes: the LAMP randomized clinical trial. JAMA Intern Med. Published online November 3, 2025. doi:10.1001/jamainternmed.2025.5684

7. Bushnell C, Kernan WN, Sharrief AZ, et al. 2024 Guideline for the primary prevention of stroke: a guideline from the American Heart Association/American Stroke Association. Stroke. 2024;55(12):e344-e424. doi:10.1161/STR.0000000000000475

8. Bladin CF, Wah Cheung N, Dewey HM, et al. Management of poststroke hyperglycemia: results of the TEXAIS randomized clinical trial. Stroke. 2023;54(12):2962-2971. doi:10.1161/STROKEAHA.123.044568