GLP-1s: From weight loss to brain gain
Therapies well known for helping patients drop pounds show potential in fighting dementia and stroke.
GLP-1 targeted therapies have made headlines for their efficacy in treating Type 2 diabetes and obesity. Now they are revealing potential benefits for the brain.
Those potential benefits will be highlighted Thursday at the session “GLP-1 Targeted Therapies for Cerebrovascular and Brain Health.”
“The role GLP-1 plays in the body is to help regulate blood sugar by boosting glucose-dependent insulin secretion, slowing digestion and reducing appetite,” said Samarth Shah, PharmD, BCPS. GLP-1 medications “have been used effectively in the management of diabetes and weight loss, and we are starting to learn the impact they have on other disease states.”
Their growing popularity means there is also a growing need for physicians to be aware of the medications’ uses and behaviors, said Shah, clinical pharmacy specialist at the Hospital of the University of Pennsylvania in Philadelphia.
“Proper initiation, titration and oversight of these agents is important to ensure a balance between patient efficacy and safety,” he said. “Additionally, there are important considerations when picking the optimal agent based on your patient’s specific needs.”
Although the latest American Heart Association/American Stroke Association primary stroke prevention guideline recommends the use of GLP-1 receptor agonists for patients with diabetes and high cardiovascular risk, session presenter Alireza Atri, MD, PhD, says there may soon be a time when the medications are given specifically to address neurological conditions, including stroke and Alzheimer’s disease.
Atri, a cognitive neurologist and chief medical officer at Banner Alzheimer’s and Research Institutes in Sun City, Arizona, predicts the way we approach brain health and neurodegenerative conditions in the coming decades will change dramatically. He pointed to growing evidence that GLP-1 medications may play a big part in the prevention of multi-etiology cognitive impairment and dementia. The key will be recognizing people at greatest risk or with early biological signs of disease and treating these conditions years before symptoms appear.
“Our understanding now of neurodegenerative conditions is that the processes start decades before people actually show symptoms,” he said. “Neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease and Lewy body disease involve proteins with certain brain functions. Over time, because of some combination of our genetics, environmental and exposure factors and aging, they start to clump and become toxic.”
Atri said these pathological protein clumping diseases, or proteinopathies — whether involving plaques or tangles (as in Alzheimer’s) or other proteins (such as alpha-synuclein in Lewy body disease) — begin forming 10 to 20 years before people start having memory, cognitive, motor or behavioral symptoms.
Between the time these pathological proteins appear and when symptoms arise, the brain is affected in multiple ways, Atri said, with impact in areas including:
- How brain cells use energy
- How neurons and supporting cells get rid of debris of other toxic proteins
- The integrity of brain blood vessels and synaptic connections
- Immune regulation and neuroinflammation
These areas are where GLP-1s may be able to make a difference, he said.
“GLP-1s have multifaceted effects on multiple organs and bodily functions including blood vessels, immune and inflammatory regulation, energy metabolism, kidneys, the pancreas and the brain,” Atri said. “There are layers of evidence ranging from test tube and animal experiments to data from registries and studies in humans — including people with diabetes or Alzheimer’s — that support signals that GLP-1s could potentially be changing immune, inflammatory and metabolic processes and also that there may be benefits on cognition and slowing down aspects of cognitive decline.”
But while there is some evidence, a lot more research is needed, he said. A recent pair of clinical trials, EVOKE and EVOKE Plus, sought to test the effect of a GLP-1 therapy called semaglutide on people with early-stage, symptomatic Alzheimer’s disease. Although that study program did not show a benefit of the medication in slowing symptomatic Alzheimer’s disease, Atri said that doesn’t mean it’s the end of the road for this line of research.
“What still holds great promise is to figure out if there are potentially subpopulations — such as people with diabetes or with higher cerebrovascular risk factors but without frank cognitive impairment — who are in nonsymptomatic phases that could benefit from preventative treatment in that area 10, 15 or 20 years before people actually show symptoms but are at high risk or show early biological signs of disease,” he said. “Those studies have not been done.
“I think there’s a tremendous potential for GLP-1 receptor agonists to be part of our armamentarium to help with primary or secondary prevention of cognitive impairment.”
Atri said it’s already documented that in people with diabetes, semaglutide decreases cerebrovascular events such as stroke. And studies in mice have shown that those treated with GLP-1s suffered less brain damage from stroke than mice that were not treated, he said.
One of the reasons semaglutide was studied in Alzheimer’s disease is because researchers noticed in multiple studies and registries that patients with diabetes who were treated with semaglutide also experienced lower rates of dementia, he said.
It’s important not to be discouraged by the negative results of the EVOKE and EVOKE Plus trials, he said, because those were conducted with a population that had already been diagnosed with symptomatic Alzheimer’s disease. He calls for similar trials enrolling asymptomatic subjects with a high risk of cerebrovascular cognitive decline or with positive biomarkers.
“In this Alzheimer’s study, the clinical results were negative, but we saw some biomarker changes very much in the right direction for affecting inflammation and Alzheimer’s,” he said. “They weren’t enough to change the clinical outcomes in symptomatic Alzheimer’s, but these drugs are doing something biologically in the brain and body that seems potentially beneficial to some.
“There’s a lot of excitement to see if the drugs can be tested in a cognitively unimpaired, but high-risk, population — particularly for risk of cerebrovascular cognitive decline, with or without other neurodegenerative biomarkers.”
