• The effect of GLP-1 therapies on inflammatory disease may be mediated by the brain-immune axis.
• In the future, GLP-1 therapy could be used as an anti-aging treatment.

HUNTINGTON BEACH, Calif. — A growing body of data suggest GLP-1 receptor agonists may demonstrate direct anti-inflammatory properties beyond weight loss, according to data presented at the Congress of Clinical Rheumatology West.

In his presentation, Leonard H. Calabrese, DO, RJ Fasenmyer chair of clinical immunology in the department of rheumatic and immunologic diseases at Cleveland Clinic, told attendees that the latest data additionally point to the possibility that these effects are mediated by the brain-immune axis.

“There is a lot of excitement about the use of GLP-1s and inflammatory diseases like psoriasis, psoriatic arthritis and osteoarthritis, which is not an inflammatory disease,” Calabrese, who is also a professor of medicine at the Cleveland Clinic Lerner College of Medicine, and chief medical editor of Healio Rheumatology, said in an interview. “I talked a lot this afternoon about the direct role of GLP-1s as anti-inflammatories. It appears to be mediated by the brain-immune axis, in large part, and I think it has a lot of potential for other immune-mediated inflammatory diseases, potentially even without obesity.”

According to Calabrese, evidence for GLP-1 therapy’s anti-inflammatory impacts beyond weight loss can be found in multiple published studies. He cited the phase 3b TOGETHER-PsO and TOGETHER-PsA trials, evaluating combination therapy with ixekizumab (Taltz, Eli Lilly) and tirzepatide (Zepbound, Eli Lilly), a dual GLP-1/glucose-dependent insulinotropic polypeptide agonist, in patients with psoriatic disease and obesity.

According to 1-year data recently released by Eli Lilly, more than 40% of participants in TOGETHER-PsO who received combination therapy achieved complete skin clearance by week 52 vs. 29.1% in the monotherapy group.

“Skin is not a weight-bearing organ,” Calabrese said. “Could there be something else contributing to this?

“The most telling aspect of this is the temporal argument,” he added. “Even by 4 weeks of the study, where there was trivial weight loss, there was separation of effects on inflammatory joint changes, as well as skin, suggesting that other mechanisms may be contributing to this.”

Another study, published in 2022 in Cardiovascular Diabetology by Mosenzon and colleagues, examined the effects of GLP-1 therapy and attendant glucose control on high-sensitivity C-reactive protein in patients with type 2 diabetes. According to the findings, glucose and control and weight loss accounted for “only” 60% of high-sensitivity CRP in these patients, Calabrese said.

“CRP is moving independently of the effects of mere weight loss alone,” he said. “Provocative, indirect, inferential, but something to grab our attention.”

There are also molecular and sub-cellular rationales for why GLP-1s may be directly anti-inflammatory, according to Calabrese. He noted that the GLP family of receptors are G-coupled protein receptors, which are “intimately linked” to signal transduction pathways both in innate and adaptive cells.

“For adaptive cells, these have direct modifying properties for T-cell activation,” Calabrese said. “This is particularly important for resident T cells that are found in the gut.”

This process also influences inflammasome biology.

“Inflammasomes, as you are familiar, are powerhouses of inflammatory cytokine production, including TNF, IL-1, IL-6 and beyond,” he added.

However, one study, published in 2024 in Cell Metabolism by Drucker and colleagues, stands out from the rest in that it suggests the anti-inflammatory impacts of GLP-1s may be mediated by the brain-immune axis, according to Calabrese.

“It’s a groundbreaking trial,” he said. “When I read this, I had to stop and think about what was going on here, and I continue to think about this.”

Through a series of genetically modified mouse models, the researchers showed that GLP-1 receptor activation weakens the induction of plasma TNF-alpha by multiple Toll-like receptor agonists. Moreover, this process is not mediated by hematopoietic or endothelial GLP-1 receptors, but requires central neuronal GLP-1 receptors, according to the researchers.

“Eliminating the neuronal tissue compromised the anti-inflammatory property of the GLP-1 agonist that was used,” Calabrese said. “What this tells us, is that the brain is controlling the immune response. Now, these are pre-clinical models. We’re humans. But the evidence is pretty strong.”

Looking to the future of GLP-1 use, Calabrese pointed to current studies examining their potential impacts on fibromyalgia and long COVID. One 2025 editorial, published in Nature Biotechnology, especially piqued his interest.

That editorial was titled, “Are GLP-1s the first longevity drugs?”

According to Calabrese, GLP-1 therapies could potentially act as “broad gerotherapies” based on their impacts on anti-senescence, mTOR modulation, mitochondrial enhancement, autophagy promotion, oxidative stress reduction and adipose tissue remodeling.

“I did open up Pandora’s box about what the next generation might be,” Calabrese told Healio. “There’s interest in these drugs as gerotherapeutics because of their many beneficial effects on inflammation and aging. I think this is exciting times for GLP-1 medicines, and I look forward to seeing what happens over the next year.”

Leonard H. Calabrese, DO, can be reached at CALABRL@ccf.org.