GLP-1 agents ‘can help lower systemic inflammation,’ show promise in rheumatology
The apparent success — and now almost ever-present ubiquity — of GLP-1 receptor agonists in weight loss has led to research, and possible uses, far beyond its initial indications in diabetes, including those under rheumatology umbrella.
However, while GLP-1 receptor agonists may eventually play a role — perhaps even a significant one — in the specialty, more information is needed to more concretely determine its benefits.

“One important impact these medications have had is that they can reduce the incidence of shaming people who live with obesity and increase the opportunities for people to seek help for weight management,” Grace C. Wright, MD, PhD, president of the Association of Women in Rheumatology, told Healio. “The problem, however, is that these medicines are being promoted as a cure for everything. That is most certainly not the case.”

Currently approved GLP-1 receptor agonists for treating type 2 diabetes and, in some cases, obesity, include dulaglutide (Trulicity, Eli Lilly & Co.), exenatide (Byetta, Amylin Pharmaceuticals; and Bydureon, AstraZeneca), liraglutide (Victoza, Novo Nordisk), lixisenatide (Adlyxin, Sanofi-Aventis), semaglutide (Ozempic, Rybelsus; Novo Nordisk) and tirzepatide (Mounjaro, Eli Lilly & Co.).
Among those, only semaglutide and liraglutide carry specific FDA approvals for obesity. However, this has opened the door for their potential use in a variety of diseases in which obesity is an exacerbating factor.
According to Daniel J. Drucker, MD, a professor of medicine at the Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital and the University of Toronto, knee osteoarthritis, often exacerbated by concomitant obesity, may be more amenable to improvement via weight loss. Patients with other conditions, including systemic lupus erythematosus, psoriatic arthritis and rheumatoid arthritis, could be potential benefactors as well.
“A key question for disorders like SLE or PsA or RA is whether GLP-1 medicines might exert useful weight loss-independent benefits through reduction of inflammation,” Drucker told Healio. “This is an important topic for ongoing study in both preclinical experiments and in clinical trials.”
This ongoing research — into whether GLP-1 receptor agonists can impact immunity — will ultimately be key to the drugs’ future use in rheumatology, according to Wright.
“From an obesity management perspective, we have seen that these medications can impact the hormone receptors in the gut and the brain that become dysregulated to tell patients when to stop eating,” she said.
“Visceral adipose cells create many inflammatory cytokines,” she added. “They change the way immune, adipose and inflammatory cells operate. This is where these medications could have a role in rheumatology.”
In the meantime, the most convincing results in rheumatology so far have come in OA.
‘Convincing improvement’ in OA
In a 2024 paper published in The New England Journal of Medicine, Bliddal and colleagues enrolled 407 patients with knee OA and obesity in a double-blind, randomized, placebo-controlled trial, called STEP-9, at 61 sites across 11 countries.
Results showed a mean change in body weight from baseline to week 68 of –13.7% among patients assigned semaglutide, and –3.2% for those in the placebo group (P < .001). Semaglutide also yielded improvements in the WOMAC pain score compared with placebo at week 68, with patients demonstrating changes of –41.7 points vs. –27.5 points, respectively (P < .001). Physical function also improved in the treatment arm. Adverse event rates were comparable between groups.
“The STEP-9 trial showed convincing improvement in symptoms and less use of pain medication in people with knee osteoarthritis randomized to semaglutide 2.4 mg once weekly,” Drucker said. “There was insufficient documentation of joint status using imaging. Nevertheless, these studies appear encouraging and more trials are underway.”
Although pain reduction remains important in OA, the big question — and one representing a massive unmet need — is whether the drugs can actually modify OA disease course.

“Some research suggests that GLP-1 agonists could potentially serve as disease-modifying agents for osteoarthritis, meaning they could slow down or even halt the progression of the disease,” Nancy E. Lane, MD, distinguished professor of medicine and rheumatology at the University of California Davis Health, and president-elect of the Osteoarthritis and Cartilage Research Society International (OARSI), said in an interview.
In a 2023 paper published in the Annals of the Rheumatic Diseases, Zhu and colleagues identified individuals with knee OA and comorbid type 2 diabetes mellitus from a cohort of more than 40,000 participants in the Shanghai Osteoarthritis Cohort study. They aimed to assess the incidence of knee surgery after enrollment, along with parameters of pain and disease progression as assessed by medial femorotibial joint cartilage thickness.
According to the researchers, patients treated with GLP-1 receptor agonists experienced a lower incidence of knee surgery compared with patients who were not treated with these medications.
Moreover, GLP-1 receptor agonist use was also associated with significantly lower cartilage-loss velocity in the medial femorotibial joint (adjusted mean difference, –0.02 mm; P = .004).
“This study published in the Annals of the Rheumatic Diseases indicates that GLP-1 receptor agonists might be disease-modifying for knee OA patients with comorbid T2DM, possibly mediated by weight loss,” Lane said. “In addition, preclinical data suggest that GLP-1 agonists may have anti-inflammatory, immunoregulatory, and chondroprotective effects, potentially benefiting OA patients.”
According to Wright, further analysis is necessary to understand if these medications can truly impact OA patients beyond pain management.
“We are seeing that pain has improved, but we still do not know if these drugs can modify or change the course of disease,” she said. “The impact we are seeing in OA might be real, but we have to define it more clearly.”
Although no data are conclusive yet, preclinical studies have shown that GLP-1 receptor agonists can inhibit the NF-kB pathway, a key pathway involved in inflammation and cartilage destruction, according to Lane.
“GLP-1 agonists can help lower systemic inflammation, which can contribute to joint pain and cartilage damage,” Lane said. “These medications may have a direct impact on articular chondrocytes and other joint tissues, potentially improving cartilage health and reducing inflammation.”
As researchers drive toward this goal, early research in lupus and other conditions has offered mixed results.
‘Not a cure,’ but ‘a new approach’
In a 2024 paper published in Rheumatology (Oxford), Carlucci and colleagues assessed whether GLP-1 receptor agonists triggered flares in a cohort of 18 patients with SLE. According to the researchers, in addition to weight loss, only one flare was reported.
“There are some preliminary reports of real-world data in people with SLE using GLP-1 medicines, potentially showing reduced progression to chronic kidney disease,” Drucker said. “All of these studies are hypothesis-generating and await confirmation in RCTs.”
According to Lane, the rationale for GLP-1 receptor agonists in lupus stems from the drugs demonstrating anti-inflammatory properties, potentially by inhibiting the NF-B pathway, which plays a crucial role in inflammation.
End-stage renal disease risk in lupus nephritis may also be mitigated by GLP-1 agonism, she added.
“GLP-1 agonists have been shown to improve cardiovascular outcomes in other populations,” Lane said. “There may be evidence that similar benefits might extend to patients with SLE.”
Meanwhile, according to Drucker, there are multiple trials of GLP-1 receptor agonists underway in PsA and several other rheumatic conditions that are exacerbated in people with increased BMI.
“There is even a trial underway in China looking at semaglutide therapy in systemic scleroderma,” he said.
Karacabeyli and Lacaille reviewed GLP-1 therapy use in inflammatory arthritis in a 2024 paper published in the Journal of Clinical Rheumatology.
“Basic science experiments demonstrated weight-independent immunomodulatory effects of GLP-1 analogs through inhibition of the NF-B pathway (via AMP-activated protein kinase phosphorylation in psoriasis and prevention of IB phosphorylation in rheumatoid arthritis),” the researchers wrote.
They added that while many of the studies are limited by small sample sizes, short follow-up and a lack of control groups, further study of these medications in PsA and RA are warranted.
Looking deeper into results involving patients with psoriatic diseases could be useful, according to Wright.
“We have seen patients report that their psoriasis is better before any significant change in their weight,” she said. “This is a clue for us to build on.”
Wright added that RA is also a “ripe” area for research into GLP-1 agonism.
“Studies suggest that GLP-1 agonists may reduce disease activity, joint pain and swelling in RA patients,” Lane said. “Some research indicates that these drugs may help protect joints and reduce bone erosion, potentially preserving mobility and quality of life. The cardioprotective effects of GLP-1 agonists could be a significant advantage for RA patients, who are at increased risk for heart disease.”
As that research continues, other questions that require interrogation involve the duration of therapy and whether GLP-1 receptor agonism will yield adverse events over the long term.
‘Very few concerns’
Asked about the optimal duration of GLP-1 therapy, Drucker gave a simple answer.
“We don’t know,” he said.
“If someone loses weight and they experience disease remission, how long will this last? Or are the benefits of weight loss independent and do they require ongoing therapy with GLP-1 medicines? We simply do not have enough information to answer these questions today,” he added.
Treatment may require at least “a few years,” according to Lane.
“However, patients may require another full course of therapy, or they may continue the therapy microdosing, as is being evaluated in other disease states,” she said.
Currently, low doses or microdoses are being used to treat or prevent weight gain in some menopausal women, Lane added.
“Maybe some of this microdosing, which we are seeing in clinics for people taking these drugs for cosmetic reasons, is OK,” Wright said. “The problem is that these doses have not been studied on a population scale. People are just making up the doses.”
Although Wright stated she has concerns about this approach, she noted that rheumatologists are no strangers to dose adjustments.
“We use medications off-label all the time in our specialty, and we adjust doses to suit individual patients,” she said. “So, maybe some of these uses will end up being good, but we need to study them first.”
Further study is also necessary for potential long-term adverse events.
“Gastrointestinal issues like nausea, vomiting, diarrhea and constipation have been reported, along with less common but serious risks like pancreatitis and gallbladder problems,” Lane said.
Headaches and injection site reactions may also occur, along with decreased appetite, which is largely responsible for the weight-loss mechanism, she added.
“Gastroparesis may also occur, along with hypoglycemia, especially when combined with other medications that lower blood sugar,” Lane said.
Along with kidney injury, more significant concerns with GLP-1 receptor agonists may also include diabetic retinopathy, thyroid tumors or allergic reactions.
However, Drucker stated he hopes that future research will ease some of these concerns.
“There are very few concerns about serious long term side effects in people with type 2 diabetes or obesity,” he said. “The GLP-1 class of medicines is almost 20 years old. Of course, we have no experience on how people with immune-related or inflammatory disease or individuals, who are also taking immunosuppressive agents, will fare with long term GLP-1 use, and this must be studied.”
In this sense, the class’s history of use over the past 20 years could be a great asset, according to Wright.
“Semaglutide has been around for a while and has been proven to be effective and acceptably safe,” she said. “However, when we start to treat massive numbers of people with less curated care, that is when we have to watch out for adverse effects.”
That means more studies. However, with its list of potential uses and benefits seemingly growing by the day, the opportunities to have significant research into the class moving forward appear robust.
‘Main directions for research’
“The main directions for research are how and where do they suppress inflammation, and whether this related in part, or not related, to their actions in reducing heart, kidney and liver disease, as well as sleep apnea and arthritis,” Drucker said. “It seems that weight loss will likely be very important for the benefits of the GLP-1 medicines in some conditions, and much less important, or not at all essential, for benefits in other disorders.”
According to Lane, although GLP-1 receptor agonists show promise in reducing cardiovascular risk factors, long-term cardiovascular safety trials are needed to assess cardiovascular mortality and events.
“Beyond diabetes and obesity, research is now underway to explore the potential of GLP-1 agonists for other conditions like kidney disease, heart failure, Alzheimer’s, Parkinson’s, sleep apnea and drug addiction,” she said.
Further study should also investigate the mode of delivery, Lane added.
“Developing oral GLP-1 agonists would improve convenience, acceptance and adherence, potentially leading to better treatment outcomes,” she said. “Research should focus on extending the duration of action of GLP-1 agonists, potentially reducing the frequency of injections and improving patient experience.”
Combination therapy with other medications could also be explored. According to Lane, the potential of combining GLP-1 receptor agonists with other therapies, such as dual agonists like GLP-1/GIP or triple agonists like GLP-1/GIP/glucagon, could lead to enhanced efficacy.
“GLP-1 agonists are not a cure for rheumatic diseases, but they may offer a new approach to managing symptoms and improving outcomes,” she said.
References:
Bliddal H, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2403664.
Carlucci PM, et al. Rheumatology (Oxford). 2024;doi:10.1093/rheumatology/keae547.
Karacabeyli D, Lacaille D. J Clin Rheumatol. 2024doi:10.1097/RHU.0000000000001949.
Zhu H, et al. Ann Rheum Dis. 2023;doi:10.1136/ard-2023-223845.
For more information:
Daniel J. Drucker, MD, can be reached at drucker@lunenfeld.ca.
Nancy E. Lane, MD, can be reached at nelane@ucdavis.edu.
Grace C. Wright, MD, PhD, can be reached at grace.wright@awirgroup.org.