Two real-world analyses presented at the American College of Rheumatology Convergence 2025 revived an important clinical question for rheumatologists and endocrinologists: Can medications developed for type 2 diabetes also modulate articular inflammation?

“We are seeing the boundary between metabolism and inflammation dissolve in practice,” said Licia Maria Henrique da Mota, MD, PhD, professor of rheumatology at the Department of Rheumatology, University of Brasília, Brasília, Brazil. “These findings reinforce the hypothesis that the immunometabolic axis is not theoretical. It has clinical implications, particularly in rheumatoid arthritis, obesity, and metabolic syndrome.”

Marcelo de Medeiros Pinheiro, MD, PhD, associate professor of rheumatology at the Federal University of São Paulo in São Paulo, Brazil, said, “The results are provocative. They suggested that drugs originally developed for metabolic diseases may exert anti-inflammatory effects. But we need pragmatic trials to separate metabolic effects from immunologic effects.”

Rheumatoid arthritis (RA) is a chronic autoimmune disease mediated by the activation of T and B lymphocytes, as well as the production of pro-inflammatory cytokines, including TNF-alpha and interleukin-6. In addition to joint destruction, patients with RA have a 1.5-2 times higher risk for cardiovascular events, an effect resulting from persistent systemic inflammation.

A study led by Shreya Sakthivel, DO, chief resident in internal medicine at Luminis Health Anne Arundel Medical Center, Annapolis, Maryland, analyzed data from the TriNetX global electronic health network between 2019 and 2024.

Speaking with Medscape’s Portuguese edition, she said, “Patients with RA have chronic inflammation and a high cardiovascular risk; if drugs that improve metabolism also modulate immunity, this could change clinical practice.”

Adults with RA who had more than 1 year of follow-up after initiating disease-modifying antirheumatic drugs (DMARDs) were grouped into DMARDs only (n = 12,214), DMARDs + SGLT2 inhibitor (n = 226), and DMARDs + GLP-1 receptor agonist (n = 329).

Patients with other types of inflammatory arthritis, cancer, transplants, pregnancy, or prolonged corticosteroid use were also excluded from the study.

The primary endpoint was the total flare burden based on a composite score of flare-related events: one point each for oral prednisone use, elevated C-reactive protein level (≥ 10 mg/L), elevated erythrocyte sedimentation rate (≥ 20 mm/h), and DMARD escalation, and one point per three intravenous steroid uses or per three joint injections.

Key Outcomes

In the SGLT2 inhibitor group, the flare proportion reduced from 34.1% to 12% (P = .0407), whereas in the GLP-1 receptor agonist group, it decreased from 41% to 20.7% (P = .1525).

The results demonstrated that DMARDs + GLP-1 receptor agonist users had the highest composite score (1.71), suggesting a greater flare burden than DMARDs + SGLT2 inhibitor (1.30) and DMARDs alone (1.12) (P < .001).

“There is a biological signal of benefit with SGLT2 inhibitors that extends beyond glycemia,” said Sakthivel. “They appear to influence inflammatory pathways directly, reduce oxidative stress, and modulate innate immunity.”

According to Pinheiro, this finding aligns with emerging evidence: “SGLT2 inhibitors have been shown to affect oxidative stress and inflammatory pathways in experimental models. Seeing this pattern in RA is intriguing, but it is too early to infer a causal effect.”

The absence of standardized clinical indices, including the Disease Activity Score in 28 joints scores or the Clinical Disease Activity Index, is acknowledged by the author as a limitation. 

“Prospective studies with objective measures and stratification by body mass index and comorbidities are needed to determine whether these findings hold true in patients without diabetes,” said Sakthivel.

“The pathophysiological rationale is strong,” Henrique da Mota added.

“SGLT2 inhibitors influence the NLRP3 inflammasome and reduce subclinical inflammation. GLP-1 agonists act indirectly through metabolic improvement. Even so, that may not be sufficient to modulate an established autoimmune condition.”

Joint Degeneration

Another study, led by Michael LaValley, PhD, professor of biostatistics at Boston University School of Public Health, Boston, evaluated 323,000 adults from the Merative MarketScan database (2015-2022). Participants were aged 45-65 years, had a mean age of 55 years, and 49% were men.

Individuals with a prior diagnosis of osteoarthritis, fibromyalgia, RA, or arthroplasty were excluded from the study.

The comparison of GLP-1 receptor agonists (n = 129,603) and SGLT2 inhibitors (n = 193,842) included only those without previous osteoarthritis or arthroplasty, and they were followed for 5 years. A per-protocol approach was used with adjustments for treatment switches and discontinuation to better reflect routine clinical practice.

“We wanted to understand the sustained effect of the therapy,” said LaValley. “Since there is a high discontinuation rate with GLP-1 [agonists], the per-protocol model allows us to capture the real impact of continuous use.”

Nene Ukonu, PhD candidate and coauthor at the Boston University School of Public Health, Boston, noted that the analysis was designed to emulate the structure of a clinical trial. “In complex diseases, when randomized trials may be unfeasible or expensive, we use observational data to emulate a ‘targeted trial.’ This means analyzing the data as if it were a randomized study, considering adherence and medication changes,” she said.

The findings showed that users of GLP-1 receptor agonists had an 18% higher risk for knee arthroplasty (hazard ratio [HR], 1.18) and a 16% higher risk for osteoarthritis (HR, 1.16) than users of SGLT2 inhibitors.

“The effect of SGLT2 [inhibitors] was comparable to that of semaglutide, which is the GLP-1 agonist associated with the greatest weight loss,” Ukonu said. 

“But when we analyzed the entire class of GLP-1 receptor agonists, especially those not based on semaglutide, the use of SGLT2 inhibitors was associated with a lower risk for osteoarthritis, suggesting that these drugs may have their own therapeutic effect on the disease.”

Sensitivity analyses showed that semaglutide did not increase this risk, suggesting differences within classes. “Studies show that semaglutide promotes approximately 10% more weight loss than other drugs in the same class,” added Ukonu.

This supports the need to understand whether weight or BMI mediates the effect of GLP-1 receptor agonists on osteoarthritis.

According to Henrique da Mota, the paradox is understandable, and he stated that “Patients who receive GLP-1 agonists are generally more obese and have more advanced osteoarthritis. In addition, rapid weight loss without preservation of lean mass can lead to instability of the joints.

“If confirmed, the chondroprotective effect of the SGLT2 inhibitor would add to the already known cardioprotective and nephroprotective benefits,” said Pinheiro. “But it needs to be proven with imaging and biomarkers before any clinical repositioning.”

Immune Metabolic Axis

The research presented at the meeting highlighted SGLT2 inhibitors as immunometabolic modulators with anti-inflammatory effects that may benefit patients with rheumatic diseases and degenerative joint processes.

Recent evidence supports this pattern. An Israeli national cohort (n = 138,397), published in 2025, found that among people with type 2 diabetes and established atherosclerotic cardiovascular disease, treatment with SGLT2 inhibitors and/or GLP-1 receptor agonists was associated with substantial reductions in all-cause mortality. The relative risk for death decreased to 0.28 (95% CI, 0.27-0.29) with an SGLT2 inhibitor, to 0.39 (95% CI, 0.37-0.4) with a GLP-1 agonist, and to 0.17 (95% CI, 0.16-0.18) when both classes were used compared with untreated individuals.

These real-world data support the view that metabolic modulation by SGLT2 inhibitors and GLP-1 receptor agonists can reduce inflammatory pathways and improve cardiovascular and systemic outcomes, consistent with the biological mechanisms described in rheumatologic findings.

According to Pinheiro, these implications are conceptual. “We are entering an era in which metabolism dictates the pace of inflammation.” He stated that the boundaries between endocrinology, cardiology, and rheumatology are narrowing as chronic disease management becomes increasingly integrated.

Henrique da Mota noted that the results remain hypothesis-generating. She stated that clinical trials with primary rheumatology endpoints and cost-effectiveness analyses, particularly in Brazil, are still needed to determine the therapeutic potential of these drug classes.

“Metabolism, the immune system, and the joints speak the same language. In this context, perhaps SGLT2 inhibitors are the first translators of this new era of integrated medicine,” concluded Shreya, who viewed this as the beginning of a new phase in modern rheumatology.

Daniela Barros is a journalist from Brazil, specializing in social journalism at the Pontifical Catholic University of São Paulo, Brazil, and a master’s student in the Department of Social Medicine at the Ribeirão Preto Faculty of Medicine, Ribeirão Preto, Brazil. She has been involved in medicine for 23 years and has contributed to several specialized publications.

This story was translated from Medscape’s Portuguese edition.