Glucagon-like peptide-1 receptor agonists (GLP-1RA) were originally developed for treatment of type 2 diabetes and obesity. Interest in rheumatology has increased because these agents demonstrate multiple effects beyond glycemic control, including metabolic improvement, weight reduction, and immunomodulatory actions. The reviewed article synthesizes mechanistic data and clinical findings that link GLP-1RA to potential therapeutic roles in several rheumatic diseases, noting both promising signals and important evidence gaps.
The reviewed work highlights two principal pathways by which GLP-1RA may influence rheumatic disease activity.
Indirect metabolic pathway: GLP-1RA promote weight loss and improve components of metabolic dysfunction. These metabolic effects can reduce systemic inflammation and thereby indirectly lower inflammatory burden in rheumatic conditions.
Direct cellular effects: GLP-1 receptors are expressed on immune cells and on cells of the musculoskeletal system. GLP-1RA can directly act on these receptors to exert anti-inflammatory and tissue-protective effects that are described as independent of weight loss. The review emphasizes that both pathways likely contribute to clinical outcomes, but that disentangling their relative contributions remains a challenge.
The article summarizes available clinical data across multiple rheumatic conditions with emerging evidence of benefit from GLP-1RA:
Osteoarthritis: Evidence from real-world studies and randomized trials suggests potential improvements in disease activity and reductions in cardiovascular outcomes in patients receiving GLP-1RA, though study designs and populations vary.
Rheumatoid arthritis (RA): Several studies report associations between GLP-1RA use and improved disease activity metrics as well as cardiovascular benefits. The body of evidence includes observational data and some randomized controlled trial data, but limitations are noted.
Psoriasis and psoriatic arthritis: Clinical signals indicate that GLP-1RA may improve skin and joint disease activity and could reduce cardiovascular events in these populations, based on available cohort and trial data.
Systemic lupus erythematosus (SLE): Preliminary studies indicate potential improvements in disease parameters and cardiovascular outcomes with GLP-1RA, but the evidence is still limited.
Across these disease areas, the review reports that several large real-world studies and randomized controlled trials have shown potential benefits, including reduced cardiovascular events and mortality. However, the authors consistently caution that many findings derive from heterogeneous study designs and populations.
The authors identify multiple important constraints in the evidence supporting GLP-1RA use in rheumatology:
Predominance of retrospective and observational studies in the literature, which are susceptible to bias and confounding.
Limited sample sizes in many studies, reducing statistical power.
Tendency to analyze different GLP-1RA agents as a single drug class, which obscures potential agent-specific effects.
Difficulty separating the anti-inflammatory effects that result from weight loss from direct pharmacologic immunomodulation.
Lack of randomized controlled trials specifically enrolling non-obese, non-diabetic rheumatic patients to test efficacy independent of metabolic comorbidities.
These limitations mean current positive signals must be interpreted cautiously and cannot yet support broad application beyond selected populations.
Based on the synthesized evidence and its limitations, the authors recommend a conservative clinical stance. They propose that, at present, GLP-1RA should be considered for rheumatic patients who have comorbid overweight or obesity or type 2 diabetes and who also carry high cardiovascular risk. The rationale is that these patients may obtain both metabolic and cardiovascular benefit in addition to any disease-specific effects, while the evidence in metabolically healthy rheumatic patients remains insufficient.
The review outlines specific research priorities to address current gaps:
Head-to-head clinical comparisons of different GLP-1RA agents to determine whether effects vary across specific drugs rather than the class as a whole.
Mechanistic studies explicitly designed to dissociate effects that are independent of weight loss, for example through trials in non-obese populations or mechanistic biomarker studies.
Exploration of combination strategies pairing GLP-1RA with established rheumatology therapies to define additive or synergistic effects.
The authors argue these priorities are essential to clarify the role of GLP-1RA within a proposed “metabolic-immune” intervention framework for rheumatic disease.
GLP-1RA represent a promising avenue for integrated metabolic-immune therapy in rheumatology. Accumulating data suggest benefits for disease activity and cardiovascular outcomes in osteoarthritis, RA, psoriasis/psoriatic arthritis, and SLE, mediated through both indirect metabolic improvements and direct receptor-mediated actions on immune and musculoskeletal cells. Nevertheless, the current evidence base has substantial methodological limitations. The authors advocate restricting GLP-1RA use to rheumatic patients with overweight/obesity or type 2 diabetes who have high cardiovascular risk, while calling for targeted randomized trials, head-to-head comparisons, and mechanistic research to define efficacy and safety across broader rheumatology populations.
Conflict of interest: the authors declared no conflicts. Funding sources noted in the original article include National Natural Science Foundation of China grants 82302018 and 82372369.