Findings hint at a dual-purpose role for the drugs in managing both systemic inflammation and comorbidities in RA.
Medications that have already reshaped the landscape of obesity and diabetes care may be on the verge of transforming treatment for rheumatoid arthritis as well.
A new retrospective study from UCLA, published in ACR Open Rheumatology, suggests that GLP-1 RAs such as semaglutide and tirzepatide not only lower body weight and improve metabolic health, but also reduce RA disease activity and patient-reported pain.
The findings open the door to a possible dual-purpose role for these drugs in treating both systemic inflammation and cardiovascular comorbidity in RA.
The study found that semaglutide and tirzepatide, drugs widely prescribed for diabetes and obesity, were linked to lower RA disease activity, reduced pain, and better metabolic outcomes compared with patients who did not use them.
“To our knowledge, this is the first study to examine the effect of GLP-1 RA use on RA disease activity and cardiovascular risk profile in patients with RA and overweight or obesity,” the researchers wrote.
“We found that GLP-1 RA use was associated with significant improvement in RA disease activity, pain, and cardiovascular risk profile. The presence of diabetes did not meaningfully affect these results, suggesting that these benefits were not unique to patients with diabetes.”
The study included 229 patients with RA and overweight or obesity (BMI ≥27) who were prescribed a GLP-1 RA between 2018 and 2024.
Of these, 173 patients initiated therapy while 42, who were prescribed but did not take the medication, served as controls.
Patients were followed for up to one year, with outcomes assessed at three-month intervals. Disease activity was classified as remission, mild, moderate or severe based on rheumatology notes, and cardiometabolic measures and laboratory values were collected when available.
Results showed that patients who used a GLP-1 RA experienced greater reductions in disease activity and pain compared with controls.
On average, RA disease activity scores decreased while controls experienced a slight worsening. Pain scores also declined in treated patients, while they increased in the control group.
Beyond joint symptoms, GLP-1 RA users lost significantly more weight, lowered their haemoglobin A1c and improved their cholesterol profile. Within the treatment group, further reductions were seen in inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein, as well as triglycerides and low-density lipoprotein cholesterol.
Interestingly, the improvements in RA outcomes were not strongly correlated with the degree of weight loss. Patients who lost more than 5% of their body weight showed greater improvement in glycaemic control, but reductions in pain and inflammatory markers occurred independently of weight loss.
This finding hints at potential anti-inflammatory effects of GLP-1 RAs beyond their impact on adiposity, the researchers said.
Preclinical studies have suggested that GLP-1 signalling may downregulate proinflammatory cytokines, and clinical evidence from trials in osteoarthritis has shown reductions in pain with semaglutide. The present study raises the possibility that similar mechanisms could be at play in RA, the researchers said.
Tolerability and access, however, remain significant considerations. Nearly one-third of patients discontinued treatment during the study period, most often due to gastrointestinal side effects or insurance coverage issues.
About 15% of the treatment group experienced gastrointestinal intolerance. The authors noted that discontinuation rates may have limited the overall effectiveness of therapy, particularly given that many patients did not reach target doses typically prescribed for weight loss.
Also notable were disparities in treatment continuation. White patients were significantly more likely than patients of other racial or ethnic groups to remain on GLP-1 RAs, despite similar prescribing rates.
The authors suggested that insurance barriers, cultural beliefs and concerns about side effects may play a role in this discrepancy, echoing findings from prior research showing lower uptake of GLP-1 RAs among black, Hispanic and Asian patients.
They recommended that future studies should prioritise more diverse cohorts to assess the generalisability of outcomes.
Although encouraging, the results of this study should be interpreted in the context of several key limitations, the researchers said.
“These include its single-centre, retrospective design; the limited sample size; and the potential for unmeasured confounding factors – such as reasons underlying the decision to initiate GLP-1 RA therapy – that could have influenced RA outcomes,” they wrote.
“Although we performed sensitivity analyses adjusting for diabetes, hypertension, race, and seropositivity, residual confounding from unmeasured factors may still be present.”
Additionally, EHR progress notes often lacked composite RA disease activity scores, such as Disease Activity Score in 28 joints and Clinical Disease Activity Index.
“We assessed disease activity using the categorisation system described already, but this is less precise than a validated RA disease activity score,” they wrote.
“Despite these limitations, our observational data provide timely and important insights that may inform future research.”
They described their findings that GLP-1 RAs are associated with decreases in RA disease activity, cardiovascular risk factors, and pain in patients with RA and overweight or obesity as “promising” and said they could have substantial clinical implications for this patient population.
“They [the findings] suggest that this drug class, typically used for managing diabetes and obesity, may serve as a dual-purpose treatment for patients with RA, addressing both systemic inflammation and associated comorbidities, such as cardiovascular disease, which is especially prevalent in patients with RAO and remains the leading cause of death in patients with RA overall,” they said.
“Going forward, clinicians may consider integrating GLP-1 RAs into the treatment regimens for patients with RAO, not only to target obesity-related complications but also possibly to target the underlying inflammatory disease process.
“However, further research is needed to confirm that the improvements in systemic inflammation and joint symptoms observed with these therapies are also tied to improvements in joint inflammation.”
