GLP-1 Receptor Agonists: Impacts Beyond Metabolism? Save

The GLP-1 story has been hard to miss this year, and at ACR Convergence, it’s clear that these drugs are starting to make real waves in rheumatology. Across multiple abstracts, investigators have used a large real-world dataset, the TriNetX network, to explore how GLP-1 receptor agonists (GLP-1RAs) might influence cardiovascular, renal and immune-mediated outcomes in our patients.

Cardiovascular and mortality benefits in psoriatic arthritis

In a large retrospective analysis of more than 90,000 psoriatic arthritis (PsA) patients, Tsibadze et al (Abstract 0849) reported that GLP-1RA use was linked to lower risk of major adverse cardiovascular events (MACE) and reduced all-cause mortality compared with PsA patients not taking GLP-1RA. After propensity matching, the outcomes remained the same, despite comparable age, sex, and comorbidity profiles.

While the mechanism is likely multifactorial, including weight loss, improved glycaemic control and reduced systemic inflammation, these data suggest a class effect that may be particularly valuable for PsA, where metabolic and cardiovascular risk are major drivers of long-term morbidity. For clinicians managing patients with both inflammatory arthritis and obesity or type 2 diabetes mellitus (T2DM), this could certainly change how we think about comorbidity management.

Kidney and cardiometabolic outcomes in lupus nephritis

Abstract 0841 compares GLP-1RA and SGLT-2 inhibitors in over 2000 patients with lupus nephritis (LN). After propensity matching, those on GLP-1RA had markedly less progression of chronic kidney disease, lower mortality and fewer myocardial infarctions than patients receiving SGLT-2 inhibitors.

Although retrospective, this is a striking finding. The GLP-1 class has already proven renoprotective in diabetic nephropathy. Seeing similar trends in autoimmune-driven nephritis raises interesting questions about anti-inflammatory or endothelial effects beyond glucose lowering.

Could GLP-1 agonists reduce the risk of developing rheumatic disease?

We may well have suspected the beneficial metabolic outcomes of GLP-1RA in our patients with rheumatic diseases, but what about reducing their onset in the first place? This has been tested in a propensity-matched analysis of over 400,000 individuals with diabetes (Abstract 2657). Compared with DPP-4 inhibitor users, those taking GLP-1RAs had a 13% lower risk of rheumatoid arthritis, 18% lower risk of gout and a modest reduction in osteoarthritis incidence over one year.

No significant effect was seen with lupus, psoriatic arthritis or scleroderma, but the consistent downward trend across multiple inflammatory and metabolic arthropathies adds to the growing notion that GLP-1s may exert broad anti-inflammatory effects.

Safety and inflammatory disease risk in obesity and diabetes

Finally, Chen and Chao (Abstract 2658) analysed the data of nearly 800,000 people with T2DM and 80,000 with obesity. Initiation of GLP-1RAs was not associated with increased risk of immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis, lupus, inflammatory bowel disease or psoriasis. GLP-1RA use was also associated with lower all-cause mortality, fewer cardiovascular events and even reduced incidence of dementia.

So, there is currently no evidence that GLP-1s trigger autoimmunity, a concern occasionally raised in public discussions. Instead, the abstracts presented at ACR appear to indicate multiple benefits.

Where does this leave rheumatologists?

Taken together, these studies reinforce the message that GLP-1Ras may have a role far beyond metabolic control, with positive impacts on comorbidities that dominate long-term outcomes in rheumatic disease.

For our PsA and rheumatoid arthritis patients with obesity or diabetes, GLP-1s might reduce cardiovascular risk and possibly even blunt systemic inflammation. For lupus nephritis, they may offer renal protection. For patients with diabetes alone, GLP-1 use appears not only safe from an autoimmune standpoint but perhaps protective against future rheumatic diseases.

Of course, all four studies share limitations typical of big-data research, with retrospective design, potential coding biases and limited follow-up. However, the combination of findings across independent cohorts and disease states is striking. Future research should focus on prospective, mechanistic work to clarify how these drugs interact with inflammatory pathways and existing medication in our field.