Joint Ventures: GLP-1 Receptor Agonists — From Metabolic Drug to Immunomodulator? Part 2

View part 1 of the episode here.

In this episode of Joint Ventures, hosts Jack Arnold, MBBS, PhD, an academic clinical lecturer in rheumatology at the University of Leeds, and Rihards Buss, MD, a consultant rheumatologist at Freeman Hospital, Newcastle, turn from osteoarthritis to the inflammatory arthritides — examining what early data in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and lupus can and cannot yet tell us about the role of GLP-1 receptor agonists in disease modification.

The RA discussion centers on a 2025 retrospective cohort study published in ACR Open Rheumatology by Kellner and colleagues, which compared 173 patients receiving GLP-1 agonists against 42 controls.¹ The study showed reductions in disease activity, pain scores, ESR, and CRP in the GLP-1 group — but notably, weight loss did not correlate with improvements in inflammatory markers, while it did correlate with metabolic improvements. Arnold and Buss are measured about this: the real-world data caveats are real, and the central mechanistic question remains unresolved — is inflammation being driven down by reduced adipose tissue cytokine production, or is there direct immunomodulatory activity at the level of synovial tissue?

The more striking signal comes from PsA. A press release for a first-of-its-kind trial comparing ixekizumab plus tirzepatide against ixekizumab alone generated considerable discussion.² The primary endpoint — ACR 50 response combined with more than 10% weight reduction — was met decisively by the combination arm (31% vs 0.8%), though Buss raises a pointed question about why that composite endpoint was chosen. The more clinically telling finding sits in the secondary data: ACR 50 achieved without the weight loss criterion showed a 33.5% vs 20.4% response rate, suggesting a meaningful additive effect of incretin-based therapy on top of IL-17 blockade. Both hosts agree this represents the strongest signal yet in rheumatology for adipose tissue as an active driver of disease.

The lupus data is thinner — a small retrospective case series, reassuring on safety with minimal flare signal over 8 months, but not yet hypothesis-confirming. Arnold pivots to what he considers the more immediately compelling argument: across inflammatory diseases, accelerated cardiovascular disease remains a leading cause of mortality, and GLP-1 agonists already have robust evidence for cardiovascular and renal protection in broader populations. Real-world data are beginning to show reduced acute coronary syndrome rates in RA cohorts, lower rates of major adverse cardiovascular events in lupus, and slower CKD progression — outcomes that may justify engagement with these therapies independent of any disease-modifying effect.

The episode closes on a candid note. Buss raises legitimate concerns about stepping outside rheumatology's traditional scope — weight management requires dietary counseling, resistance training, and long-term lifestyle support that most rheumatology services are not currently configured to provide. Arnold agrees but is cautiously optimistic that services will adapt. Both acknowledge that patients are already accessing these drugs privately, and that the field is moving fast enough that waiting for randomized control trial (RCT)-level evidence before forming a clinical view may not be realistic.

“Everyone is talking about [GLP-1 RAs] and what it can do for our patients. Much more evidence is needed to be much more better understanding about increasing effects beyond weight loss is needed. And I think that evidence will be just coming out very rapidly, year by year… but I think this is not the case where we're going to wait for strong evidence, good quality RCT data before we start to start to use them,” Buss said.

Arnold’s disclosures include Alumis, Roche, and Novartis. Buss has no relevant disclosures to report.

References

1. Kellner DA, Dente E, Tran V, et al. Effect of glucagon-like peptide 1 receptor agonists on patients with rheumatoid arthritis. ACR Open Rheumatol. 2025;7(9):e70103. doi:10.1002/acr2.70103

2. Eli Lilly and Company. Lilly's Taltz (ixekizumab) and Zepbound (tirzepatide) used together delivered superior efficacy in first-of-its-kind phase 3b trial for adults with active psoriatic arthritis and obesity or overweight [press release]. January 8, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-taltz-ixekizumab-and-zepbound-tirzepatide-used-together