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

View part 2 of this 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, examine the growing evidence for GLP-1 receptor agonists in rheumatological disease — drugs originally developed for glycemic control that are now drawing serious attention as potential immunomodulators with implications across the specialty.

The conversation opens by tracing the arc of GLP-1 agonist development, from exenatide's approval in 2005 through to semaglutide's landmark cardiovascular and renal data in the SELECT¹ and FLOW² trials, before turning to the question now quietly circulating in rheumatology clinics: are these drugs doing something beyond shifting weight?

Buss sets the immunological groundwork, outlining how adipose tissue functions as an active endocrine organ, driving pro-inflammatory cytokine production — IL-6, IL-1, TNF-alpha — and disrupting T regulatory cell populations in ways that may lower the threshold for autoimmune disease. The obesity–autoimmunity link is far from new, but the mechanisms remain incompletely understood, and the scale of the problem continues to grow.

The clinical consequences are familiar to most rheumatologists: reduced remission rates in rheumatoid arthritis, poorer responses to TNF inhibition, accelerated progression in spondyloarthritis, and the self-perpetuating difficulty of controlling inflammation while corticosteroids actively undermine metabolic health. Weight loss, as bariatric surgery data has long suggested, can meaningfully interrupt this cycle — GLP-1 agonists now offer a far more accessible route to achieving it.

The STEP 9 trial in knee osteoarthritis provides the most direct evidence to date, demonstrating a 41.7% reduction in pain scores with semaglutide over 68 weeks — a magnitude of improvement that has largely eluded the OA field across multiple previous drug trials.³ Whether the benefit reflects reduced mechanical load, direct GLP-1 receptor activity in synovial tissue, or central pain modulation remains an open and genuinely interesting question.

With over 190 incretin-based agents in development and early preclinical data pointing to local anti-inflammatory effects within joints, Arnold and Buss reflect on what rheumatology's relatively late arrival to this field means — and what the specialty still needs to find out.

“We often celebrate quite incremental improvements in rheumatology, and in medicine generally. And I think just seeing somebody come in and say that [a significant] level of pain reduction was met… is fantastic for people in that situation,” Arnold said, referencing the STEP 9 trial data.

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

References

1. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al; SELECT Trial Investigators. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563

2. Perkovic V, Tuttle KR, Rossing P, et al; FLOW Trial Committees and Investigators. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. 2024;391(2):109-121. doi:10.1056/NEJMoa2403347

3. Bliddal H, Bays H, Czernichow S, et al; STEP 9 Study Group. Once-weekly semaglutide in persons with obesity and knee osteoarthritis. N Engl J Med. 2024;391(17):1573-1583. doi:10.1056/NEJMoa2403664