From Diabetes to Inflammation: The Expanding Therapeutic Landscape of GLP-1 receptor agonists and Multi-Hormone Receptor Modulators

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Glucagon-like peptide-1 (GLP-1) receptor agonists have attracted significant attention as a relatively new class of drugs. Initially developed for diabetes management, their therapeutic scope quickly expanded beyond glycemic control. They demonstrated strong effects on obesity, even in patients without diabetes (1). Soon after, drugs combining GLP-1 receptor agonism with other hormone receptor modulators—often derived from the gut or pancreas, such as glucose-dependent insulinotropic polypeptide (GIP) or amylin—emerged. Collectively termed multi-hormone receptor modulators (MHRM) (2), these agents achieved impressive weight loss previously seen only with bariatric surgery (3).

Alongside studies describing newer and more potent MHRMs, evidence emerged supporting their broader therapeutic potential. These agents can now be used across a wide range of conditions (4), offering cardiorenal protection (5, 6) and improving metabolic dysfunction-associated steatotic liver disease (MASLD) (7), obstructive sleep apnea (8), and polycystic ovary syndrome (9). Interestingly, many of these effects appear to extend beyond fat mass reduction alone and likely relate to decreased systemic inflammation.

This raises questions about their role in treating autoimmune and inflammatory conditions, which are often linked to obesity and metabolic dysfunction (10). In knee osteoarthritis, semaglutide reduces knee pain and improves physical function (11). Future studies will hopefully clarify whether this occurs via weight loss or through a direct anti-inflammatory effect, as well as their potential in other rheumatic diseases.

Dr. Eline van der Valk

Endocrinologist

Utrecht University Medical Centre, Netherlands

References

  1. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF; STEP 1 Study Group. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. doi: 10.1056/NEJMoa2032183.
  2. Muskiet MHA, Smits MM. Beyond a singular focus on glp-1: Why we need a new nomenclature now. Lancet Diabetes Endocrinol. 2025;13(9):730-3. doi: 10.1016/S2213-8587(25)00197-4.
  3. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A; SURMOUNT-1 Investigators. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-16. doi: 10.1056/NEJMoa2206038.
  4. Moiz A, Filion KB, Tsoukas MA, Yu OHY, Peters TM, Eisenberg MJ. The expanding role of glp-1 receptor agonists: A narrative review of current evidence and future directions. EClinicalMedicine. 2025;86:103363. doi: 10.3390/cimb47040285. 
  5. Hosseinpour A, Sood A, Kamalpour J, Zandi E, Pakmehr S, Hosseinpour H, Sood A, Agrawal A, Gupta R. Glucagon-like peptide-1 receptor agonists and major adverse cardiovascular events in patients with and without diabetes: A meta-analysis of randomized-controlled trials. Clin Cardiol. 2024;47(7):e24314. doi: 10.1002/clc.24314.
  6. Colhoun HM, Lingvay I, Brown PM, Deanfield J, Brown-Frandsen K, Kahn SE, Plutzky J, Node K, Parkhomenko A, Rydén L, Wilding JPH, Mann JFE, Tuttle KR, Idorn T, Rathor N, Lincoff AM. Long-term kidney outcomes of semaglutide in obesity and cardiovascular disease in the select trial. Nat Med. 2024;30(7):2058-66. doi: 10.1038/s41591-024-03015-5. 
  7. Sanyal AJ, Newsome PN, Kliers I, Østergaard LH, Long MT, Kjær MS, Cali AMG, Bugianesi E, Rinella ME, Roden M, Ratziu V; ESSENCE Study Group. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089-99. doi: 10.1056/NEJMoa2413258.
  8. Malhotra A, Grunstein RR, Fietze I, Weaver TE, Redline S, Azarbarzin A, Sands SA, Schwab RJ, Dunn JP, Chakladar S, Bunck MC, Bednarik J; SURMOUNT-OSA Investigators. doi: 10.1056/NEJMoa2404881.
  9. Zhou L, Qu H, Yang L, Shou L. Effects of glp1ras on pregnancy rate and menstrual cyclicity in women with polycystic ovary syndrome: A meta-analysis and systematic review. BMC Endocr Disord. 2023;23(1):245. doi: 10.1186/s12902-023-01500-5
  10. den Braanker H, van der Valk ES, Bisoendial RJ. A lymphatic perspective on obesity and inflammatory arthritis: New disease-modifying potential in rheumatology. J Clin Med. 2025;14(21). doi: 10.3390/jcm14217641.
  11. Bliddal H, Bays H, Czernichow S, Uddén Hemmingsson J, Hjelmesæth J, Hoffmann Morville T, Koroleva A, Skov Neergaard J, Vélez Sánchez P, Wharton S, Wizert A, Kristensen LE; STEP 9 Study Group. Once-weekly semaglutide in persons with obesity and knee osteoarthritis. N Engl J Med. 2024;391(17):1573-83. doi: 10.1056/NEJMoa2403664.

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