The central role of IL-6 in the differential effects of GLP-1 receptor agonists and metformin across multiple health conditions

An earlier publication suggested that elevated TGF-β1 together with IL-1β and IL-6 drives neutrophilic asthma, increases cancer risk, and is associated with metabolic dysregulation. This article examines how these cytokines shape the therapeutic efficacy and safety profiles of GLP-1 RAs compared with metformin. Integrating published data, stronger suppression of circulating IL-6 likely contributes to the superior efficacy of GLP-1 RAs in lowering blood glucose, improving insulin sensitivity in patients with polycystic ovary syndrome (PCOS), reducing cardiovascular risk, and reducing osteoarthritis-related perioperative infections, but not to their superior weight-loss effects. Superior weight loss, which is IL-6 independent, further enhances the efficacy of GLP-1 RAs in improving metabolic dysfunction-associated steatohepatitis (MASH), PCOS, and survival in cancer patients. Systemic IL-6 suppression may also explain the higher frequency of allergic adverse effects with GLP-1 RAs, whereas local interference with IL-6 signaling in the gastrointestinal tract, shared by both agents, likely accounts for frequent gastrointestinal adverse events reported with both. Although metformin may be more effective in improving asthma outcomes in the general asthma population, GLP-1 RAs are likely to be more effective in neutrophilic asthma. Metformin also reduces osteoarthritis-related joint pain, consistent with the limited efficacy of IL-6R inhibition in reducing this pain. Finally, the lack of effect of IL-6 pathway inhibitors on cancer incidence may explain the similar efficacy of GLP-1 RAs and metformin in reducing the risk of most cancers.