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

Sep 22, 2026

An earlier hypothesis links elevated TGF-b1 with IL-1b and IL-6 to neutrophilic asthma, cancer risk, and metabolic dysregulation. This article evaluates how IL-1b, IL-6, and TGF-b/Smad signaling help explain differences in therapeutic efficacy and safety between GLP-1 receptor agonists (GLP-1 RAs) and metformin across multiple conditions. Integrating published evidence, stronger IL-6 suppression may underlie superior glucose control, insulin sensitivity in PCOS, cardiovascular risk reduction, and fewer osteoarthritis-related perioperative infections, while weight loss appears IL-6 independent. Systemic IL-6 suppression may also increase allergic adverse effects, whereas shared gastrointestinal pathway interference likely drives GI events. Metformin may better address general asthma and osteoarthritis pain, and similar cancer risk reduction may reflect limited cancer effects of IL-6 pathway inhibitors.

LanguageEnglish

CategoryResearch & Report

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Pages27

Reading Time1 h 8 min

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Introduction

GLP-1 RAs downregulate IL-1b, IL-6, and the TGF-b/Smad signaling pathway in T2D patients

TYPE Hypothesis and Theory PUBLISHED 21 July 2026 DOI 10.3389/fimmu.2026.1864104 OPEN ACCESS EDITED BY Li-Tung Huang, Kaohsiung Chang Gung Memorial Hospital, Taiwan REVIEWED BY Hua Tang, Shandong First Medical University, China Alessandra Tomasello, University of Palermo, Italy *CORRESPONDENCE Zeev Elkoshi [zeev.elkoshi@gmail.com](zeev.elkoshi@gmail.com) RECEIVED 24 April 2026 REVISED 18 June 2026 ACCEPTED 22 June 2026 PUBLISHED 21 July 2026 CITATION Elkoshi Z (2026) The central role of IL-6 in the differential effects of GLP-1 receptor agonists and metformin across multiple health conditions. Front. Immunol. 17:1864104 . doi: 10.3389/fimmu.2026.1864104 COPYRIGHT © 2026 Elkoshi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. The central role of IL-6 in the differential effects of GLP-1 receptor agonists and metformin across multiple health conditions Zeev Elkoshi* Retired, Kfar Saba, Israel An earlier publication suggested that elevated TGF-b1 together with IL-1b 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 inneutrophilic 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. KEYWORDS cancer, cardiovascular disease, GLP-1 receptor agonists, metabolic dysfunction– associated steatohepatitis, metabolic dysregulation, metformin, osteoarthritis, polycystic ovary syndrome Frontiers in Immunology 01 [frontiersin.org](frontiersin.org) Elkoshi 10.3389/fimmu.2026.1864104 GRAPHICAL ABSTRACT Introduction Glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially introduced for type 2 diabetes (T2D), have increasingly become central to medical obesity treatment. In clinical trials, these agents frequently achieve 15–20% reductions in body weight, marking a substantial therapeutic impact. The regulatory authorization of liraglutide, semaglutide, and tirzepatide for long-term weight management has further broadened their clinical application (1) . Multiple large cardiovascular outcomes trials have shown that GLP-1 RAs lower the incidence of major adverse cardiovascular events (MACE) in patients with T2D who are at elevated cardiovascular

FAQs

What earlier hypothesis does the article build on?

It builds on an earlier publication proposing that elevated TGF-b1 together with IL-1b and IL-6 drives neutrophilic asthma, increases cancer risk, and is linked to metabolic dysregulation.

How does IL-6 suppression relate to the efficacy of GLP-1 receptor agonists versus metformin?

Stronger suppression of circulating IL-6 is suggested to contribute to greater efficacy of GLP-1 RAs for lowering blood glucose and improving insulin sensitivity, including in PCOS, and for reducing cardiovascular risk and osteoarthritis-related perioperative infections.

Why might GLP-1 receptor agonists and metformin differ in adverse effect profiles?

The article proposes that systemic IL-6 suppression may explain higher frequencies of allergic adverse effects with GLP-1 RAs, while local interference with IL-6 signaling in the gastrointestinal tract—shared by both agents—may account for common gastrointestinal adverse events.

Sep 22, 2026

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