Beyond Weight-Loss: How GLP-1-Based Therapies Affect Immunity and Inflammation
- MedReport Foundation
- Jul 21
- 5 min read
Introduction
Obesity is a complex medical condition that is closely linked with serious health complications, including type 2 diabetes, cardiovascular diseases, hypertension among others. Medications aimed at weight reduction have been attempted since the early 20th century, although most are limited by significant adverse effects. Since the early 2020s, a new class of drugs known as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1Ras) has demonstrated safe and effective use in large clinical trials (1). Following FDA approval, these medications have shown substantial real-world impact, with placebo-adjusted weight loss from approximately 4 to 18% of total body weight at the highest dose studies depending on the specific medication (2). These medications include dulaglutide (Trulicity), semaglutide (Wegovy, Ozempic, Rybelsus) liraglutide (Victoza/Saxenda) and tirzepatide (Mounjaro, Zepbound). Since 2024, a health tracking poll by KFF estimated that approximately 1 in 8 U.S. adults aged 18 or order report having used these medications, including 26.5% of adults with diagnosed diabetes (3, 4). This widespread use necessitates a deeper understanding of the effects of GLP-1RAs on the body beyond weight-loss.
How do GLP-1 receptor agonist-based medications work?
Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin hormone produced in the gut that plays a key role in metabolic regulation. It lowers blood glucose levels by stimulating
insulin secretion by pancreatic beta cells and inhibiting glucagon release from pancreatic alpha cells, slowing gastric emptying and promoting feelings of fullness (1). However, this hormone has a very short half-life being rapidly broken down by dipeptidyl peptidase-4 (DPP-4) enzymes. GLP-1RAs are structurally modified in various ways to resist this degradation,
extending their half-life and prolonging GLP-1 activity (1). Dual-incretin hormone agonists
such as Tirzepatide (Mounjaro/Zepbound) uniquely combine the remarkable effects of GLP-
1RAs with a second incretin hormone agonist, GIP (Gastric inhibitory polypeptide). This dual
agonist stimulates insulin release upon oral food intake producing greater reductions of
hyperglycemia compared with GLP-1RA alone (1,5).
Do GLP-1 receptor agonists affect the immune system?
Our immune system protects our body from harmful stimuli such as pathogens, foreign
substances, and allergens through inflammatory responses. When inflammation fails to resolve and becomes persistent, it is considered chronic. Chronic inflammation can lead to tissue damage, loss of organ function, reducing quality of life, increasing mortality and higher
healthcare costs. Obesity is widely recognized a state of low-grade chronic inflammation
prompting researchers to investigate both direct and indirect effects of GLP-1RAs on immune
responses(5,6,7,8). GLP-1 exerts its effects by binding to GLP-1 receptors expressed on certain cells in a “lock-and-key” manner. When this binding occurs, it sets off signalling cascades within the cells that alter cellular behaviour (1). GLP-1 and GIP receptors are expressed on multiple cell types, including immune cells such as monocytes, natural killer (NK) cells, T cells, B cells and regulatory T cells (5,6). When these incretin hormones bind their receptors on these cells, they modulate signalling pathways such as NF-kB, MAPK, PKA/STAT and P13K/Akt (5,6,7). This signalling shift reduces levels of pro-inflammatory cytokines including IL-17, TNF-a, IL-6, IL-1b (5,6,7). Certain immune cells such as monocytes/macrophages were also found to produce anti-inflammatory cytokines such as IL-10 when exposed to GLP-1Ras. These effects have been observed in animal disease models and in vitro studies using human or murine cells (6). In addition to the direct immunomodulatory effects, GLP-1RAs indirectly influence immune function through the more systemic changes in glucose metabolism, changes in adipose tissue and altered gut microbiota, all of which contribute to reduced inflammatory activity (6).
What inflammatory conditions might be improved by GLP-1 receptor agonists?
To date, most evidence regarding the effects of GLP-1 receptor agonists on inflammatory
diseases comes from retrospective studies. In these studies, patients receiving GLP-1RAs for type 2 diabetes or weight loss are evaluated for changes in pre-existing inflammatory
conditions or the development of new inflammatory diseases (8). The most promising findings have emerged in chronic autoimmune disorders, including multiple sclerosis (MS), inflammatory arthritis, systemic lupus erythematosus (SLE), and psoriasis. Observational studies in MS suggest that GLP-1RA use does not increase adverse outcomes and may even confer protective effects. Animal models of MS similarly demonstrate reduced inflammation, decreased disease activity, and enhanced neuronal repair following GLP-1RA treatment (8,9). In inflammatory arthritis, one study reported that approximately 60% of patients with rheumatoid arthritis or psoriatic arthritis experienced reduced disease
activity while receiving GLP-1 receptor agonists (7,8). In patients with psoriasis, treatment
with liraglutide resulted in significant improvement in skin lesions (7,8). Reduced disease onset has also been observed for SLE among patients with type 2 diabetes and obesity (8). The relationship between GLP-1 receptor agonists and inflammatory bowel disease (IBD),
including Crohn’s disease and ulcerative colitis, appears more complex. Two out of three
studies reported a lower incidence of new-onset IBD among GLP-1RA users. Additional
studies observed reductions in steroid use, hospitalization, surgery, and mortality among IBD
patients receiving GLP-1RAs, although some also reported a higher incidence of adverse
events (7,8).
Another inflammatory context in which GLP-1RAs may have therapeutic potential is solid
organ transplantation, where graft rejection is driven in part by inflammatory processes. In
animal models, GLP-1RAs have been shown to reduce immune cell infiltration into
transplanted tissue, decrease inflammatory biomarkers, and increase anti-inflammatory
markers (6). Whether these effects translate into clinical benefit in human transplantation
remains to be determined.
What’s next?
The emerging evidence that GLP-1 receptor agonists may beneficially modulate chronic
inflammation in patients treated for obesity or type 2 diabetes highlights exciting opportunities for drug repurposing. These already FDA-approved therapies could potentially be used as primary or adjunctive treatments for inflammatory diseases, particularly in patients with coexisting metabolic syndrome. However, further clinical investigations are essential. Large-scale retrospective and prospective studies are needed to identify which patient populations are most likely to benefit while minimizing adverse effects. Additionally, mechanistic studies are required to better understand how GLP-1 receptor agonists influence immune responses in different contexts. Such insights will be critical for predicting their effects in situations where robust pro-inflammatory immunity is required, including infection control, vaccine responses, and tumor surveillance (10).
Overall, GLP1RAs hold enormous potential in improving outcomes and the quality of life in
patients with chronic inflammatory diseases.
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