A major scientific review published in the Journal of Clinical Investigation has shed new light on the wide-ranging anti-inflammatory effects of glucagon-like peptide 1 (GLP-1)-based therapies, medications originally developed for managing diabetes and obesity.
GLP-1 is a gut-derived hormone encoded by the proglucagon gene and released by intestinal L cells in response to nutrient intake. It plays a central role in regulating insulin and glucagon secretion and led to the development of GLP-1 receptor agonists such as exendin-4, now widely used in the treatment of type 2 diabetes (T2D). Beyond glucose regulation, GLP-1 acts on receptors in organs including the brain, heart, kidneys, and lungs, underscoring its extensive physiological influence.
Over recent years, GLP-1-based drugs like semaglutide, liraglutide, and tirzepatide have transformed the management of diabetes and obesity, particularly in individuals who struggle with weight reduction through lifestyle measures alone. In addition to improving glycemic control and inducing weight loss, these agents reduce the risk of major complications linked to obesity and T2D.
Emerging evidence now shows that GLP-1 therapies also exert direct anti-inflammatory effects, independent of their metabolic benefits. The review highlights that these immune-regulating actions may explain the broad spectrum of clinical advantages observed in patients.
Clinical studies have demonstrated significant reductions in C-reactive protein (CRP), a key marker of systemic inflammation, in patients receiving GLP-1 drugs. Landmark trials such as SUSTAIN and PIONEER reported that only 20–60% of the CRP reduction could be attributed to changes in body weight and glycemic control, suggesting additional mechanisms of inflammation modulation. Experimental work further supports this finding, showing that even a single dose of semaglutide or exenatide can suppress inflammatory cytokines like TNF-α and IL-1β, indicating rapid immune effects that precede measurable weight loss.
In animal studies, GLP-1-based therapies demonstrated neuroprotective potential by reducing microglial inflammation and preventing neuronal injury in conditions such as Parkinson’s and Alzheimer’s disease. PEGylated exenatide (NLY01) was found to inhibit inflammatory signaling in brain cells, while liraglutide improved cognitive performance in Alzheimer’s models.
The review also emphasized cardiovascular benefits. In preclinical models, liraglutide reduced atherosclerotic plaque size and inflammation independently of weight loss, while large clinical trials confirmed that GLP-1 drugs lower cardiovascular event rates in diabetic and obese populations, with benefits observed early in therapy.
Similar anti-inflammatory effects were seen in kidney and liver disease. GLP-1 therapies such as semaglutide and dulaglutide improved organ function and slowed the progression of chronic kidney disease (CKD), reducing the combined risk of kidney failure and cardiovascular death by nearly 24% over four years. In hepatic studies, exenatide analogs decreased liver fat accumulation and inflammation.
Emerging data also indicate potential roles in lung and joint inflammation. Animal experiments showed that liraglutide reduced lung injury and cytokine release during inflammatory responses, while semaglutide alleviated arthritis symptoms and lowered joint inflammatory markers. Early human observations suggest improved osteoarthritis outcomes among obese patients receiving semaglutide.
Although GLP-1 receptors are scarce on immune cells, researchers propose that these anti-inflammatory effects arise through indirect crosstalk between neural, immune, and metabolic pathways. Dual-acting agents such as tirzepatide, which activate both GLP-1 and GIP receptors, may further enhance these actions.
The review concludes that GLP-1-based drugs deliver comprehensive organ-protective and anti-inflammatory benefits, extending well beyond glucose and weight control. While further studies are exploring their roles in neurodegenerative disorders, arthritis, and liver disease, their proven efficacy in improving cardiovascular, renal, and metabolic health marks a new era for these therapies, positioning them as promising tools in combating chronic inflammatory and metabolic diseases.
References
- Wong CK, Drucker DJ. Anti-inflammatory actions of glucagon-like peptide-1-based therapies beyond metabolic benefits. J Clin Invest. 2025 Nov 3;135(21):e194751.
- Mechanisms of action of glucagon-like peptide 1 in the pancreas. | DrugBank Online [Internet]. [cited 2025 Nov 7]. Available from: https://go.drugbank.com/articles/A19193