Antiinflammatory actions of glucagon-like peptide-1–based therapies beyond metabolic benefits
Chi Kin Wong, Daniel J. Drucker · 2025 · 103 citationsRead the paper
Therapies based on glucagon-like peptide-1 (GLP-1) reduce rates of cardiovascular and chronic kidney disease in people with type 2 diabetes and/or obesity, with ongoing clinical trials investigating their effects in people with metabolic liver disease, arthritis, and both substance use and neurodegenerative disorders. Acute and chronic activation of GLP-1 receptor signaling also reduces systemic and tissue inflammation in mice and humans, through weight loss-dependent and -independent mechanisms, actions that may contribute to the expanding spectrum of clinical benefits ascribed to GLP-1 medicines. In this Review, we highlight current understanding of the direct and indirect antiinflammatory effects and mechanisms of GLP-1 medicines in both preclinical and clinical studies, covering emerging concepts, clinical relevance, and areas of uncertainty that require further investigation.
What the full text shows
Tested in real conditions- Oral semaglutide reduced C-reactive protein (CRP) levels independently of weight loss compared to empagliflozin. — 30% reduction in CRP (PIONEER 2 trial; participants with ~4% weight loss)
- Weight loss and glucose reduction only partially explain the CRP reductions observed with semaglutide. — 20%–60% of CRP reduction explained by metabolic changes (SUSTAIN and PIONEER trials)
- Liraglutide reduced atherosclerotic plaque size in the aorta independently of weight loss. — Not specified (Apoe –/– mice; 1 mg/kg for 14 weeks)
- Exenatide reduced circulating proinflammatory cytokines in mice challenged with LPS. — Reduced TNF-α (Single dose of exenatide or semaglutide in mice)
- Liraglutide improved memory and reduced amyloid plaque load and microglial activation in Alzheimer's models. — Not specified (7-month-old APP/PS1 mice; 100 μg/kg daily for 2 months)
- Exenatide reduced circulating T-cell cytokines in mice. — Reduced IFN-γ, TNF-α, and IL-2 (42 μg/kg exenatide in mice challenged with anti-CD3 antibodies)
- Setup
- Diverse setup including Apoe –/–, Ldlr –/–, and APP/PS1 mice, as well as human cohorts with T2D, obesity, and Parkinson's disease.
- How
- The paper is a review synthesizing data from preclinical mouse models (including transgenic knockouts like Glp1r Lck–/– and Tie2–/–) and human clinical trials (SUSTAIN, PIONEER, STEP). It analyzes the effects of GLP-1 receptor agonists on inflammatory markers, tissue pathology, and cognitive function.
- Limitations
- Low GLP-1R expression in many peripheral organs and immune cells makes detection difficult. · Difficulty in distinguishing weight loss-dependent from weight loss-independent antiinflammatory effects. · Species differences in GLP-1 regulation (e.g., IL-6 does not increase GLP-1 in humans as it does in mice). · Inconsistent results across different GLP-1 medicines in neurodegenerative models (e.g., semaglutide vs. liraglutide in APP/PS1 mice).
Summarized by Gemma 4 from the open-access full text · 13 Oct 2026. Read it