Title : The Effect of GLP-1 receptor agonists on tendon and ligament healing: A systematic review
Abstract:
Background: Glucagon-like Peptide-1 Receptor Agonists (GLP-1RAs) are widely used for type 2 diabetes and obesity, with emerging evidence suggesting effects on inflammation and tissue metabolism. However, their impact on tendon and ligament healing remains poorly understood. This systematic review evaluates the direct effects of GLP-1RAs on tendon and ligament healing across preclinical and clinical studies.
Methods: Following PRISMA 2020 guidelines, we searched PubMed, Web of Science, Scopus, Cochrane Central, Google Scholar, and Clinical Key from inception through 2025. Included studies comprised animal models of tendon/ligament injury and human studies (experimental, retrospective, and reviews) assessing GLP-1RA exposure and soft tissue healing outcomes. Risk of bias was evaluated using SYRCLE, Newcastle-Ottawa, ROBINS-I, AMSTAR 2, and SANRA tools.
Results: From 773 citations, 30 studies met inclusion criteria: 6 animal studies, 3 human experimental studies, 6 clinical retrospective studies, and 15 reviews. Animal studies demonstrated that Exendin-4 accelerates wound healing by increasing fibroblast density, angiogenesis, and mast cell degranulation, while liraglutide reduces fatty infiltration and improves functional recovery after rotator cuff repair. Human mesenchymal stem cells exposed to Exendin-4 showed enhanced tenogenic differentiation with elevated expression of scleraxis and mohawk. Clinical studies (n=5,204–178,114 patients) revealed that perioperative GLP-1RA use is not associated with increased reoperation risk; semaglutide users demonstrated lower 2-year rotator cuff retear rates (12.5% vs. 18.3%, p<0.001). Proposed mechanisms include anti-inflammatory effects (reduced IL-6, TNF-α, MMPs), improved angiogenesis via SIRT1 upregulation, and direct fibroblast modulation. Potential concerns include rapid weight loss-associated sarcopenia, though liraglutide preserved lean mass in animal studies.
Conclusions: Current evidence suggests GLP-1RAs may exert beneficial effects on tendon and ligament healing through anti-inflammatory and pro- regenerative mechanisms. Clinical data support perioperative continuation without increased complication risk. Further research is needed across diverse GLP-1RA classes and anatomical sites.
