Angiogenesis and inflammation in the retinopathy risk of insulin and semaglutide - a review
Abstract
PURPOSE: To critically evaluate evidence supporting the angiogenesis-inflammation hypothesis in diabetic retinopathy (DR); to examine the roles of angiogenic growth factors and inflammatory cytokines in the biphasic effects of insulin on DR - early worsening followed by long-term risk reduction; and to explore broader implications of this hypothesis, including potential biphasic effects of semaglutide due to its insulinotropic action and strategies to mitigate the transient DR exacerbation associated with insulin and insulin secretagogues. METHODS: Literature review. RESULTS: Hyperglycemia and the accumulation of advanced glycation end products upregulate angiogenic growth factors and inflammatory cytokines, notably vascular endothelial growth factor (VEGF) and angiopoietin-2. These mediators compromise the retinal neurovascular unit and disrupt the blood-retinal barrier, while promoting endothelial adhesion molecule expression. The resulting leukostasis triggers hypoxia, leukocyte activation, and self-perpetuating ischemic-inflammatory loops. Insulin-like growth factor-1 further enhances retinal VEGF and angiopoietin-2 expression, potentially driving DR to the proliferative stage. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has paradoxically been linked to DR deterioration like insulin therapy. In contrast, insulin-independent antidiabetic agents such as empagliflozin and metformin are not associated with DR worsening and may even slow its progression.…
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