Glucagon-like peptide 1 receptor agonists, diabetic retinopathy and angiogenesis: The AngioSafe type 2 diabetes study.

AIMS Recent trials provide conflicting results on the association between glucagon-like peptide 1 receptor agonists (GLP-1RA) and diabetic retinopathy (DR). The aim of the AngioSafe T2D study was to determine the role of GLP-1RA in angiogenesis using clinical and preclinical models. METHODS We performed two studies in humans. In study 1, we investigated the effect of GLP-1RA exposure from T2D diagnosis on the severity of DR, as diagnosed with retinal imaging (fundus photography). In study 2, a randomized 4-week trial, we assessed the effect of Liraglutide on circulating hematopoietic progenitor cells (HPCs), and angio-miRNAs.We then studied the experimental effect of Exendin-4, on key steps of angiogenesis: in vitro on human endothelial cell proliferation, survival and 3D vascular morphogenesis; and in vivo on ischemia-induced neovascularization of the retina in mice. RESULTS In the cohort of 3154 T2D patients, 10 % displayed severe DR. In multivariate analysis, sex, disease duration, HbA1c, micro and macroangiopathy, insulin therapy and hypertension remained strongly associated with severe DR, while no association was found with GLP-1RA exposure (OR1.139 [0.800-1.622], p=0.47). We further showed no effect of Liraglutide on HPCs, and angio-miRNAs. In vitro, we demonstrated that exendin-4 had no effect on proliferation and survival of human endothelial cells, no effect on total length and number of capillaries. Finally, in vivo, we showed that exendin-4 did not exert any negative effect on retinal neovascularization. CONCLUSIONS The AngioSafe T2D studies provide experimental and clinical data confirming no effect of GLP-1RA on angiogenesis and no association between GLP-1 exposure and severe DR.