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Randomized Controlled Trial
. 2020 Apr 1;105(4):dgz069.
doi: 10.1210/clinem/dgz069.

Glucagon-like Peptide 1 Receptor Agonists, Diabetic Retinopathy and Angiogenesis: The AngioSafe Type 2 Diabetes Study

Bénédicte Gaborit  1   2 , Jean-Baptiste Julla  3   4 , Samaher Besbes  5 , Matthieu Proust  5 , Clara Vincentelli  1   2 , Benjamin Alos  5 , Patricia Ancel  1 , Fawaz Alzaid  4 , Rodrigue Garcia  5 , Philippe Mailly  5 , Florence Sabatier  1 , Maud Righini  6 , Pierre Gascon  6   7 , Frédéric Matonti  6   7 , Marie Houssays  8 , Louisa Goumidi  1 , Lucile Vignaud  9 , Xavier Guillonneau  9 , Ali Erginay  10 , Bénédicte Dupas  10 , Jennifer Marie-Louise  10 , Marianne Autié  10 , Tiphaine Vidal-Trecan  3 , Jean-Pierre Riveline  3   4 , Nicolas Venteclef  4 , Pascale Massin  10 , Laurent Muller  5 , Anne Dutour  1   2 , Jean-François Gautier  3   4 , Stéphane Germain  5
Affiliations
Randomized Controlled Trial

Glucagon-like Peptide 1 Receptor Agonists, Diabetic Retinopathy and Angiogenesis: The AngioSafe Type 2 Diabetes Study

Bénédicte Gaborit et al. J Clin Endocrinol Metab. .

Abstract

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 type 2 diabetes (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 three-dimensional 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, glycated hemoglobin (HbA1c), micro- and macroangiopathy, insulin therapy and hypertension remained strongly associated with severe DR, while no association was found with GLP-1RA exposure (o 1.139 [0.800-1.622], P = .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.

Trial registration: ClinicalTrials.gov NCT02686177 NCT02671864.

Keywords: angiogenesis; angiosafe Type 2 diabetes study; fundus photography; glucagon like peptide 1 receptor agonist; retinopathy; type 2 diabetes.

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