CLINICAL RESEARCH ARTICLE doi:10.1210/clinem/dgz069 J Clin Endocrinol Metab, April 2020, 105(4):e1549–e1560 https://academic.oup.com/jcem e1549 *These co-frst authors contributed equally. † These co-second authors contributed equally. ‡ These co-last authors contributed equally. Abbreviations: 3D, three-dimensional; 7-AAD, 7-aminoactinomycin D; CI, confdence interval; DPP-IV, dipeptidyl peptidase-IV inhibitors; DR, diabetic retinopathy; eGFR, es- timated glomerular fltration rate; GLP-1RA, glucagon-like peptide 1 receptor agonist; HPC, hematopoietic progenitor cell; HUVEC, Human umbilical vein endothelial cell; Ig, immunoglobulin; miRNA, micro-RNA; T2D, type 2 diabetes; VEGF, vascular endothelial growth factor ISSN Print 0021-972X ISSN Online 1945-7197 Printed in USA © Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals. permissions@oup.com Received 20 May 2019. Accepted 3 October 2019. First Published Online 7 October 2019. Corrected and Typeset 10 March 2020. 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,‡ and Stéphane Germain 5,‡ 1 Aix Marseille University, INSERM, INRA, C2VN, F-13005 Marseille, France; 2 Endocrinology, Metabolic Diseases and Nutrition Department, Assistance Publique Hôpitaux de Marseille, France; 3 Department of Diabetes and Endocrinology, Assistance Publique - Hôpitaux de Paris, Lariboisière Hospital, University Paris-Diderot Paris-7, F-75010 Paris, France; 4 Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, France; 5 Center for Interdisciplinary Research in Biology (CIRB), College de France – Centre National de la Recherche Scientifque (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Sciences et Lettres (PSL) Research University, F-75005 Paris, France; 6 Department of Ophtalmology, AP HM, Marseille, France; 7 Aix Marseille University, CNRS, INT, Inst Neurosci Timone, F-13005 Marseille, France; 8 Aix Marseille University, APHM, INSERM, CIC1409, Hôpital de la Conception, F-13005 Marseille, France; 9 Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012, Paris, France; and 10 Department of Ophthalmology, Lariboisière Hospital, AP HP, University Paris-Diderot Paris-7, F-75010 Paris, France ORCiD number: 0000-0002-4180-158X (B. Gaborit). Aims: Recent trials provide conficting 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 Downloaded from https://academic.oup.com/jcem/article/105/4/e1549/5582609 by guest on 04 July 2023