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

J Clin Endocrinol Metab. 2020 Apr 1;105(4):dgz069. doi: 10.1210/clinem/dgz069.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Biomarkers / analysis
  • Blood Glucose / analysis
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetic Retinopathy / drug therapy
  • Diabetic Retinopathy / etiology
  • Diabetic Retinopathy / pathology*
  • Endothelial Cells / drug effects*
  • Exenatide / pharmacology*
  • Female
  • Follow-Up Studies
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Male
  • Mice
  • Middle Aged
  • Morphogenesis
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / etiology
  • Neovascularization, Pathologic / pathology*
  • Prognosis
  • Retina / drug effects
  • Retina / metabolism
  • Retina / pathology

Substances

  • Biomarkers
  • Blood Glucose
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Exenatide

Associated data

  • ClinicalTrials.gov/NCT02686177
  • ClinicalTrials.gov/NCT02671864