GLP-1R as a Target for the Treatment of Diabetic Retinopathy: Friend or Foe?

Glucagon-like peptide 1 receptor (GLP-1R) agonists are increasingly being used as treatment for type 2 diabetes. Since the U.S. Food and Drug Administration published recommendations about the cardiovascular safety of new antidiabetes therapies for treating type 2 diabetes in 2008, the results of two outstanding clinical trials using GLP-1R agonists addressing this issue (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results-A Long Term Evaluation [LEADER] and Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes [SUSTAIN-6]) have been published. Both studies found beneficial effects in terms of reducing the rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. However, their results regarding the progression of diabetic retinopathy (DR) were neutral with liraglutide (LEADER) or worse when compared with placebo in the case of semaglutide (SUSTAIN-6). These results are surprising because of the beneficial effects of GLP-1R analogs reported in experimental models of DR. In this Perspective, an overview of the mechanisms by which GLP-1R activation exerts its effects in preventing or arresting experimental DR is given. In addition, we consider the possible reasons for the negative results regarding the progression of DR in the SUSTAIN-6 study, as well as the gaps that still need to be covered to further clarify this important issue in the management of type 2 diabetes.