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

Abstract

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.

Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes

“…The mechanisms by which GLP-1R activation exerts its neuroprotective and vasculotropic action are complex and have recently been revised [25]. In the present study, we found that saxagliptin and sitagliptin were able to increase both mRNA and protein levels of EPAC-1, a downstream cAMP signalling mediator.…”

“…However, this critical information was not available due to the absence of diabetic retinopathy grading. A comprehensive review regarding the limiting factors of this study, which prevent valid results for diabetic retinopathy outcomes from being drawn, has recently been published [25].…”

Comparisons of diabetic retinopathy events associated with glucose‐lowering drugs in patients with type 2 diabetes mellitus: A network meta‐analysis

“…In contrast, some GLP‐1RAs (liraglutide and exenatide) and 1 DPP‐4i (sitagliptin) had no effect on capillary perfusion in patients with T2DM . Although some experimental studies and small clinical trials indicated overall beneficial effects on the development of DR with GLP‐1RA and DPP‐4i, this is balanced by evidence of progressive worsening or a net neutrality of these agents on DR . Varadhan et al found a progressive worsening of DR in patients treated for at least 6 months with exenatide .…”

“…Several possible explanations for this observed phenomenon may lie in the short follow‐up. Generally, 5 years is considered sufficient time to separate the incidence of DR between intervention and control groups . However, the median duration of follow‐up in the included RCTs was 1.5 years (range, 0.5‐5.5 years).…”

“…However, the median duration of follow‐up in the included RCTs was 1.5 years (range, 0.5‐5.5 years). Finally, a lack of data on the grading of DR at baseline and during follow‐up were reported in the clinical trials . Further studies are required to clarify the risk of DR associated with DPP‐4i or GLP‐1RA.…”