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Background: Diabetic retinopathy (DR) is a leading cause of end-stage blindness globally and is arguably one of the most disabling complications of both Type 1 and Type 2 diabetes. Sodium Glucose Cotransporter-2 (SGLT2) inhibitors have now been successfully introduced to clinical medicine and exert multiple beneficial effects in diabetic patients. Given the broad therapeutic application of SGLT2 inhibitors, we hypothesised that SGLT2 inhibition may alleviate the progression of DR. Therefore, we aimed to compare the effectiveness of two clinically available SGLT2 inhibitors, Empagliflozin and Canagliflozin, on the progression of Retinopathy and DR using well-characterised mouse models, Kimba and Akimba, respectively. Methods: Empagliflozin, Canagliflozin (25 mg/kg/day) or vehicle was administered to 10-week-old mice via drinking water for 8-weeks. Urine glucose levels were measured to ascertain SGLT2 inhibition promoted glucose excretion. Weekly body weight and water intake measurements were obtained. After 8-weeks of treatment, body weight, daily water intake, fasting blood glucose levels were measured and eye tissue was harvested. The retinal vasculature was assessed using immunofluorescence. Results: Empagliflozin treated Akimba mice exhibited metabolic benefits suggested by healthy body weight gain and significantly reduced fasting blood glucose levels. Treatment with Empagliflozin reduced retinal vascular lesions in both Kimba and Akimba mice. Canagliflozin improved body weight gain, reduced blood glucose levels in Akimba mice, and reduced the development of retinal vascular lesions in Kimba mice. Conclusions: Our data demonstrates that Empagliflozin has future potential as a therapeutic for Retinopathy and DR and should now be considered for human trials.

Background: Diabetic retinopathy (DR) is a major cause of blindness globally. Sodium Glucose Cotransporter-2 (SGLT2) inhibitors have been demonstrated to exert cardiorenal protection in patients with diabetes. However, their potential beneficial effect on DR is less well studied. The aim of the present study was to determine the effects of the SGLT2 inhibition with Dapagliflozin (DAPA) on DR in well-characterised DR mouse models and controls. Methods: Dapagliflozin was administered to mice with and without diabetes for 8 weeks via their drinking water at 25 mg/kg/day. Urine glucose levels were measured weekly and their response to glucose was tested at week 7. After 8 weeks of treatment, eye tissue was harvested under terminal anaesthesia. The retinal vasculature and neural structure were assessed using immunofluorescence, immunohistochemistry and electron microscopy techniques. Results: Dapagliflozin treated DR mice exhibited metabolic benefits reflected by healthy body weight gain and pronounced glucose tolerance. Dapagliflozin reduced the development of retinal microvascular and neural abnormalities, increased the beneficial growth factor FGF21 (Fibroblast Growth Factor 21). We highlight for the first time that SGLT2 inhibition results in the upregulation of SGLT1 protein in the retina and that SGLT1 is significantly increased in the diabetic retina. Conclusions: Blockade of SGLT2 activity with DAPA may reduce retinal microvascular lesions in our novel DR mouse model. In conclusion, our data demonstrates the exciting future potential of SGLT1 and/or SGLT2 inhibition as a therapeutic for DR.