Determining the role of SGLT2 inhibition with Empagliflozin in the development of diabetic retinopathy

Abstract

Diabetes mellitus is a chronic metabolic disease that occurs when the pancreas is not producing enough insulin or when the insulin that it does produce is not able to be used effectively in the body. This results in hyperglycemia and if the blood sugars are not controlled, then it can lead to serious damage of various body systems, especially the nerves and the blood vessels. Uncontrolled diabetes is a major cause of kidney failure, heart attacks, stroke and amputation. One of the most devastating complications for patients is diabetic retinopathy (DR) which represents the leading cause of preventable vision loss in people between 20 and 65 years of age. Sodium glucose transporter 2 (SGLT2) inhibitors have been shown to reduce the risk for cardiovascular and renal events, however literature highlighting their potential role to prevent DR is limited. We therefore used a relevant mouse model (Akimba) to explore the effects of the SGLT2 inhibitor, Empagliflozin (EMPA), on the development of diabetic retinal changes. Here we show that when given in the early stages of type 1 diabetes (T1D), EMPA reduced the weight loss usually associated with T1D, decreased diabetes-associated polydipsia, lowered fasting blood glucose levels, decreased kidney-to-body weight ratios and, most importantly in the current context, substantially reduced retinal abnormalities associated with DR. We show that EMPA reduces vascular leakage indicated by lower albumin staining in the vitreous humor and diminishes expression of the pathogenic factor VEGF in the retina. Additionally, EMPA significantly alters the retinal genetic signature. Our findings suggest that SGLT2 inhibition may be a useful therapeutic approach to prevent the development of DR and its severity if given early in the disease process.

Determining the Role of SGLT2 Inhibition with Dapagliflozin in the Development of Diabetic Retinopathy

“…1C,D). In both models with retinopathy (Kimba) and DR (Akimba), the development of retinal vascular lesions was evident as previously published [16,[21][22][23]25]. Therefore, the number of vascular lesions were counted in Kimba and Akimba mice to determine the effect of SGLT2 inhibition on the retinal vascular features.…”

“…Our recent studies show that diabetic Akimba mice have increased SGLT2 expression in the eye compared to non-diabetic Kimba mice [16]. The SGLT family member, SGLT1, is an integral membrane protein responsible for the mechanism of active glucose transport and it may be expressed in the eye/retina [17,32].…”

“…Therefore, in addition to SGLT2 inhibition, SGLT1 inhibition is considered an additional target to achieve maintenance of good glycaemic control and improvement of renal dysfunction [14,15]. Interestingly and importantly in the context of DR, expression of SGLT1 and SGLT2 has recently been reported in the eye and the retina by us and others [16][17][18]. Given the encouraging findings from clinical studies in regards to SGLT2 inhibitor mediated protection from microvascular disease, specifically in the kidney, it appears plausible that similar benefits may extend to the retinal microvasculature.…”

Will GLP-1 Analogues and SGLT-2 Inhibitors Become New Game Changers for Diabetic Retinopathy?

“…In type 2 diabetic mice, long-term tofogliflozin treatment significantly improved impaired retinal neurovascular coupling through the inhibition of retinal glial activation, VEGF protein expression in the retina and improved regulation of retinal blood flow [ 65 ]. Similarly, in a study conducted on Akimba mice, an established representative DR model, empagliflozin treatment resulted in reduction of microaneurysms, IRMA, neovascular tufts, vessel tortuosity and vascular leakage, as well as significant reduction of VEGF and albumin expression in the retina and retinal genetic signature alteration [ 66 ]. Interestingly, in a study comparing microvascular complications in type 1 and type 2 DM groups in murine models, empagliflozin reduced DR in almost 50% of the type 1 DM model, while no such effects were observed for the type 2 DM model [ 67 ].…”

Status and Trends of the Association Between Diabetic Nephropathy and Diabetic Retinopathy From 2000 to 2021: Bibliometric and Visual Analysis

“…SGLT2 inhibitors are nephroprotective and play a role in the primary prevention of DN ( Mosenzon et al, 2021 ; Nagasu et al, 2021 ). Matthews et al found that SGLT2 inhibition may be a useful therapeutic approach to prevent the development of DR and lessen its severity if administered early in the disease process ( Matthews et al, 2022 ).…”