Sodium-glucose co-transporter 2 inhibitors and diabetic retinopathy: insights into preservation of sight and looking beyond

Abstract

Sodium-glucose co-transporter 2 Inhibitors (SGLT2i) were initially developed as therapeutic options for patients with type 2 diabetes mellitus (T2DM). Recently, randomized clinical trials have investigated their effects in cardiorenal protection through major adverse cardiovascular event reduction and reductions in diabetic nephropathy. While multiple mechanisms are proposed for this protection, microvascular protection is the primary component of their efficacy. While not primarily emphasized in clinical trials, evidence in other studies suggests that SGLT2i may confer retinoprotective effects via some of the same mechanisms in the aforementioned cardiorenal trials. Diabetic patients are susceptible to vision loss with chronic hyperglycemia promoting inflammation, edema, and retinal pathological changes. Targeting these pathways via SGLT2i may represent opportunities for providers to decrease retinopathy in high-risk T2DM patients, reduce disease progression, and lower drug burden in diabetic retinopathy patients. Further comprehensive clinical trials investigating these associations are needed to establish the potential retinoprotective effects of SGLT2i.

Keywords: diabetes; diabetic; diabetology; microvascular; ophthalmology; retina; retinopathy; sodium-glucose co-transporter 2 inhibitors; translational biology; vision loss.

Fig. 1

Improvements in glucose control, as measured by decreased HbA_1c, confer benefits of interest related to the development of diabetic retinopathy.

Fig. 2

A review of the intracellular dynamics in the retinal cell of the hyperglycemic patient with implications for SGLT2 inhibition. Basic lipid bilayer template adapted from Servier Medical Art by Servier, which is licensed under a Creative Commons Attribution 3.0 Unported License. Physiological dynamics and artwork created by authors with adaptations from Wakisaka et al. [50,51]. SGLT2, sodium-glucose co-transporter 2.

Fig. 3

Effects of prolonged hyperglycemia on systemic physiology with an emphasis on ocular manifestations. This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited [48,50].

Fig. 4

SGLT2 inhibitors exhibit potential in reducing macular edema. This phenomenon can be appreciated when noting improvements in macular edema seen on optical coherence tomography (see Mieno et al. [105] human scans). A reduction in macular edema and visual acuity in patients with T2DM was found to be statistically significant (P < 0.01). Image of the retina created using Servier Medical Art images (http://smart.servier.com) under Creative Commons License. OCT images were adapted from Mieno et al. [105] under Creative Commons License 5.5. Subretinal fluid representing macular edema is noted by white arrows, while the fovea is oriented using the blue arrow for orientation. OCT, optical coherence tomography; SGLT2, sodium-glucose co-transporter 2.

Fig. 5

The following chart is a representation of a five-patient cohort with T2DM and diabetic retinopathy who underwent treatment with SGLT2 inhibitors. A statistically significant reduction from baseline in CRT was observed within a year. While this phenomenon should be investigated with a larger sample size, current data show a meaningful potential avenue in treating compromised vision in the patient with T2DM. Image adapted from Silva-Cardoso et al. [99]. CRT, central retinal thickness; SGLT2, sodium-glucose co-transporter 2; T2DM, type 2 diabetes mellitus.