How and why SGLT2 inhibitors should be explored as potential treatment option in diabetic retinopathy: clinical concept and methodology

Abstract

Patients suffering from type 2 diabetes are at an increased risk of developing classical microvascular complications such as retinopathy, neuropathy, and nephropathy, which represent a significant health burden. Tight control of blood glucose, blood pressure, and serum cholesterol reduce the risk of microvascular complications but effective pharmacologically targeted treatment options for the treatment and prevention of diabetic microangiopathy are still lacking. Pharmacological inhibition of sodium glucose cotransporter 2 (SGLT2) might have the potential to directly protect against microvascular complications and could represent a potential treatment option. Randomized controlled clinical proof of concept trials are needed to investigate a potential central role of SGLT2 inhibitors in the prevention of diabetic microangiopathy and its classical clinical complications of retinopathy, neuropathy, and nephropathy.

Keywords: SGLT2 Inhibition; academia; diabetes mellitus; diabetic macula edema; diabetic retinopathy; methods; pharmacology; trial design.

Figure 1.

Pathomechanisms involved in the pathogenesis of diabetic retinopathy. Intracellular hyperglycemia induces the increased formation of advanced glycation end products (AGEs), upregulated hexosamine pathway, increased flux through the polyol pathway, and increased activation of protein kinase C (PKC). Because of these toxic pathways, reactive oxygen species and thus oxidative stress is increased, expression of inflammatory proteins and growth factors are triggered and, ultimately, damage to the retinal microvasculature is induced. These cell toxic consequences are worsened by activation of the renin–angiotensin–aldosterone system (RAAS) in retinal cells, uncontrolled hypertension, and dyslipidemia. Increased angiogenesis, vascular permeability, vascular occlusion, and neurodegeneration present the pathologic correlate and together characterize the pathology of diabetic retinopathy.

Figure 2.

Ophthalmologic findings in patients with diabetes. Examples of pathological ophthalmologic findings in the left eye of a patient with diabetes. (a) Fundus photography showing optic nerve head and macula with signs of moderate DR: microaneurysms (red dots), small hemorrhages (red spots), hard exudates (yellow spots), and cotton-wool spots (white spots). (b) Fluorescein angiography showing the dye within the retinal vessels and capillaries, leakage of the dye outside the vessel is visible in multiple spots. (c) Spectral-domain OCT showing diabetic macula edema, the intraretinal fluid appears as black circles. (d) OCT showing near normal retinal thickness after intravitreal injection of anti-VEGF, the intraretinal fluid is almost completely resorbed. (e) OCT-angiography (without dye) showing the flow within the retinal microvessels around the central avascular arcade and (f) the corresponding OCT-angiography scan highlighting the particular segmentation of the retina (red lines) and the flow measurement (yellow) within all layers of the retina.

Figure 3.

Proposed study design.