Updates on the Current Treatments for Diabetic Retinopathy and Possibility of Future Oral Therapy

Abstract

Diabetic retinopathy (DR) is a complication of diabetes and one of the leading causes of vision loss worldwide. Despite extensive efforts to reduce visual impairment, the prevalence of DR is still increasing. The initial pathophysiology of DR includes damage to vascular endothelial cells and loss of pericytes. Ensuing hypoxic responses trigger the expression of vascular endothelial growth factor (VEGF) and other pro-angiogenic factors. At present, the most effective treatment for DR and diabetic macular edema (DME) is the control of blood glucose levels. More advanced cases require laser, anti-VEGF therapy, steroid, and vitrectomy. Pan-retinal photocoagulation for non-proliferative diabetic retinopathy (NPDR) is well established and has demonstrated promising outcomes for preventing the progressive stage of DR. Furthermore, the efficacy of laser therapies such as grid and subthreshold diode laser micropulse photocoagulation (SDM) for DME has been reported. Vitrectomy has been performed for vitreous hemorrhage and tractional retinal detachment for patients with PDR. In addition, anti-VEGF treatment has been widely used for DME, and recently its potential to prevent the progression of PDR has been remarked. Even with these treatments, many patients with DR lose their vision and suffer from potential side effects. Thus, we need alternative treatments to address these limitations. In recent years, the relationship between DR, lipid metabolism, and inflammation has been featured. Research in diabetic animal models points to peroxisome proliferator-activated receptor alpha (PPARα) activation in cellular metabolism and inflammation by oral fenofibrate and/or pemafibrate as a promising target for DR. In this paper, we review the status of existing therapies, summarize PPARα activation therapies for DR, and discuss their potentials as promising DR treatments.

Keywords: anti-VEGF therapy; diabetic macula edema; diabetic retinopathy; fenofibrate; laser photocoagulation; pemafibrate; vitrectomy.

Figure 1

A schematic illustration of the pathophysiology and stages of diabetic retinopathy (DR). Hyperglycemia evokes various pathological metabolic mechanisms such as accumulation of AGEs and induction of PKC, the polyol, and the hexosamine pathways. Microvascular injuries, inflammation, and glutamate excitotoxicity combine to damage the diabetic retina more severely after induction of these pathways. During these processes, representative features are highlighted: loss of pericytes/endothelial cells, thinning of the basement membrane, increases in IL-6, IL-1β, CCL-2, and TNF-α, retinal vascular permeability, and loss of neuroprotective molecules. These outcomes exacerbate neuronal dysfunction, retinal hypoxia, and increases in various angiogenic factors, including VEGF, which ultimately causes retinal neovascularization. All processes are inter-connected to the development and progression of DR. Furthermore, lipid metabolic abnormalities (changes in levels of lactate, ascorbic acid, arginine, proline, glycine, or creatine) in diabetes could aggravate the intensities of retinal injuries. The stages of DR depending on the severity of the disease: mild NPDR (microaneurysm), moderate NPDR (hemorrhage), severe NPDR (more severe hemorrhage, venous beading, and intraretinal microvascular abnormalities), PDR (new vessel formation, retinal detachment, and vitreous hemorrhage); DME (retinal detachment). Solid line; direct interaction, Dash line; indirect interaction. AGEs; advanced glycation end products, PKC; protein kinase C, CCL; Chemokine (C-C motif) ligand TNF; tumor Necrosis Factor, VEGF; vascular endothelial growth factor, DR; diabetic retinopathy, DME; diabetic macular edema, NPDR; non-proliferative diabetic retinopathy.

Figure 2

A flowchart of suggested treatment for diabetic retinopathy (DR) without macular edema. DR is categorized as non-PDR (NPDR) and PDR. NPDR falls into three subcategories: mild, moderate, and severe. The control of glucose and lipid levels and blood pressure is crucial at any stage. NPDR; non-proliferative diabetic retinopathy, DME; diabetic macular edema, TRP; Targeted retinal photocoagulation, FA; Fluorescein angiography, NPA; non-perfusion area.

Figure 3

A flowchart of suggested treatment for diabetic macular edema (DME). The strategy of treatment is decided by whether the edema includes the fovea or not. Controlling levels of glucose, lipid, and blood pressure is crucial at any stage. SDM; subthreshold diode laser micropulse photocoagulation, DME; diabetic macular edema.

Figure 4

A flowchart of promising treatments for diabetic retinopathy (DR) and diabetic macular edema (DME). PPARα activation by pemafibrate/fenofibrate is associated with modulating energy homeostasis in hyperglycemia and lipid metabolic abnormalities through the regulation of both lipid and glucose levels. Continuous control of levels of glucose and lipid is available with this promising treatment. DR; diabetic retinopathy, DME; diabetic macular edema.