Novel pharmacotherapies in diabetic retinopathy: Current status and what's in the horizon?

Abstract

The blood-retinal barrier (BRB) alteration is the hallmark feature of diabetic retinopathy. Vascular endothelial growth factor (VEGF) is a potent vasopermeability factor that has been implicated in the pathogenesis of BRB alteration. Inflammation also plays a crucial role in this process with involvement of several chemokines and cytokines. Multiple anti-VEGF drugs are widely used as in the treatment of diabetic macular edema (DME) as well as proliferative diabetic retinopathy. Several clinical trials have proved the beneficial effects of these drugs in improvement of vision and prevention of vision loss. However, the response to anti-VEGF drugs in DME is not complete in a significant number of patients. The effect seems transient in this latter group, and many patients do not show complete resolution of fluid. Potential novel therapies targeting molecules beyond VEGF are being developed and examined in clinical trials.

Figure 1

Alteration of the blood–retinal barrier in diabetes mellitus. Chronic inflammation in diabetes leads to production of chemokines (including monocyte chemoattractant protein-1, also known as chemokine ligand 2) that result in leukostasis, diapedesis, and influx of monocytes into the retina and extravascular space. Monocytes are differentiated into macrophages which along with activated microglia produce an array of cytokines and chemokines including vascular endothelial growth factor. These mediators then break down the cell-cell junction molecules resulting in alteration of the blood–retinal barrier

Figure 2

Optical coherence tomography images of a patient with center-involving diabetic macular edema who responded well to anti-vascular endothelial growth factor drugs. Right eye (a and c). Left eye (b and d). (a and b) Fundus and optical coherence tomography images a 57-year-old diabetic visual acuity of 20/100 and central retinal thickness of 697 um in the right eye (a) and visual acuity of 20/200 and central retinal thickness of 763 um in the left eye (b). (c and d) Just after one dose of bevacizumab injection in each eye, there was dramatic improvement, and her visual acuity and central retinal thickness were 20/40 and 266 um in the right eye and 20/40 and 280 um in the left eye, respectively

Figure 3

(a) Mean change in visual acuity letter score over time for the full cohort over a period of 1 year, the mean visual acuity letter score improved by about 13 with aflibercept, by 10 with bevacizumab, and by 11 with ranibizumab. (b) When the initial visual acuity letter score was 78–69 (equivalent to approximately 20/32–20/40), the mean improvement was about 8.0 with no significant difference between aflibercept, bevacizumab, and ranibizumab. (c) When the initial letter score was < 69 (approximately 20/50 or worse), the mean improvement was about 19 with aflibercept, 12 with bevacizumab, and 14 with ranibizumab. (d) Mean change in optical coherence tomography central subfield thickness over time the overall decrease in central subfield thickness over 1 year was 101 um for bevacizumab, 147 um for ranibizumab, and 169 um for aflibercept (courtesy of Diabetic Retinopathy Clinical Research Network)

Figure 4

Novel pharmacotherapies for diabetic macular edema based on mechanisms of actions. Several anti-vascular endothelial growth factor inhibitors (ranibizumab and aflibercept) and steroids (dexamethasone and fluocinolone) are approved for use in diabetic macular edema patients while many other drugs are in clinical trials and preclinical stage for development. DARPin: Designed ankyrin repeat protein, NSAIDs: Nonsteroidal anti-inflammatory drugs, TNFα: Tumor necrosis factor α, CCR2/CCR5: Chemokine receptor 2 and 5, KK: Kallikrein-kinin, mTOR: Mammalian target of rapamycin, bFGF: Basic fibroblast growth factor, PDGF: Platelet-derived growth factor, IGF: Insulin-like growth factor