Clinical biomarkers and molecular basis for optimized treatment of diabetic retinopathy: current status and future prospects

Figures & data

Table 1 International DR disease severity scale and recommended management strategies^146,147

Disease severity level	Signs	Management options
No apparent retinopathy	No abnormalities.	Optimize medical therapy of glucose, blood pressure, and lipids.
Minimal NPDR	Microaneurysms only.	Optimize medical therapy of glucose, blood pressure, and lipids.
Mild-to-moderate NPDR	More than just microaneurysms but less than severe NPDR.	Optimize medical therapy of glucose, blood pressure, and lipids and ophthalmology referral.
Severe NPDR	Any of the following: more than 20 intraretinal hemorrhages in each of four quadrants; definite venous beading in two or more quadrants; and prominent intraretinal microvascular abnormalities in one or more quadrants and no signs of proliferative retinopathy.	Consider scatter (panretinal) laser treatment for patients with type 2 diabetes. Optimize medical therapy of glucose, blood pressure, and lipids.
PDR	One of the following: neovascularization or vitreous/preretinal hemorrhage.	Strongly consider scatter (panretinal) laser treatment, without delay for patients with vitreous hemorrhage or neovascularization within one disc diameter of the optic nerve head. Optimize medical therapy of glucose, blood pressure, and lipids.
Macular edema
Absent	No retinal thickening or hard exudates in posterior pole.	Laser treatment for PDR and center not involving DME.
Present	Mild – some retinal thickening or hard exudates in posterior pole but distant from the macula. Moderate – retinal thickening or hard exudates approaching the center of the macula but not involving the center. Severe – retinal thickening or hard exudates involving the center of the macula.	Intravitreal drug administration for center involving DME and eventual additional later laser treatment. Vitrectomy as a microsurgical approach for traction-induced DME, later changes in PDR such as vitreous hemorrhage, and tractional retinal detachment, sometimes in conjunction with prior intravitreal anti-VEGF treatment.

Abbreviations: DME, diabetic macular edema; DR, diabetic retinopathy; NPDR, nonproliferative DR; PDR, proliferative DR.

Table 2 Drugs currently available or under investigation for management of DR and their status

Drug or formulation	Mechanism or category	Clinical status/regulatory approval	Remarks
Anti-inflammatory
Intravitreal injection of triamcinolone acetonide	Corticosteroid	Off-label use	Off-label use in combination with anti-VEGF agents and as adjunct with surgical intervention for PRP.
Dexamethasone implant	Corticosteroid	FDA approved
Fluocinolone acetonide	Corticosteroid	FDA approved
Ketorolac Nepafenac	NSAID NSAID	Phase II study Phase II study	Under different clinical and preclinical development phases.
Etanercept Infliximab	TNF-α inhibitor TNF-α inhibitor	Preclinical studies Phase III study	Under different clinical and preclinical development phases.
Mab2F1	Monoclonal antibody: Wnt coreceptor blocker	Animal study
VEGF inhibitors
Bevacizumab	VEGF inhibitor: monoclonal antibody	Off-label use	FDA-approved anticancer, off-label use for DR in conjunction with anti-VEGF agents and surgical intervention.
Ranibizumab	VEGF inhibitor: monoclonal antibody	FDA approved	FDA approved for DME in 2014 (AMD 2006; RVO edema 2010).
Pegaptanib	VEGF inhibitor: RNA aptamer	Off-label use	FDA approved for AMD in 2004; Phase III trial completed for DME.
Aflibercept	VEGF inhibitor: decoy receptor fusion protein	FDA approved	FDA approved for DME in 2014; also FDA approved for macular edema following RVO and neovascular AMD.
KH902	VEGF inhibitor: VEGFR decoy	Phase II study
Rapamycin	mTOR inhibitor	Phase II study
Decursin	VEGFR2 phosphorylation	Animal study
Bevasiranib	Short interfering RNA targeting VEGF	Phase II study
Angiogenesis inhibitor
TG100801	Tyrosine kinase inhibitor	Phase II study
Pazopanib	Tyrosine kinase inhibitor	Animal study
Aldose reductase inhibitor
ARI-809	Aldose reductase inhibitor	Animal study
Epalrestat	Aldose reductase inhibitor	Animal study
Fidarestat	Aldose reductase inhibitor	Animal study
Sorbinil	Aldose reductase inhibitor
Tolrestat	Aldose reductase inhibitor
PKC inhibitors
Ruboxistaurin	PKC-β inhibitor	Phase III study
PKC-412	PKC-β inhibitor	Phase III study
Fasudil	Rho-associated protein kinase inhibitor	Phase III study
Growth hormone/insulin-like growth factor inhibitors
Octreotide	Somatostatin analog	Phase III study
Pegvisomant	IGF-1R inhibitor	Preclinical studies
AGE inhibitors
Aminoguanidine	AGE inhibitor	Phase III study
GLY-230	Selective inhibitor of glycation	Phase II study
OPB-9195	AGE inhibitor	Animal study
ALT-711/Alagebrium	AGE inhibitor	Animal study
LR-90	AGE inhibitor	Animal study
N-Phenacylthiazolium bromide	AGE inhibitor	Animal study
Antiplatelet agents
Ticlopidine	ADP receptor inhibitor
Vitreous clearing agents
Vitrase (hyaluronidase)	Protease, spreading agent	Phase III	FDA approved as spreading agent; under Phase III clinical trial to investigate its promotion of the clearance of vitreous hemorrhage from PDR.
Plasmin	Proteolytic enzyme
Ocriplasmin	Recombinant protease with activity against fibronectin and laminin	FDA approved
Agents for blood pressure control
ACE inhibitors: lisinopril, captopril, enalapril	NA
Candesartan, losartan, telmisartan	Angiotensin-2 receptor antagonist
PD 123319	Angiotensin-2 receptor antagonist	Animal study
Valsartan	AT-1 receptor antagonist	Animal study
Mecamylamine	Nicotinic acetylcholine receptor	Phase II study
Neuroprotective agents
PEgylated PEDF	PEDF bioactive derivative	Animal study
S-Nitrosoglutathione	Nitric oxide synthase inhibitor	Animal study
Antioxidants
Baicalein	Flavonoid: lipoxygenase inhibitor	Animal study
Apocynin	Reactive oxygen species inhibitor	Animal study
Curcumin	PPAR-gamma upregulator	Animal study
PJ-34	PARP inhibitor	Animal study

Abbreviations: AGE, advanced glycation end-product; AMD, age-related macular degeneration; DME, diabetic macular edema; DR, diabetic retinopathy; PKC, protein kinase C; VEGF, vascular endothelial growth factor; FDA, Food and Drug Administration; NSAID, nonsteroidal anti-inflammatory drug; PDR, proliferative DR; PEDF, pigment epithelium-derived factor; TNF-α, tumor necrosis factor-α; PRP, panretinal photocoagulation; RVO, retinal vascular occlusion; NA, not applicable.

DedaniaVSBakriSJNovel pharmacotherapies in diabetic retinopathyMiddle East Afr J Ophthalmol201522216417325949073

 PubMedGoogle Scholar

KumarBGuptaSKSaxenaRSrivastavaSCurrent trends in the pharmacotherapy of diabetic retinopathyJ Postgrad Med201258213213922718058

 PubMed Web of Science ®Google Scholar