Advances in diabetic retinopathy.

Diabetic retinopathy (DR) is a complication of long-term diabetes mellitus (DM). Over the last 2 decades lot of work has been on early diagnosis of DR and screening programs have been designed to help the masses. Large numbers of clinical studies have been done for patients of diabetes and DR wherein the role of blood sugar control, metabolic control, role of oral medicines for DR, role of imaging, fluorescein angiography, and retinal photocoagulation has been studied. Newer treatment modalities are being devised and studied for better patient care. We discuss these issues in our review highlight and newer advances over the last few years.

INTRODUCTION

Diabetic retinopathy (DR) is a well-known long term complication of diabetes mellitus (DM). DR is a significant cause of blindness and ocular morbidity in developed nations. In India, the number of diabetics is increasing and hence the number of DR patients is bound to increase over the next few decades.[12] In patients with DM, the prevalence of any form of DR is about 24%.[2]

The Early Treatment Diabetic Retinopathy Study (ETDRS) was a landmark study done between 1980 and 1985, which laid down the principles of classification of DR and provided guidelines for management by retinal laser treatment in cases of advanced disease, that is, proliferative DR (PDR).[3] In one of the arm of ETDRS designed to study the role of photocoagulation for diabetic macular edema, 3,711 patients were recruited. The results showed that use of focal laser decreased the risk of moderate visual loss (defined as loss of 15 letters of ETDRS chart) by 50%. In another arm, the risk of severe visual loss in severe or very severe nonproliferative DR (NPDR) or early PDR reduced by approximately 50% by panretinal photocoagulation. This formed the basis for further studies and future of DR treatment. The primary outcome in ETDRS was stabilization of vision and prevention of further loss. However, vision improvement was seen in only 3% of patients. Laser photocoagulation was the main intervention in ETDRS apart from systemic control of sugars and other metabolic parameters.[34]

ETDRS defined clinically significant macular edema (CSME) in DR which is the commonest cause of decrease in vision and provided for treatment parameters for the same using macular grid retinal laser. However since ETDRS, dramatic changes have occurred in the field of retinal imaging. With new digital high quality stereoscopic fundus camera and optical coherence tomogram, understanding of retinal diseases has increased and newer treatments are now available. In this review newer treatment options will be discussed.

PATHOGENESIS OF DR

The pathogenesis of early DR revolves around damage to the retinal capillary bed caused by persisting high blood glucose levels and high advance glycation end (AGE) products resulting in retinal ischemia. Retinal ischemia in turn leads to production of diffusible angiogenic factor which was earlier called as Factor X by Isaac in 1949.[5] In 1989, Ferrara and Henzel named it as vascular endothelial growth factor (VEGF). Studies have demonstrated the hypoxia could trigger VEGF expression which causes ocular neovascularization.[6]

MANAGEMENT OF DR

Control of systemic metabolic state

One of the aspects of treatment is the management of systemic parameters such as intensive control of blood glucose levels, blood pressure, tight lipid control and management of nephropathy. The United Kingdom Prospective Diabetes Study (UKPDS) showed that reducing glucose exposure (HbA1c 7.0% versus 7.9% over median 10.0 years), with sulfonylurea or insulin therapy, reduced the risk of “any diabetes-related endpoint” by 12% and microvascular disease by 25%, with a 16% trend to a reduced risk of myocardial infarction (P = 0.052). Also it showed that improving blood pressure (142/82 vs 154/87 mmHg over median 8.4 years) with an angiotensin converting enzyme (ACE) inhibitor or a beta blocker, reduced the risk of both microvascular and macrovascular disease.[7] The Diabetes Control and Complications Trial (DCCT) showed that intensive control of blood sugars over the course of diabetes reduces the risk of complication of DM such as retinopathy, nephropathy, and neuropathy by 60%. The benefit of intensive therapy resulted in a delay in the onset and a major slowing of the progression of the above complications.[8]

Management of retinopathy

Early detection and treatment of retinal disease is the second aspect of management of DR. Early diagnosis of DR is possible only with strict screening protocols. In most of the developed nations, all diabetics are routinely screened as a part of national programs. An easy method of screening is the standard retinal photographs taken by trained technicians, optometrists, or specialist.[910] These photographs can later be evaluated by specialist and further course of management can be planned.[11] If there is any evidence of DR on standard retinal photographs, the patients are referred to retina specialists. Tests such as fundus fluorescein angiography (FFA) and optical coherence tomography (OCT) can be done as required. FFA is a procedure wherein, sodium fluorescein dye (10%) is injected intravenously through peripheral vein and retinal photographs are taken with help of camera system. The leakage of dye through blood ocular barrier or neovascular fronds is easily diagnosed. Peripheral capillary nonperfusion or ischemic maculopathy can also be diagnosed with the help of FFA.[1213] OCT is another advancement over the last decade which provides a schematic histology like picture of layers of retina. It provides for thickness of retina to diagnose macular edema. Intraretinal cysts, vitreoretinal traction, epiretinal membranes, and other retinal macular pathologies of DR can be easily diagnosed.[1415] Ocular treatment revolves around four major strategies: Retinal laser photocoagulation, anti-VEGF drugs, steroids, and surgical intervention.

RETINAL LASER PHOTOCOAGULATION

Until 1980 there was no effective treatment for DR. ETDRS trial was a landmark which introduced retinal photocoagulation as a treatment modality. The modified grid laser or focal laser was advocated by ETDRS for patients with CSME. The goal was to give mild laser burns in the macular area and help decrease macular edema.[3] For PDR, panretinal photocoagulation was advocated which decreased the hypoxia-induced neovascularization process.[16] However, loss of visual field was a major side effect. The laser treatment is permanent; however, visual gain is modest or low in most cases. With the advancement in bioengineering, now double frequency neodymium-doped yttrium aluminum garnet (Nd-YAG) laser is available which is compact and easy to use. Pattern laser systems are available which give multiple spots in predetermined pattern in fraction of seconds; thereby reducing the time required.[17] Also the risk of inadvertent burns is less. The size, degree, and spacing can be predefined and achieved with newer advance machines. Subthreshold laser and diode laser are also being studied and advocated by retina specialists to reduce collateral damage of healthy tissue and achieve good results.[1819] Till date retinal laser photocoagulation is the primary and permanent treatment of DR.

VEGF ACTIONS AND INHIBITORS

Over the last decade, extensive research on VEGF molecule has improved our understanding of its prominent role in DR. VEGFs are a subfamily of growth factors that lead to vasculogenesis and angiogenesis. VEGF is primarily secreted from retinal pigmented epithelial cells, pericytes, astrocytes, Muller cells, glial cells, and endothelial cells. VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PGF). VEGF-A is 36-48 kDa glycosylated protein. It has five isoforms: 121, 145, 165, 189, and 206 depending on the number of amino acids present. Among these isoforms, VEGF-A165 isoform plays the most important role in DR. Tissue hypoxia leads to production of hypoxia inducible factor 1 (HIF-1) which upregulates production of VEGF. There are two receptors for VEGF: VEGFR1 and VEGFR2. VEGF receptor 2 is the primary receptor for cellular effects of VEGF-A. The actions of VEGF-A are mediated further through various pathways such as tyrosine kinase pathway, protein kinase C (PKC), and nitric oxide synthesis.[20] [Figure 1].

Figure 1

Retinal angiogenesis pathway

The flow chart below depicts the various steps in the synthesis and action of VEGF. All these steps are amenable to intervention. The production and actions of VEGF can be inhibited. If VEGF actions are inhibited angiogenesis can be prevented. Further complications of PDR such as vitreous hemorrhage and tractional retinal detachment can be prevented.[202122]

VEGF actions also cause dilatation of blood vessels through release of NO and transudation, which accentuates macular edema. Inhibition of VEGF will inhibit transudation and decrease macular edema.[23]

Inhibition of VEGF at various steps

Gene transcription stage- A new small interfering RNA (siRNA) named bevasiranib is being developed to inhibit the genes that produce VEGF. In RNAi assessment of bevasiranib in diabetic macular edema (RACE) trial, a phase 2 pilot study, preliminary safety and efficacy was proved. It was a double masked multicentric randomized clinical trial which showed positive results in decreasing macular edema in patients with diabetes macular edema (DME).[24]

Inhibition of extracellular VEGF

Bevacizumab (Avastin, Genentech Inc, San Francisco, CA) is monoclonal antibody against all isoforms of VEGF-A and commonly used off-label drug given by intravitreal injection. It was originally approved for use in colon cancer. Good results with off-label use for ocular use of bevacizumab. Dose is 0.05 ml (1.25 mg) given intravitreally under aseptic precautions. The Diabetic Retinopathy Clinical Research (DRCR) phase 2 and bevacizumab or laser therapy (BOLT) study showed favorable results with use of bevacizumab along with laser therapy rather than laser therapy alone.[252627]

Ranibizumab (Lucentis, Genetec Inc, San Francisco, CA) is a humanized monoclonal antibody fragment (fragment antigen antibody (Fab)) designed for ocular use. It is Food and Drug Administration (FDA)-approved for decreasing neovascularization due to age-related macular degeneration. It is found to be effective for decreasing macular edema and PDR. Dose is 0.05 ml (0.5 mg) given intravitreally under aseptic precautions. In three well-designed trials – RESOLVE, RIDE and RISE, and READ-2 – ranibizumab was found to be more effective than sham injections and/or focal/grid laser in improving visual acuity and reduce macular thickness. Newer trial like RESTORE and DRCT.net showed that 1-year treatment of ranibizumab along with laser therapy was more effective that laser therapy alone.[28293031]

Pegaptanib sodium (Macugen, Eyetech Pharmaceuticals Inc, New York, NY and Pfizer Inc, New York, NY) is a RNA aptamer and was approved for neovascular age related macular degeneration (AMD). The phase 2 randomized control trial done by Macugen Diabetic Retinopathy Study Group favored the use of Macugen with laser photocoagulation for better results.[3233]

Inhibitor of VEGF receptor

Aflibercept (VEGF-Trap, Regeneron Pharmaceuticals Inc, Tarrytown, NY and Sanofi Aventis Inc, Paris, France) is human recombinant protein that behaves like a decoy receptor and binds with all isoforms of VEGF-A and neutralizes their effects. The DA VINCI study showed favorable results. The visual improvement was accompanied with decrease in retinal thickness on OCT. Phase 3 trials of VEGF-Trap are underway.[34]

Inhibition of intracellular signaling pathways

Midostaurin (Fermntek Biotechnology, Israel) is an inhibitor of multiple isoforms of PKC. It did show some positive result in animal models, however was found to have significant adverse effects in humans.[3536]

Ruboxistaurin (Eli Lilly and Co., Delaware, Indiapolis, USA) is an orally available PKC-beta isoform selective inhibitor. It is being used for NPDR. Two studies done are PKC-Diabetic Retinopathy Study (PKC-DRS) and PKC-DME study (PKC-DMES). Both the studies have showed encouraging results.[3738]

STEROIDS

Corticosteroids were the first intravitreal treatment for DME. Corticosteroids reduce vascular permeability. Their exact mode of action is not well-understood; however, steroids reduce production of arachidonic acid derivatives, prostaglandins, intercellular adhesion molecule (ICAM), tumor necrosis factor (TNF)-alpha, and VEGF. Triamcinolone acetonide is the most widely used steroids used for DME. Intravitreal triamcinolone is widely used against DME for a number of years. The effect lasts for 2-6 months and requires retreatment with major side effects being cataract and glaucoma. Doses 1, 2, or 4 mg given intravitreally under aseptic precautions.[39404142]

Due to high efficacy of steroids, sustain release implants of steroids have been designed for intraocular use. Retisert is intravitreal implant of fluocinolone acetonide (0.59 mg) which is surgically implanted. It is FDA-approved for use in chronic noninfectious uveitis. However in phase 2 clinical trials, 33% patients required glaucoma surgery and 90% required cataract surgery.[434445]

Ozurdex is biodegradable injectible implant to be placed intravitreally which releases dexamethasone. The results are encouraging and it is studied for future use.[464748]

Intravitreal or subtenon steroids are good, efficacious, and are widely used. However, continuous monitoring for rise is intraocular pressure is necessary. They should be used with caution and under explained risks.

SURGICAL INTERVENTION

Vitreous humor has been found to have all the angiogenic factor that lead to DR. Elevated inflammatory markers, VEGF, and AGE are known to be present in vitreous. In addition; vitreous traction, thick posterior hyloid, and epiretinal membranes are known to produce retinal traction and possible macular edema in some cases. In selected cases, pars plana vitrectomy may be required to treat DME. For patients with vitreous hemorrhage and retinal detachment, vitreoretinal surgery is required. Newer adjuvancts such as intravitreal injection of autologous plasmin enzyme (APE) are being developed for chemical vitreolysis which help in resolution of vitreous hemorrhage and may find place in standard care in years to come.[49] Advancement in machines, better instrumentation and visualization along with adjuncts such as perfluorocarbon liquids (PFCL), vitreoretinal surgery is much safer today with good results in expert hands. Sutureless vitrectomy using 23 or 25 gauge is being advocated for minimum intervention and optimum results.[50515253]

Newer drugs

Certain newer drugs have dual role and are now known to improve the retinopathy. Fenofibrate, a common drug used for dyslipidemia has been found to be useful in DR in the FIELD study. Patients treated with fenofibrate required less photocoagulation in PDR by 30% and DME by 31%.[54] Fenofibrate reduces the progression of retinopathy by 22% in all patients and 79% in patients with preexisting retinopathy. This result was unrelated to serum lipid levels, which were statistically similar in both, the group treated with fenofibrate and the control group. Retinal endothelial cells have peroxisome proliferator-activated receptor (PPAR)-α receptors and fenofibrate is known to be a PPAR-α agonist. Various mechanisms proposed are activation of PPAR-α receptors of retinal endothelial cells, which in turn inhibits VEGF. It also induces expression and activation of antioxidant enzymes, such as superoxide dismutase, glutathione, and induces apoptosis of human monocyte-derived macrophages, providing neuroprotective effects.[5455]

To summarize, we can conclude that prevention and treatment of DR requires long-term approach. Proper control of blood sugar levels, blood pressure, lipids, and renal parameters form a major part of treatment of DR which should not be ignored. Ocular intervention requires a combined approach of intravitreal injections, retinal laser photocoagulation and vitreoretinal surgery.