General considerations and follow-up

Management of DR depends on the stage of the disease and aims at slowing down or prevention the progression of the disease. Prevention of sight-threatening complications of DR is preferable to treatment of established disease. This is why interventions may be most effective if instituted earlier in the disease course, before development of significant retinopathy.Because early detection is important, all patients with diabetes should be routinely evaluated to detect treatable DR.

Patients with type 1 diabetes should have an initial comprehensive eye examination within 3-5 years after the onset of diabetes. In general, evaluation for diabetic eye disease is not necessary before 10 years of age. Patients with type 2 diabetes should have an initial comprehensive eye examination at the time of diagnosis or shortly after that. Early referral to an ophthalmologist is particularly important for patients with type 2 diabetes and severe nonproliferative DR, since laser treatment at this stage is associated with a 50% reduction in the risk of severe visual loss and vitrectomy. In both type 1 and type 2 diabetic patients, repeated subsequent examinations are recommended once a year. More frequent follow-up should be offered to patients with abnormal findings and if retinopathy is progressing. In the early stages of nonproliferative DR, only regular monitoring may be required. For patients without retinopathy or with only few microaneurysms, longer interval between examinations can be considered. For patients with moderate-to-severe nonproliferative DR, frequent eye examinations are necessary to determine when to initiate treatment. Attention should be paid on the fact that patients with a longer duration of diabetes are more likely to progress during the next year of observation. In addition, older people are at higher risk for cataract, glaucoma, age-related macular degeneration, and other potentially blinding disorders.

Women with preexisting diabetes should have a comprehensive eye examination prior to conception and during first trimester. They should be counseled on the risk of development and/or progression of DR. Close follow-up throughout pregnancy should be assured. Vision symptoms are indications for ophthalmologic referral.

Persons with DR can suffer significant vision loss. They should be encouraged to pursue visual rehabilitation with an ophthalmologist or optometrist who is trained or experienced in low-vision care. Special low vision devices such as telescopic and microscopic lenses, hand and stand magnifiers, and video magnification systems can be prescribed to make the most of remaining vision.

Treatment approaches comprise primary and secondary interventions. In general, primary interventions (e.g. intensive glycemic and blood pressure control), can reduce the incidence of DR, while secondary interventions (e.g. laser photocoagulation) may prevent further progression of DR and vision loss. Early and aggressive treatment of DR has been proven to be successful in prolonging vision and preventing severe vision loss.

A. Primary interventions include tight glycemic and blood pressure control, and lipid-lowering therapy. These measures are beneficial in patients with both type 1 and type 2 diabetes.

Glycemic control reduces the incidence and progression of DR, especially when instituted early in the course of diabetes. Laboratory studies performed for diagnosis and long-term follow-up include fasting glucose and hemoglobin A1c (HbA1c). Keeping glucose levels in normal ranges (fasting plasma glucose 90-130 mg/dl equal to 5 to 7.2 mmol/l) and maintaining the HbA1c level in the 6-7% range are the goals in the optimal management of diabetes and DR. Beneficial effects usually persist long after the period of intensive control. Hypertension alone is capable of producing hypertensive retinopathy characterized by macro- and microaneurysms, flame hemorrhages, cotton wool spots, and macular exudates. Tight blood pressure control in patients with hypertension and diabetes is beneficial in reducing visual loss from DR. Observational studies suggest that dyslipidemia increases the risk of DR, particularly DME. Lipid lowering recommendations are currently given to all patients with diabetes and elevated cholesterol irrespective of retinopathy status, though the evidence about the benefits of lipid-lowering therapy for DR prevention remains inconclusive.

B. Secondary interventions

I. Medical interventions

The following systemic agents have been shown to decrease the rate of the DR progression: ruboxistaurin (an orally active antagonist of protein kinase C, PKC-β), fenofibrate (a fibric acid derivative used as a lipid-modifying agent), rosiglitazone (a peroxisome proliferator-activated γ ligand commonly used in the treatment of type 2 diabetes, with possible antiangiogenic properties), and somatostatin and somatostatin analogues (octreotide). Majority of these agents are under clinical investigation.

In addition to lowering plasma triglyceride levels, fenofibrate reduces the total and LDL cholesterol, raises HDL cholesterol, and decreases concentration of small LDL cholesterol particles and apolipoprotein B. Fenofibrate tested in type 2 diabetes has no effect on the incidence of DR but reduces the progression of existing DR, thus lessening the need for laser treatment in both DME and progressive DR. Beneficial effect of fenofibrate in DR seems unrelated to changes in serum lipids, however, the exact mechanism of action remains to be elucidated.

Aspirin alone and/or in combination with dipyridamole (both drugs have antiplatelet activities) have been reported to reduce the microaneurysms. Two aldose reductase inhibitors, sorbinil and tolrestat, have been investigated as promising treatment options in DR. However, clinical trials were disappointing as no statistically significant reducing in incidence or progression of DR has been documented.

The blockade of the renin-angiotensin system (RAS) with an angiotensin-converting-enzyme (ACE) inhibitor or by using angiotensin II type 1-receptor blockers is one of the most used strategies for treatment of hypertension in diabetic patients. Apart from the kidney, the RAS system is expressed in the eye where its activation may have an important role in the pathogenesis of DR. The blockade of the RAS is hypothesized to be beneficial per se in reducing the development and progression of DR. In fact, ACE inhibitors and angiotensin-receptor blockers have been documented to moderately slow the development of DR. There is growing evidence that in addition to reducing the microvascular disease, the angiotensin receptor blockers may exert neuroprotective effects that could be involved in their beneficial effects in DR. Recent pivotal study has reported beneficial effects of candesartan (an angiotensin-receptor blocker), on DR. In normotensive diabetic patients, candesartan was able to reduce the incidence of DR in those with type 1 diabetes and to favor DR regression only in type 2 diabetic patients with mild retinopathy. Fenofibrate and candesartan have been proposed as an adjunct in the management of DR.

Carbonic anhydrase inhibitors, such as dorzolamide, represent a possible drug treatment for slowing the development of DR in the early stages. The locally administered dorzolamide has been shown to dilate the capillaries in the retina and decrease the number of occluded capillaries (thus preventing this cardinal point in the DR pathogenesis) and slow substantially the progression from "no retinopathy" to non-proliferative DR.

II. Laser and surgical interventions

1) Pan-retinal laser photocoagulation

Pan-retinal laser photocoagulation (PRP), also known as scatter laser photocoagulation of the peripheral retina, is a specific treatment for proliferative DR and indicated in certain cases of nonproliferative DR. It aims at preventing the development of new vessels over the retina and elsewhere, to reduce the risk of vitreous hemorrhage and retinal detachment but not to regain lost vision (Figure 4). The benefits of PRP persist and are most marked in patients with high-risk proliferative DR, in whom PRP should be commenced without delay.

During the procedure, a special laser is used to make tiny burns that seal the retina and stop vessels from growing and leaking. The initial treatment consists of approximately 1,500-2,000 spots of laser per eye, performed in one or more individual procedures, usually performed under a local anesthesia. Immediately after the laser treatment, vision may decrease (due to edema or swelling of the retina) and restore within two to three weeks. In rare cases, it may remain permanently deteriorated. Other rare but possible adverse effects of PRP include visual field constriction (with implications for driving), night blindness, color vision changes, inadvertent laser burn, macular edema exacerbation, acute glaucoma, and traction retinal detachment.

2) Surgical vitrectomy for vitreous hemorrhage and proliferative DR

Vitrectomy is used for treatment of eyes with advanced DR, including proliferative DR with nonclearing vitreous hemorrhage or fibrosis, areas of traction involving or threatening the macula, and, more recently, persistent DME with vitreous traction. The procedure surgery (under local or general anesthesia) involves removing the clouded vitreous gel from the eye. Recovery of the vision usually takes about four weeks of receiving the operation but can take several months. Vitrectomy may also be used to remove scar tissue remaining as a result of retinal detachment. Early vitrectomy should be considered in patients with type 1 diabetes and persistent vitreous hemorrhage or when hemorrhage prevents other treatment. Often vitrectomy is followed or accompanied by laser treatment. Vitrectomy may slow or stop the progression of DR, but future retinal damage and vision loss is possible.

III. Interventions for DME

1) Focal laser treatment (focal laser photocoagulation)

Focal laser treatment is effective at slowing the progression of retinopathy and reducing visual loss, but the treatment usually does not restore lost vision. During the procedure (usually done in a single session), leaks from abnormal blood vessels are sealed with laser burns. Possible adverse effects include blurred vision, inadvertent foveal burn, central visual field defect, color vision abnormalities, retinal fibrosis, and spread of laser scars. In patients with coexistent proliferative DR and DME, focal laser treatment concurrent with or prior to PRP is recommended.

2) Pharmacological agents

Intravitreal corticosteroids: Randomized clinical trials have shown that intravitreal triamcinolone acetonide (IVTA) leads to significant improvements in DME and visual acuity. The most common complications of IVTA are cataract formation and increased intraocular pressure that may become significant in about 50% of treated eyes within 1 year. More recently, an extended corticosteroid delivery has been achieved by intravitreal or retinal implants. A surgically implanted intravitreal fluocinolone acetonide and an injectable biodegradable intravitreal dexamethasone extended-release implant were evaluated in patients with DME. Improvement in visual acuity and macular thickness has been reported. However, adverse effects included a substantially higher risk of cataract and glaucoma than that observed in eyes receiving IVTA. In some cases IVTA may be useful in eyes with persistent DME and loss of vision despite conventional treatment, though the evidence is inconclusive so far.

In addition to corticosteroids, various anti-inflammatory agents have been investigated, e.g. nepafenac (a topical non-steroidal anti-inflammatory drug) and etanercept (a recombinant fusion protein with activity against TNF-α).

Intravitreal antiangiogenesis agents: As VEGF has been identified as having a major role in the genesis of DR, agents that attenuate the VEGF action represent a promising therapeutic option. They are expected to reduce permeability and neovascularization, the hallmarks of DME and PDR. Based on successful results obtained in wet age-related macular degeneration and promising preliminary data in DR, several randomized clinical trials are currently evaluating three agents that suppress VEGF (named VEGF antagonists or anti-VEGF drugs) for treatment of DME. These are ranibizumab (a recombinant humanized antibody fragment against all isoforms of VEGF-A), pegaptanib (a pegylated aptamer with efficacy against the VEGF-A 165 isoform) and VEGF-Trap. Intravitreal injection permits antiangiogenic drugs to effectively reach the retina and theoretically overcomes the problem of the systemic blockade of angiogenesis. However, this is an invasive procedure that can have complications such as endophthalmitis and retinal detachment and could even have deleterious effects for the remaining healthy retina. This is especially important in diabetic patients for whom long-term administration is expected. Anti-VEGF agents may also produce some systemic side effects. Accordingly, long-term treatment for patients with hypertension, proteinuria, renal failure, cardiovascular disease and foot lesions with wound healing impairment should be avoided. It should be noted that in contrast to the intravitreal corticosteroids, risks of glaucoma and cataract progression associated with intravitreal VEGF antagonists have not been identified.

Pegaptamib and ranibizumab were approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMEA) for treatment of exudative (wet) age-related macular disease in 2004 and 2006, respectively. Bevacizumab was approved by the FDA (2004) for treatment of disseminated colorectal cancer but not licensed for intraocular use. Ranibizumab was recently approved for treatment of DME in Europe (EMEA, January 2011)

Several other VEGF antagonists are currently under investigation as potential treatments for DR, including aflibercept also known as VEGF Trap-Eye (a recombinant fusion protein active against all VEGF-A isoforms and placental growth factor). In addition to RD/DME, aflibercept is studied in clinical trials for exudative AMD. Sirolimus, also known as rapamycin (a macrolide antifungal drug) seems to have anti-VEGF properties. In an animal model, it has been shown to reduce the retinal and choroidal neovascularisation. Several clinical trials studying the efficacy, safety and tolerability of sirolimus in patients with DME are currently ongoing.

3) Surgical vitrectomy for DME

Widespread or diffuse DME that is nonresponsive to focal laser treatment may benefit from vitrectomy. The presence of vitreous traction and macular edema in association with visual impairment is a common indication for vitrectomy. Complications of vitrectomy include recurrent vitreous hemorrhage, retinal tears and detachment, cataract formation, and glaucoma.

The most extensively studied vitreolytic agent is the purified ovine hyaluronidase. Intravitreal administration of hyaluronidase was shown to promote the clearance of vitreous hemorrhage associated with progressive DR. In an animal model, microplasmin (another vitreolytic agent) was able to increase vitreous oxygenation levels after intravitreal injection.

IV. Cataract surgery in patients with DR

Cataract surgery (removal of the natural lens of the eye and replacement with a synthetic lens) is the standard treatment for patients with cataract and significant vision impairment. In patients with diabetes, cataract usually occurs at a younger age and progresses more rapidly. To improve cataract surgical outcomes, adequate control of DR with laser treatment before cataract surgery may be necessary.