Diabetic Retinopathy Treatment & Management

Controlling diabetes and maintaining the HbA1c level in the 6-7% range are the goals in the optimal management of diabetes and diabetic retinopathy. If the levels are maintained, then the progression of diabetic retinopathy is reduced substantially, according to The Diabetes Control and Complications Trial. ^[12]

The Early Treatment for Diabetic Retinopathy Study ^[28] has found that laser surgery for macular edema reduces the incidence of moderate visual loss (doubling of visual angle or roughly a 2-line visual loss) from 30% to 15% over a 3-year period.

Two-year results from the Diabetic Retinopathy Clinical Research network (DRCR.net) Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema, known as the Laser-Ranibizumab-Triamcinolone for DME Study, demonstrated that ranibizumab paired with prompt or deferred focal/grid laser treatment achieved superior visual acuity and optical coherence tomography (OCT) outcomes compared with focal/grid laser treatment alone. In the ranibizumab groups, approximately 50% of eyes had substantial improvement (10 or more letters) and 30% gained 15 or more letters. Intravitreal triamcinolone combined with focal/grid laser did not result in superior visual acuity outcomes compared with laser alone, but did appear to have a visual acuity benefit similar to ranibizumab in pseudophakic eyes. ^[33]

The Diabetic Retinopathy Study has found that adequate scatter laser panretinal photocoagulation reduces the risk of severe visual loss (< 5/200) by more than 50%. ^[29]

The Diabetes Control and Complications Trial has found that intensive glucose control in patients with type 1 diabetes decreases the incidence and progression of diabetic retinopathy. ^{[12, 13, 14]}

The United Kingdom Prospective Diabetes Study (UKPDS), which involved newly diagnosed patients with type 2 diabetes mellitus, revealed that the risk of retinopathy was reduced through both improved glycemic control and improved blood pressure control. A 1% reduction in HbA1c reduced the risk for retinopathy by 31%, and a 10 mm Hg reduction in systolic blood pressure reduced photocoagulation or vitreous haemorrhage by 11%. ^[34] The ADA recommends that all patients with diabetes (type 2 and type 1) strive to maintain glycated hemoglobin levels of less than 7% (reflecting long-term glucose levels) to prevent or at least minimize the long-term complications of diabetes mellitus, including retinopathy.

The Early Treatment for Diabetic Retinopathy Study found that 650 mg of aspirin daily did not offer any benefit in preventing the progression of diabetes mellitus retinopathy. Additionally, aspirin was not observed to influence the incidence of vitreous hemorrhage in patients who required it for cardiovascular disease or other conditions. ^{[28, 15]}

In large phase III clinical trials, intravitreal injections of ovine hyaluronidase (Vitrase) have been shown to be safe and to have modest efficacy for the clearance of severe vitreous hemorrhage. More than 70% of subjects in these studies had diabetes, and the most frequent etiology of the vitreous hemorrhage was proliferative diabetic retinopathy. ^[35]

In a DRCR.net clinical trial comparing Eylea (aflibercept), Lucentis (ranibizumab), and Avastin (bevacizumab) for diabetic macular edema (DME), aflibercept provided greater visual improvement, on average, than did the other 2 drugs for vision of 20/50 or worse at the start of the trial. The 3 drugs achieved similar average improvement for vision of 20/40 to 20/32. No major differences in safety were found for the 3 drugs. ^[36]

Investigators included 660 people with macular edema at 88 clinical trial sites across the United States. Only people with vision of 20/32 or worse were eligible. About half the participants had 20/32 or 20/40 vision at time of enrollment, and the other half had vision of 20/50 or worse.

Participants were randomly assigned to receive aflibercept (2.0 mg/0.05 mL), bevacizumab (1.25 mg/0.05 mL), or ranibizumab (0.3 mg/0.05 mL) and were evaluated monthly. The drug was injected into the eye until the DME resolved or stabilized. Laser treatment was used if DME persisted without continual improvement after 6 months of injections.

Vision substantially improved for most participants at one year after the trial began. For people whose vision was 20/32 or 20/40 at the start of the trial, vision improved almost two lines on an eye chart in those receiving each of the 3 drugs. However, for those whose vision was 20/50 or worse at the start of the trial, aflibercept improved vision on average almost four lines, bevacizumab improved vision on average almost 2.5 lines, and ranibizumab improved vision on average almost 3 lines.

Aflibercept and ranibizumab reduced the swelling of the macula more than bevacizumab. Also, a smaller percentage of participants on aflibercept (36%) had laser treatment for persistent edema that did not resolve with anti–vascular endothelial growth factor (anti-VEGF) treatment alone, compared with participants on bevacizumab (56%) or ranibizumab (46%). ^[36]

Aflibercept gained US Food and Drug Administration (FDA) approval for all stages of diabetic retinopathy (NPDR) in May 2019. Approval was based on the 1-year data from the PANORAMA trial (n=402). The study enrolled patients with moderately severe to severe NPDR without DME. At week 52, 80% of patients receiving aflibercept every 8 weeks and 65% of those receiving the drug every 16 weeks improved by two or more steps from baseline on the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS), compared with 15% of placebo patients. ^{[37, 38]}  A high-dose formulation with less frequent maintenance dosing was approved by the FDA in August 2023. Approval was supported by the phase-3 PHOTON trial, in which vision gains from the 8-mg, high-dose product were clinically equivalent to those from aflibercept 2 mg but were maintained with fewer injections. ^[39]   

Ranibizumab intravitreal injection was initially approved for diabetic retinopathy in patients with DME. Approval was based on the RISE and RIDE studies (n = 759). The trials measured the proportions of patients who gained 15 letters or more from baseline at month 36 in the sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab groups. Results in each group were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%, in RISE.

In the ranibizumab arms, reductions in central foveal thickness (CFT) seen at 24 months were, on average, sustained through month 36. Visual acuity (VA) gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained through month 36. In the third year, sham patients, while still masked, were eligible to cross over to monthly 0.5 mg ranibizumab. After crossover to 1 year of treatment with ranibizumab, average VA gains in the sham/0.5 mg group were lower compared with gains seen in the ranibizumab patients after 1 year of treatment (2.8 vs. 10.6 and 11.1 letters). ^[40]

Subsequent studies have also pointed to ranibizumab's efficacy in diabetic retinopathy. A literature review by Stewart found that in a large minority of eyes, regular injections of ranibizumab resulted in improved diabetic retinopathy severity scores. In proliferative diabetic retinopathy, patients experienced less visual field loss with the drug than with laser photocoagulation. The literature also indicated that ranibizumab is superior to laser photocoagulation for the treatment of diabetic macular edema. ^[41]

Similarly, a literature review by Vergmann and Grausland indicated that in the treatment of proliferative diabetic retinopathy, VEGF inhibitors are less damaging to visual fields than is conventional panretinal photocoagulation (PRP). ^[42]

A 4-year study by Epstein and Amrén found that after receiving a loading dose of ranibizumab (three monthly injections of 0.5 mg), best-corrected visual acuity in patients could be maintained with the drug administered on an as-needed basis. The number of required injections was low, the mean numbers during the first through fourth years being 4.7, 1.4, 0.7, and 0.9, respectively. ^[43]

Ranibizumab’s indication for diabetic retinopathy was expanded in 2017 to include all forms (ie, patients who have been diagnosed either with or without DME). Approval for treatment of diabetic retinopathy without DME followed an evaluation of the Diabetic Retinopathy Clinical Research Network's (DRCR.net) Protocol S study (n=305). The study assessed ranibizumab therapy in comparison with panretinal laser treatment in diabetic retinopathy patients with or without DME, with the analysis finding that retinopathy improved in patients in the ranibizumab group, either with or without DME. ^[44]  

Other intravitreal VEGF inhibitors approved include brolucizumab and faricimab.  

Bevacizumab intravenous (IV) has been used off-label to treat vitreous hemorrhage. In addition, this agent has been used to treat optic nerve or retinal neovascularization as well as rubeosis. ^{[45, 46]} In August, 2011, FDA announced a warning regarding several cases of intravitreal infections associated with repackaged bevacizumab that was potentially due to poor aseptic compounding technique. ^[47] Bevacizumab is commonly used to treat DME throughout the world and is a much lower cost alternative. An investigational bevacizumab intravitreal formulation is under development.

The advent of laser photocoagulation in the 1960s and early 1970s provided a noninvasive treatment modality that has a relatively low complication rate and a significant degree of success. This involves directing a high-focused beam of light energy to create a coagulative response in the target tissue. In nonproliferative diabetic retinopathy, laser treatment is indicated in the treatment of clinically significant macular edema. The strategy for treating macular edema depends on the type and extent of vessel leakage.

If the edema is due to leakage of specific microaneurysms, the leaking vessels are treated directly with focal laser photocoagulation. ^[16] In cases where the foci of leakage are nonspecific, a grid pattern of laser burns is applied. Medium intensity burns (100-200 µm) are placed 1 burn-size apart, covering the affected area. Other off-label potential treatments of diabetic macular edema include intravitreal triamcinolone acetonide (Kenalog) and bevacizumab; these medications can result in a substantial reduction or resolution of macular edema.

Maintaining a healthful lifestyle with regular exercise is important, especially for individuals with diabetes. Exercise can assist in maintaining optimal weight and with peripheral glucose absorption. This can help with improved diabetes control, which, in turn, can help reduce the complications of diabetes and diabetic retinopathy.

Panretinal photocoagulation

Panretinal photocoagulation (PRP) is the preferred form of treatment of proliferative diabetic retinopathy (PDR). ^{[15, 16]} It involves applying laser burns over the entire retina, sparing the central macular area, and may be performed using a variety of delivery systems, including the slit lamp, an indirect ophthalmoscope, and the EndoProbe.

Application starts in a circumference of 500 µm from the disc and 2 disc diameters from the fovea to wall off the central retina. Moderate intensity burns of 200-500 µm (gray-white burns) are placed 1 spot-size apart, except in areas of neovascularization where the entire frond is treated if DRS criteria are used, but most specialists today avoid directly treating neovascularization. This procedure is continued peripherally to achieve a total of 1200-1600 applications in 2 to 3 sessions.

The presence of high-risk PDR is an indication for immediate treatment.

In cases where macular edema and PDR coexist, laser treatments are performed: first, laser treatment is used for the macular edema; then for PDR, the PRP is spread over 3 to 4 sessions. If it is necessary to complete the 2 procedures at the same time, the PRP is applied initially to the nasal third of the retina.

The strategy for treating macular edema depends on the type and extent of vessel leakage. If the edema is due to focal leakage, microaneurysms are treated directly with laser photocoagulation. In cases where the foci of leakage are nonspecific, a grid pattern of laser burns is applied. Burns (100-200 μm) are placed 1 burn-size apart, covering the affected area.

The exact mechanism by which PRP works is not entirely understood. One theory is that destroying the hypoxic retina decreases the production of vasoproliferative factors, such as VEGF, thus reducing the rate of neovascularization. Another theory is that PRP allows increased diffusion of oxygen from the choroid, supplementing retinal circulation. The enhanced oxygen delivery also down-regulates vasoproliferative factor production and subsequent neovascularization.

Vitrectomy

Vitrectomy may be necessary in cases of long-standing vitreous hemorrhage (where visualization of the status of the posterior pole is too difficult), tractional retinal detachment, and combined tractional and rhegmatogenous retinal detachment. More uncommon indications include epiretinal membrane formation and macular dragging.

According to The Diabetic Retinopathy Vitrectomy Study, vitrectomy is advisable for eyes with vitreous hemorrhage that fails to resolve spontaneously within 6 months. ^[48] Early vitrectomy (< 6 mo, mean of 4 mo) may result in a slightly greater recovery of vision in patients with type I diabetes.

When treatment is delayed, monitoring the status of the posterior segment by ultrasound is mandatory to watch for signs of macular detachment.

The purpose of surgery is to remove the blood to permit evaluation and possible treatment of the posterior pole, to release tractional forces that pull on the retina, to repair a retinal detachment, and to remove the scaffolding into which the neovascular complexes may grow. Laser photocoagulation through indirect delivery systems or through the EndoProbe can be performed as an adjunctive procedure during surgery to initiate or continue laser treatment.

Cryotherapy

When laser photocoagulation is precluded in the presence of an opaque media, such as in cases of cataracts and vitreous hemorrhage, cryotherapy may be applied instead.

The principles behind the treatment are basically the same—that is, to ablate retinal tissue for oxygen demand to be decreased and to induce a chorioretinal adhesion, which could increase oxygen supply to the retina in the hope of preventing or down-regulating the vasoproliferative response.

The Diabetes Control and Complications Trial and United Kingdom Prospective Diabetes Study were large randomized clinical trials that demonstrated the importance of tight glucose control with respect to reducing the incidence and progression of diabetes complications, including diabetic retinopathy for both type I and type II diabetes.

All individuals with diabetes should be aware of the importance of regular dilated retinal examinations. Early diagnosis and treatment of diabetic retinopathy can help prevent blindness in more than 90% of cases. In spite of treatment, however, individuals can sometimes still lose vision.

The patient, ophthalmologist or retina specialist, and internist or endocrinologist must work together as a team to optimize the diabetes control and help to reduce the risk of blindness.

The frequency of follow-up care is dictated primarily by the baseline stage of the retinopathy and its rate of progression to proliferative diabetic retinopathy (PDR). Only 5% of patients with mild nonproliferative diabetic retinopathy (NPDR) would progress to PDR in 1 year without follow-up care, and thus, monitoring these patients every 6-12 months is appropriate. As many as 27% of patients with moderate NPDR would progress to PDR in 1 year; therefore, they should be seen every 4 to 8 months.

More than 50% of patients with severe NPDR (preproliferative stage) would progress to PDR in a year without follow-up care and 75% would develop high-risk characteristics within 5 years; thus, follow-up care as frequently as every 2 to 3 months is mandated to ensure prompt recognition and treatment.

Any stage associated with clinically significant macular edema should be treated promptly with laser panretinal photocoagulation and observed closely (every 1-2 mo) to monitor the status of the macula and decrease the chance of severe visual loss.

Diabetes mellitus, in general, and diabetic retinopathy, in particular, are progressive conditions, and regular follow-up care with a physician is crucial for detection of any changes that may benefit from treatment.