WRITERS Associate Professor Abhishek Sharma and Dr Thanh Nguyen

Management of severe diabetic retinopathy involves well-established treatment options, including laser therapy, intravitreal injections, and surgery. There are also promising upcoming therapies, as Associate Professor Abhishek Sharma and Dr Thanh Nguyen discuss in this article.

Diabetic retinopathy andmaculopathy are common complications of diabetes. The early stages may not be symptomatic, but over time can result in severe central and peripheral vision loss, and eventually blindness. Diabetic retinopathy has been reported as the leading cause of preventable blindness in Australia. 1

Up to two million Australians are expected to have a diagnosis of diabetes by 2025,2 with nearly 20% developing some level of diabetic retinopathy, including 2–3% with proliferative diabetic retinopathy or diabetic macular oedema (DMO). 3 Australian eye care professionals need to be up-to-date on best practices to manage the tens of thousands of Australians at risk of preventable vision loss.

WHAT IS CONSIDERED SEVERE?

Severe diabetic retinopathy can be loosely defined as when treatment for the eye is specifically required, and the eye is beyond systemic control and eye monitoring alone. It is important to note that systemic control, including control of blood glucose levels, blood pressure, and lipids, are still vital for the long-term success of any eye treatments.

For the peripheral retina, treatment level retinopathy is considered at the stage of proliferative diabetic retinopathy (PDR),4 and occasionally severe non-proliferative diabetic retinopathy, depending on the patients’ psychosocial situation and medical conditions. Proliferative diabetic retinopathy occurs when fragile new blood vessels are present that can result in vitreous haemorrhage, tractional and rhegmatogenous retinal detachments, and neo-vascular glaucoma.

For DMO, there is good evidence that reliable asymptomatic patients can be monitored if their vision level is 6/9 or better.5The Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol V was a largescale clinical trial conducted to investigate the best treatment approaches for DMO, including observation, anti-VEGF injections, or focal/grid laser therapy. The study found that for patients with mild DMO, observation alone was an appropriate treatment strategy, rather than immediately initiating treatment with anti-VEGF injections or laser therapy. 5

However, with the excellent outcomes from current treatment options, it’s good practice to involve an ophthalmologist for closer monitoring and early treatment if the macular oedema worsens or vision deteriorates.

Figure 1. What is severe retinopathy?

DIABETIC MACULAR OEDEMA

The best treatment for DMO depends on the severity of the condition and the individual patient’s needs. It’s important to note that the treatments are not mutually exclusive, and a combination of therapies may be necessary to achieve the best results.

Anti-VEGF

Anti-VEGF drugs block the action of vascular endothelial growth factor (VEGF), a protein that stimulates abnormal blood vessel growth and leakage in the retina. Anti-VEGF intravitreal injections have been extensively demonstrated as effective treatment for DMO, with significant improvement in visual acuity and reduction in central retinal thickness observed in numerous large, well-conducted randomised controlled trials (RCTs). In Australia, we are lucky to have government funded options of ranibizumab, aflibercept, brolucizumab, faricimab, and off-label bevacizumab.

The RISE and RIDE studies were large RCTs that compared the efficacy of monthly injections of ranibizumab with placebo in patients with DMO. The studies demonstrated that treatment with ranibizumab led to significant improvement in visual acuity and reduction in central retinal thickness compared to placebo.6

VIVID and VISTA RCTs evaluated the efficacy of aflibercept in the treatment of DMO. The studies found that treatment with aflibercept led to significant improvement in visual acuity and reduction of central retinal thickness compared to placebo.7

The DRCR.net Protocol T study compared the efficacy of three different anti-VEGF medications (ranibizumab, aflibercept, and bevacizumab) in patients with DMO.

Figure 2. OCT image demonstrating diabetic macular oedema.

The study found all three medications were effective in improving visual acuity, with no significant differences in efficacy between the three drugs at > 6/12 vision but with vision at <6/12 aflibercept had slightly better visual and anatomic improvement.8

Faricimab is a new type of medication that was approved for the treatment of DMO in Australia in January this year. It is a bispecific antibody that targets both VEGF and angiopoietin-2 (ANG-2).

YOSEMITE and RHINE are recent Phase 3 trials that evaluated the efficacy of faricimab in comparison to aflibercept in patients with DMO. The studies compared different dosing regimens of faricimab and demonstrated that this medication was non-inferior to aflibercept with similar visual gains and with over three-quarters of patients able to go to 12 to 16 weekly intervals between injections.9

Overall, there is extensive evidence that anti-VEGF and derivatives are an excellent treatment option for DMO and are considered first line.

Focal/Grid Laser

Focal laser involves using a laser to create small burns on the retina in areas of vascular leakages that caused the macular oedema.

The laser treatment seals off leaking blood vessels and reduces the oedema, which can improve vision.

Evidence going back to the 1980s, with the Early Treatment Diabetic Retinopathy Study (ETDRS), supports the use of focal grid laser as an effective treatment for DMO.10 However, its use has significantly reduced in recent years due to the advent of anti-VEGF medications, which have been shown to be more effective in improving visual acuity. One such study was the DRCR.net Protocol I study, which compared the efficacy of focal grid laser with intravitreal injections of ranibizumab in patients with DMO, and found ranibizumab was more effective than focal grid laser in improving visual acuity although focal laser was still of benefit. 11

Focal laser is now more often relegated to special circumstances, such as in patients who have contraindications to anti-VEGF therapy, or are unable to attend the frequent appointments required for intravitreal injections.

Corticosteroids

Several different forms of corticosteroids have been used as a treatment for DMO due to their anti-inflammatory properties.

Intravitreal injections of triamcinolone acetonide (IVTA), dexamethasone intravitreal implant (DEX implant), and fluocinolone acetonide intravitreal implant (FA implant) have been evaluated in clinical trials.

The DRCR.net Protocol B study compared the efficacy of IVTA, focal/grid laser photocoagulation, and observation in patients with DMO. The study demonstrated that IVTA was more effective than observation in improving visual acuity, but not as effective as focal/grid laser photocoagulation.12

The Fluocinolone Acetonide in Diabetic Macular Edema (FAME) study evaluated the efficacy of the FA implant in patients with DMO.13 The study found that the FA implant was more effective than standard of care (focal/grid laser photocoagulation or observation) in improving visual acuity and reducing central retinal thickness, and that the effect lasted for up to three years.

Figure 3. OCT demonstrating resolution of recurrent DMO with dexamethasone implant.

While evidence suggests that corticosteroids can be effective in improving visual acuity and reducing central retinal thickness in patients with DMO, their use is associated with several potential side effects, such as cataract formation, and secondary glaucoma with increased intraocular pressures. Steroids suppress inflammation and reduce the permeability of blood vessels. Anti-VEGF therapy is more targeted and specific to the underlying cause of DMO while avoiding the major side effects of steroids, thus keeping anti-VEGF as our first-line choice.

Surgery

Surgery is not typically considered as a firstline treatment for DMO, as there are other effective treatment options available, such as anti-VEGF therapy and steroids.

Several clinical studies have investigated the effectiveness of vitrectomy for DMO, with mixed results. Some studies have reported significant improvement in visual acuity and reduction in macular oedema after vitrectomy, while others have not found significant benefits.

The Diabetic Retinopathy Vitrectomy Study (DRVS) was a randomised clinical trial that compared vitrectomy (albeit in the early days of vitrectomy surgery) with observation in patients with severe non-proliferative diabetic retinopathy or early proliferative diabetic retinopathy. Although the primary outcome was not specifically related to DMO, the study did report that vitrectomy was associated with improved visual acuity in patients with DM0.14

The DRCR.net Protocol D Vitrectomy for DME Study evaluated the effectiveness of vitrectomy in patients with DMO who have not responded to anti-VEGF therapy and have vitreomacular traction. It did not definitively indicate that early surgery is warranted.15 On the other hand, a metaanalysis of current literature found that vitrectomy was associated with significant improvement in visual acuity and reduction in macular thickness, though the quality of studies is limited. 16

Overall, the evidence for vitrectomy as a treatment option for DMO is limited, and the decision to perform vitrectomy should be based on individual patient factors and development of other secondary macular issues.

Diabetic Macular Oedema and Cataract Surgery

Foveal involving DMO should be controlled prior to any cataract surgery, to avoid prolonged recovery or worse visual outcome. 17 The DRCR.net team provided further evidence with their Protocol Q study that even in patients with non-centreinvolving DMO, it is worthwhile controlling the DMO. In their study, patients with noncentral DMO or history of DMO were more likely to develop fovea-involving DMO at 16 weeks after cataract surgery. 17

Other Therapies

Several newer trial therapies being investigated for the treatment of DMO or awaiting larger trials include:

Gene TherapyGene therapy is a promising new approach to treating DMO. One such therapy is RGX-314, which is a gene therapy that uses a viral vector to deliver a gene that produces a protein called aflibercept directly to the retina. This therapy is currently being evaluated in clinical trials. 18

Combination TherapySeveral clinical trials are investigating the use of combination therapies for DMO, such as the combination of an anti-VEGF medication with a corticosteroid or a tyrosine kinase inhibitor. 19

New Anti-VEGF MedicationsNew anti-VEGF medications, such as abicipar, are being developed and evaluated in clinical trials for the treatment of DMO. These medications may have longer halflives than current anti-VEGF medications, reducing the need for frequent injections. 20

Subthreshold Micropulse LaserSubthreshold micropulse laser is being investigated, either as a sole non-destructive treatment for DMO, or as adjunct with anti-VEGF therapy. There are some promising results that this may reduce the burden of long-term frequent intravitreal injections. 21,22

These newer trial therapies hold promise for the treatment of DMO and may offer additional options for patients who do not respond well to current treatments.

PROLIFERATIVE DIABETIC RETINOPATHY

PDR is a serious complication of diabetes that occurs when abnormal blood vessels grow on the retina. If left untreated, PDR can lead to vision loss or blindness. The treatment for PDR depends on the severity of the condition and we will go through the current paradigm.

Figure 4. Proliferative diabetic retinopathy with vitreous haemorrhage and superotemporal tractional retinal detachment.

Figure 5. Pan-retinal photocoagulation scars following proliferative diabetic retinopathy.

Laser

Laser retinopexy throughout the peripheral retina, known as pan-retinal photocoagulation (PRP), is the most common treatment and standard-of-care for PDR. It involves using a laser to destroy the ischaemic retina, to reduce the ischaemic drive that stimulates the formation of new blood vessels to form in the first place. While the treatment remains an effective option, it is associated with a host of potential side effects.

These include decreased peripheral vision, decreased night vision, potentially decreased central vision and colour vision, precipitating macular oedema and vitreous haemorrhages.23 The treatment is uncomfortable and thus often divided over several sessions for each eye. The vitreous haemorrhage itself may limit the ability to apply laser.

The best evidence that PRP is still relevant decades later comes from the ETDRS team from the 1980s that investigated the effects of laser photocoagulation on PDR.23 The study found that PRP laser treatment reduced the risk of severe visual loss by 50% in patients with high-risk PDR. It also found that early treatment was more effective than deferred treatment. More recently, the DRCR.net Protocol S, although noting benefits of anti-VEGF treatment, still noted that PRP provided good control of PDR, albeit with similar side effects as noted decades ago.24

Figure 6. PDR progressed to total tractional retinal detachment.

PRP versus PRP plus intravitreal ranibizumab for high-risk proliferative diabetic retinopathy compared the efficacy of laser photocoagulation to intravitreal injections of the anti-VEGF drug ranibizumab for PDR. The study demonstrated that PRP with adjunctive use of ranibizumab resulted in better protection against macular oedema and less vision loss compared to PRP alone.25

Overall, strong evidence exists for the use of laser photocoagulation in the treatment of PDR, and there are opportunities now to tailor this treatment to each patient’s individual needs and circumstances.

Intravitreal Injections

Several studies have provided good evidence that anti-VEGF agents are suitable for treatment of PDR, with the benefit of avoiding many of the side-effects associated with a full-PRP.

The DRCR.net team provided evidence in their Protocol S study, which compared the efficacy of early PRP versus ranibizumab with deferred PRP.24 This study demonstrated that anti-VEGF therapy with ranibizumab was safe and effective for PDR, not inferior to PRP, with the added benefit of reduced risk of developing diabetic macular oedema and tractional detachment. Unfortunately, there was the ongoing need for injection. It has been demonstrated that patients with proliferative disease undergoing intravitreal injection loss to follow-up resulted in significant visual loss, including from tractional redtail detachment and rubeosis. 26

Protocol N by the DRCR.net team provided further evidence for anti-VEGF use in patients with vitreous haemorrhage due to their PDR.27 In this trial, ranibizumab injections were associated with faster clearing of the vitreous haemorrhage and decreased recurrence at 16 weeks, although by 52 weeks the rates of vitrectomy or visual acuity were similar to the group without ranibizumab.

The PANORAMA and DRCR.net Protocol W studies28 were randomised controlled trials that evaluated the efficacy of the anti-VEGF medication, aflibercept, in the treatment of moderately severe to severe non-proliferative diabetic retinopathy (NPDR) or proliferative diabetic retinopathy (PDR) without DMO. The studies found that treatment with aflibercept led to significant reduction in the risk of progression to visionthreatening complications of proliferative retinopathy. 29 However, there were no visual acuity benefits in those treated with intravitreal aflibercept.

As a result of these studies anti-VEGF drugs are often used as adjunct to laser treatment for PDR, particularly in cases of recurrent vitreous haemorrhages or persisting rubeosis post PRP treatment.

Surgery

Vitrectomy surgery is generally considered when PDR has caused secondary complications of vitreous haemorrhage, significant scarring of the vitreoretinal interface such as with worsening epiretinal membrane, vitreoretinal traction, or tractional retinal detachment. While laser and anti-VEGF injections continue to be the mainstay of treatment for severe retinopathy, vitreous haemorrhage often limits the view or ability to perform injections or laser.

The Diabetic Retinopathy Vitrectomy Study (DRVS) was a large randomised clinical trial conducted in the 1970s and 1980s investigating vitrectomy surgery for PDR. Even at this early phase of vitrectomy equipment and techniques, there was a clear benefit noted in reducing the risk of severe vision loss when compared to observation or delaying surgery for more than six months.14

More recently, the DRCR.net Protocol AB study looked at vitreous haemorrhage and treatment with aflibercept versus vitrectomy with endolaser.30 This study found vision at six months and two years was equivalent although, as could be expected, dense haemorrhages took longer to clear. Current practice is to monitor for a period to see if the haemorrhage clears without a detachment developing, often with the aid of ultrasound if there is limited view of the fundus to ensure the retina is flat.

SUMMARY

Optometrists play a critical role in the management of diabetic retinopathy, often being the first point of contact for patients with diabetes for their eye screening. Early detection, close monitoring, and referral for patients with worsening diabetic retinopathy and maculopathy remains the key to good visual outcomes. Both optometrists and ophthalmologists should involve the patients’ primary health care providers as the patients require good control of their diabetes and associated risk factors such as blood pressure and cholesterol levels.

With the array of treatments for severe retinopathy and maculopathy discussed here, and with ongoing trials in newer intravitreal agents, long lasting steroids, gene therapy trials, nano-pulse lasers, and small-gauge early vitrectomy in collaboration with primary health care providers, eye health care professionals are in a great position to ensure excellent long-term vision for our patients.

Associate Professor Abhishek Sharma

Associate Professor Abhishek Sharma MBBS DPhil is a specialist in medical and surgical retinal eye conditions.

He completed his Bachelor of Medicine and Surgery from the University of Tasmania in 2004. He undertook his ophthalmology training at the Royal Victorian Eye and Ear Hospital in Melbourne in 2009, and completed the Royal Australian and New Zealand College of Ophthalmologists Fellowship examinations in 2013.

Prior to his ophthalmology training, he completed a PhD in the field of Public Health and Epidemiology in 2009 from the University of Oxford, as a Rhodes Scholar. His research saw him investigate China’s myopia epidemic, developing a pathway for treatment for rural communities. He is the author of Mindmaps in Ophthalmology, published through CRC Press.

Dr Thanh Nguyen

Dr Thanh Nguyen MBBS PhD FRANZCO is an ophthalmology consultant at the Royal Victorian Eye and Ear Hospital and a Research Fellow at the Centre for Eye Research Australia (CERA).

Dr Nguyen has over 40 peer-reviewed publications. In addition, he has been a peerreviewer for 17 journals including Diabetes, Diabetes Care, Annals of Neurology and a range of ophthalmology journals. His primary research interest is to utilise retinal image analysis to understand the changes of the retinal vasculature in patients with pre-diabetes and diabetes. He has been the leading author for large-scale studies that have direct relevance to diabetes and retinal vascular diseases.

For references and to earn your CPD hours, visit: mieducation.com/severe-diabetic-retinopathymanagement-update.