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Anti-VEGF treatment for diabetic retinopathy

By Dermot - 13th May 2015 | 9 views

Diabetes affects 382 million people worldwide and this number is expected to rise by 55 per cent, to 592 million, by 2035. In Ireland, there are over 200,000 people affected by diabetes, with an ongoing significant rise in this population.

Diabetic retinopathy and diabetic macular oedema (DME) are major causes of avoidable vision loss in the diabetic population. The increasing prevalence of diabetes worldwide highlights the importance of DME as a major global public health issue.

Given the growing number of diabetes patients that are at high risk for diabetic retinopathy and DME, prioritising resources is a major challenge to ensure health systems are prepared to meet future demand for treating DME patients.

<h3>Initial management</h3>

In 2013, an estimated 90 per cent of retinal specialists in the US reported using anti-vascular endothelial growth factor (anti-VEGF) therapy for initial management of vision loss from DME, and usage has also steadily increased in Europe and Ireland in recent years.

Thus, the US National Institutes of Health (NIH) sponsored the Diabetic Retinopathy Clinical Research Network ( to conduct a comparative effectiveness study (Protocol T) of the top three anti-VEGF agents used to treat DME: Intravitreal aflibercept injection; ranibizumab; and unlicensed bevacizumab.

The Protocol T study is the first major efficacy study directly comparing anti-VEGF therapies in patients suffering from DME.

<h3>Effective treatments</h3>

All three studied agents were found to be effective treatments for patients with DME, with intravitreal aflibercept demonstrating greater visual improvements on average when compared to the other two agents in the trial.

While the doses and treatment regimens used in the Protocol T study differ from those approved in Europe, the results are of significant interest to clinicians on this side of the world.

“This comparative effectiveness study will help doctors and patients make informed decisions when choosing treatments for diabetic macular oedema,” said NEI Director Dr Paul A Sieving.

The study was recently published in the <em>New England Journal of Medicine</em>.


The authors recommended that when applying the results of the study to clinical practice, the eligibility criteria for the study should be considered, ie, visual acuity, retinal thickness, and prior treatment for DME


The study investigators enrolled 660 people with DME on clinical examination and optical coherence tomography (OCT) (according to protocol-defined thresholds, and had received no anti-VEGF treatment within the previous 12 months) at 88 clinical trial sites across the US. At the study onset, participants were on average 61 years old and had type 1 (10 per cent) or type 2 diabetes (90 per cent) for 17 years on average. Only people with a visual acuity of 20/32 or worse were eligible to participate. At enrolment, about half the participants had 20/32 or 20/40 vision, and the other half had 20/50 or worse vision. In many US states, a corrected visual acuity of 20/40 or better in at least one eye is required for a driver’s license that allows both day- and night-time driving.

Each participant was randomly assigned to receive aflibercept (2.0mg/0.05mL), bevacizumab (1.25mg/0.05mL), or ranibizumab (0.3mg/0.05mL). Participants were evaluated monthly and received the assigned study drug by injection directly into the eye until the DME resolved or stabilised. Additionally, laser treatment was given if DME persisted without continual improvement after six months of injections. Laser treatment alone was the standard treatment for DME until widespread adoption of these drugs a few years ago.

All three drugs target VEGF, which can cause leakage from blood vessels and the growth of new, abnormal blood vessels. Anti-VEGF drugs work for DME by reducing vascular leakage. During the year-long study, participants on bevacizumab or ranibizumab received, on average, 10 injections, vs nine for those on aflibercept.


One month after starting treatment, vision had improved substantially for the majority of trial participants, with the improvement sustained through one year with the use of a standardised retreatment protocol. When visual acuity was 20/32 or 20/40 at the start of the trial, vision improved on average almost two lines on an eye chart in all three treatment groups.

In contrast, for participants whose visual acuity 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 three lines.

So when initial vision loss was mild, representing 51 per cent of study eyes, there was little difference in mean visual acuity at one year among the three agents. But at worse initial levels of vision, aflibercept was found to have had a clinically meaningful advantage. For example, an improvement in the visual-acuity letter score of at least 15 (three Snellen lines) was observed in 63 per cent more aflibercept-treated eyes than bevacizumab-treated eyes (67 per cent vs 41 per cent) and in 34 per cent more aflibercept-treated eyes than ranibizumab-treated eyes (67 per cent vs 50 per cent).

The effect of bevacizumab on reducing macular oedema was less than that of the other two agents in both initial visual acuity subgroups. Irrespective of initial visual acuity, few eyes treated with any one agent had substantial loss of visual acuity.

“Eylea, Avastin and Lucentis yield substantial gains in visual acuity for most people with DME; however, on average, Eylea appears to provide additional benefit for patients who start treatment with moderate or worse vision loss,” said Dr John A Wells, the lead author of the study and a retinal specialist at the Palmetto Retina Centre, Columbia, South Carolina, US.

All three drugs reduced swelling of the macula, but aflibercept and ranibizumab reduced the swelling more than bevacizumab. For example, at the one-year visit, the central subfield thickness decreased, on average, by 169±138µm with aflibercept, 101±121µm with bevacizumab, and 147±134µm with ranibizumab. The thickness was less than 250µm in 135 of 205 eyes (66 per cent), 74 of 203 eyes (36 per cent), and 116 of 201 eyes (58 per cent). The relative treatment effect on central subfield thickness varied according to initial visual acuity.

Also, during the study, a smaller percentage of participants on aflibercept (36 per cent) underwent laser treatment for persistent oedema that did not resolve with anti-VEGF treatment alone, compared with those on bevacizumab (56 per cent) or ranibizumab (46 per cent). The study authors noted that this finding probably reflects the greater proportion of aflibercept- treated eyes with resolution of central-subfield-involved DME. The three compounds differ in structure, growth factor specificity and VEGF-binding affinity, but the ways in which these differences may relate to in vivo efficacy is not fully understood.

<h3>Adverse events</h3>

Rates of serious adverse events (including death), hospitalisation and pre-specified systemic adverse events were similar in the three treatment groups. With respect to ocular complications, endophthalmitis (a very serious ocular infection) occurred rarely (in association with 0.02 per cent of the injections) and no significant difference in intraocular inflammation was observed among the three groups.

The authors recommended that when applying the results of this study to clinical practice, the eligibility criteria for the study should be considered, ie, visual acuity, retinal thickness and prior treatment for DME. The results may not apply to eyes with persistent DME or DME that are already being treated with anti-VEGF agents.

Also commenting on the study findings, Ms Marie Hickey Dwyer, Consultant Ophthalmic Surgeon at University Hospital Limerick, said it confirms the efficacy and safety of anti-VEGF injections in the successful treatment of DME. She said she uses anti-VEGF injections in the majority of her DME patients and has done for almost a decade, saying as well as efficacy, they protect against the degeneration of the retina that can be caused in the long term by laser photocoagulation.

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<h3>Diabetic retinopathy — a clinical overview</h3>

Diabetic retinopathy is a potentially sight-threatening complication that affects people with both type 1 and type 2 diabetes.

Diabetic retinopathy affects the small blood vessels in the retina at the back of the eye, causing them to leak or become blocked, leading to blurred vision and even blindness if left untreated. Macular oedema can arise during any stage of diabetic retinopathy and is the most common cause of diabetes-related vision loss. About 7.7 million Americans have diabetic retinopathy. Of these, about 750,000 have DME.

The mainstay of treatment for DME is laser or anti-VEGF injections into the eye or a combination of both.

There is an ongoing, significant rise in the number of people in Ireland with diabetes, particularly type 2, due to obesity so diabetic retinopathy is no longer a rare complication.

In fact, it is the leading cause of blindness in adults under the age of 65. Over 18,000 people in Ireland are estimated to have diabetic retinopathy, which causes, on average, one person with diabetes to go blind each week.

It is estimated that 25 per cent of people with type 1 diabetes will have some degree of diabetic retinopathy five years after their symptoms first develop, according to the HSE. In the case of type 2 diabetes, 25 per cent of people who do not require insulin will have some degree of diabetic retinopathy five years after the onset of symptoms. The figure is higher for people who require insulin (an estimated 40 per cent).

A national screening programme for diabetic retinopathy, called Diabetic RetinaScreen, was launched in Ireland on a phased basis in 2013. The programme offers regular eye screening to people with diagnosed diabetes, aged 12 years and over, who are registered with the programme.

The programme uses specialised digital photography to detect problems at an early stage to reduce or prevent damage to sight, and calculates that about 18 per cent of screened patients will have a diabetes-related pathology; an estimated 5 per cent will have sight-threatening retinopathy (3 per cent macular oedema and two per cent proliferative retinopathy); while a further 7 per cent will have a non-diabetes eye problem. Patients diagnosed with DME are treated with either laser or anti-VEGF injections under the programme.


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