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Some challenges remain in the management of DME
There can be no doubt that anti-VEGF agents have revolutionized the management of diabetic macular edema. Whether we use monoclonal antibodies as in bevacizumab, antibody fragments as in ranibizumab or fusion proteins as in aflibercept to block VEGF, the randomized controlled multicenter international clinical trials have shown superior treatment outcomes in DME compared with laser or steroids. At 1 year the visual acuity gain is around eight letters, and this is maintained into the second year. Good glycemic control, blood pressure and lipid control are also important in the prevention of DME but appear to have little or no effect on treatment response to anti-VEGF. Nevertheless, there are still areas that need further attention and improvement in order to ensure the results that we see in clinical trials can be translated into the real world.
When to start treatment — challenges in diabetic eye screening
Early intervention before center-involving DME has developed ensures the best clinical outcomes with anti-VEGF treatment. In countries where there is already a well-established diabetic retinopathy screening system, the audits show how effective such programs are at ensuring timely treatment and preserving sight. Even so, one of the major limitations with screening for DME is the high level of false positives that come through to the hospital eye service. Any screening program is rightly set up to ensure there are as few false negatives as possible (because a screening service should not miss any patients with the disease). However, with the current definition of M1 maculopathy (exudate within 1 disc diameter of the fovea, group of exudates at the macula, microaneurysms and a visual acuity worse than 6/12), many patients with a dry macula are taking up unnecessary space in medical retina clinics. The reported rates of false positive referrals are around 57.1% in a Hong Kong study, around 85% in a Singapore study and 59.7% in a U.K. study. The clinical trials using stereo imaging of the macula or OCT at the screening centers are currently ongoing, and results are anticipated shortly. In the meantime, many centers are setting up virtual clinics to reduce the number of patients with referable M1 maculopathy ending up in the medical retina clinics. In a virtual clinic, the patient has best corrected vision measured and a macular thickness OCT scan taken of both eyes. The patient is referred back to the diabetic retinopathy screening service (without ever being seen in the hospital clinics) if the retina is dry on OCT.
On the other hand, those places without an established diabetic screening service often find themselves dealing with patients who have already lost substantial vision from center-involving DME. These patients, with more advanced disease, often need more injections, which increases the cost and treatment burden to patients and health care providers. It seems a careful balance between having a screening service that has too many referrals vs. having no service at all, which relies on patients losing vision before they present to the hospitals. Ensuring the right patients receive anti-VEGF treatment at the right time is a challenge not yet fully resolved.
Cost of treatment
Perhaps this is an area of anti-VEGF treatment that is not relevant to all centers or all patients with DME. However, for those unfortunate patients who live in a country where the cost of the medication is not covered by the health care service nor have insurance that covers the costs, patients have no choice but to pay for the treatment out of their own pocket. This in conjunction with the latest evidence from the DRCR.net recommending that treatment-naïve patients with clinically significant macular edema should receive six loading doses of anti-VEGF (average eight to nine injections in the first year), means the costs can spiral out of control. Various studies comparing the cost of the treatment with quality of life years have shown that the more expensive treatments may not be cost-effective (despite the fact that they work very well). Many centers are therefore offering bevacizumab as an unlicensed, off-label alternative. With newer anti-VEGF agents due to come onto the market and many having a longer duration of action (therefore not needing monthly injection), this situation may resolve itself in due course. Many clinicians are now moving toward “treat-and-extend” or “defer-and-extend” protocols, also with the aim of personalizing treatment and reducing the total number of injections.
Treatment of non-responders
The exact definition of what constitutes a treatment non-response and when we should consider either switching therapy or using combination therapy remains to be decided. Nevertheless, there have been exciting developments in the field of management of DME non-responders with the recent publication by Campochiaro and colleagues, showing an improvement in treatment response when anti-VEGF is combined with AKB-9778 (Aerpio Therapeutics), as discussed in this month’s cover story. This study paves the way for similar studies for vein occlusions and age-related macular degeneration non-responders. Whether the intravitreal anti-angiopoietin 2 treatments currently being developed (CrossMAb by Roche and nesvacumab by Regeneron) will be equally as effective remains to be validated.
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Campochiaro PA, et al. Ophthalmology. 2016;doi:10.1016/j.ophtha.2016.04.025.
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For more information:
Dennis S.C. Lam, MD, FRCOphth, can be reached at State Key Laboratory in Ophthalmology, Sun Yat-Yen University, 54 South Xianlie Road, Guangzhou 510060, People’s Republic of China; email: dennislam.gm@gmail.com.
Disclosure: The authors report no relevant financial disclosures.