A NEW ERA IN TREATMENT OF DME

Recent advances in diagnostic imaging and various therapeutic modalities herald a new era in the management of diabetic macular oedema (DME). Progress is being made on several fronts: angio-optical coherence tomography (angio-OCT), sub-threshold lasers, new anti-VEGF molecules and sustained-release corticosteroid implants are entering
the clinic.

New insights into pathogenetic mechanisms and interindividual differences will lead to individualised treatments, and patients will benefit from these new insights and possibilities.

“We have recently experienced a major revolution in the management of DME. In fact, this is the second DME revolution. The first one took place in the 1970s, with the introduction of fluorescein angiography (FA) and macular laser treatment. The past decade has seen a similar diagnostic and therapeutic revolution, with the introduction of the OCT and anti-VEGF treatment. These are very fortunate times,†said Francesco Bandello MD, FEBO, Vita-Salute University, Milan, Italy.

Will Angio-OCT replace FA and OCT?

This revolution is ongoing. Angio-OCT is a non-invasive and dyeless technique that uses the movement of red blood cells in retinal vessels instead of dye to record the vascular network. Unlike other imaging methods that utilise contrast agents, angio-OCT allows visualisation without the blurring or obscuring effects of leakage, staining or pooling. This allows the clinician to see the individual capillaries much more clearly than with FA, identifying abnormalities with more precision than might be possible with classical FA. Small capillary dropout is visible on angio-OCT very early in the disease process, when it might be missed on FA.

Ursula Schmidt-Erfurth MD, Professor of the Department of Ophthalmology, Medical University of Vienna, Austria, and head of the Vienna Reading Center (VRC), a digital image analyses platform, foresees the eventual elimination of FA in the management of DME.

“The strength of angio-OCT is in the early detection of macular vascular changes that are not visible in FA. I predict a switch from dye-based angiography to multimodal OCT, which will lead to a progressive replacement of FA in favour of angio-OCT,†she said.

She stressed the need for new pathogenic and clinical classifications of DME based on its appearance on angio-OCT. In age-related macular degeneration (AMD), advantages of angio-OCT are already obvious regarding visualising neovascular recurrences.

Angio-OCT is poised to change the way we look at neovascularisation and vessel loss, according to Marc de Smet MD, PhD, Microinvasive Ocular Surgery Clinic, Lausanne, Switzerland.

“Because it can differentiate between the superficial capillary plexus and the deep plexus, it will allow us to determine the level at which ischaemia is present within the retinal tissue in DME. Current understanding suggests that the deep plexus probably plays a more important role than previously appreciated, because we could not see it with FA. At this level, Muller cells redirect retinal water to blood vessels by way of aquaporins (water) and potassium channels. Thus, ischaemic dysfunction in this deep layer contributes to the oedema we see clinically,†he said.

Besides several advantages in terms of imaging, clinicians can also expect economy in safety, insurance, time and various other costs associated with classical FA.

Current Standard of Care

According to a survey conducted by the American Society of Retina Specialists in 2013, 90 per cent of retinal specialists in the USA use anti-VEGF therapy for initial management of vision loss from DME involving the macular centre. But many experts have more nuanced ideas.

“We haven’t yet done enough to determine the various pathogenic mechanisms of DME. We tend to lump all patients together into one group, treat them with the same modality and then discover that a significant percentage of them do not respond,†said Dr Bandello.

“After all, approximately 30-40 per cent of patients insufficiently respond to anti-VEGF treatment. This suggests that other modalities will continue to play a significant role. I think the future of DME management lies in the subclassification of DME phenotypes, so that patients can be treated as individuals,†he notes.

Individualised treatment

All of the experts interviewed for this article agree that DME is the result of a multifactorial pathogenesis. Acute and chronic inflammatory changes occur, both of which might contribute to the pathogenesis of DME. And while the current pharmacotherapeutic approach is mainly based on the administration of VEGF inhibitors, corticosteroids have again been gaining attention as an alternative, particularly with the introduction of sustained-release intravitreal implants.

Dr de Smet agrees that there is a role for each of the therapeutic modalities, each with distinct advantages and disadvantages.

“Targeting anti-VEGF is certainly effective, but it requires multiple injections. However, since DME is more than just VEGF-induced leakage, other approaches, including steroids, are certainly viable options. Indeed, sustained release steroid preparations have an important role to play in the long-term care of patients otherwise burdened by multiple doctor visits and juggling to maintain an active career. The problem with steroids is their side-effect profile. All of them cause cataracts and a rise in intraocular pressure (IOP), though the latter does not necessarily lead to glaucoma and glaucoma surgery,†he
told EuroTimes.

The FDA approval of two sustained-release intravitreal corticosteroid implants, Ozurdex® (dexamethasone) and Illuvien® (fluocinolone acetonide), has opened new doors. Besides the potential pharmacologic advantages, this type of long-acting drug may address the issue of compliance that is often a barrier to effective therapy in this subgroup of patients.

“I also still see an important role for laser. Not necessarily the laser in its current form, but maybe sub-threshold laser. Articles published during the past 20 years suggest that this approach is less damaging while contributing to long-term control, and I think further studies will confirm this. As we gain a better understanding of the underlying mechanisms of Muller cell and retinal pigment epithelium (RPE) cell dysfunction in diabetes, we will begin to appreciate the role of non-destructive laser treatment,†predicted Dr de Smet.

Dr Schmidt-Erfurth is less optimistic regarding the future of laser treatment in DME. “We are in the midst of a paradigm shift. Laser will become a palliative and destructive modality of the past, and will in time be completely replaced by anti-VEGF injections,†she said.

Although this shift will take time to occur completely in clinical practice, she is confident that it will happen. In the age of anti-VEGF treatments, Dr Schmidt-Erfurth sees no benefit of macular laser, and indeed possibly even harm. She referred to microperimetry studies that demonstrate the damaging effect of macular laser, which can induce microscotomas which are undetectable by traditional measurements of visual acuity (VA), but which nevertheless decrease patients’ quality of vision.

“But even after patients are switched from anti-VEGF to laser treatment, some improvement is still possible.. The particular charm of anti-VEGF in DME consists in its reduced need over time,†she added.

Anti-VEGF and the promise
of aflibercept

So, for the ophthalmologist who has determined that a particular patient would be best treated with anti-VEGF injections, how does he or she decide which drug to use? What are the current views on the various anti-VEGF molecules for the treatment of DME? Since the DAVINCI, VISTA and VIVID studies established that treatment with aflibercept yields greater visual gains than macular laser treatment, various trials have focused on the molecule´s value in relation to the other VEGF inhibitors already on the market. This comparison is particularly relevant considering the price differences between the various molecules.

Several points stand out which are clinically very relevant. First, a recent trial has demonstrated that aflibercept is superior to ranibizumab or bevacizumab for eyes with DME and poorer presenting VA. Secondly, clinical investigations have indicated that eyes with DME unresponsive to multiple injections of either ranibizumab or bevacizumab can demonstrate both anatomical and visual improvement upon conversion to aflibercept. Theories for this difference are based on the pharmacodynamics of aflibercept, which binds VEGF with much greater affinity, and also binds placental growth factor.

But what about the cost of repeated anti-VEGF injections, particularly in countries in which only the ranibizumab and/or aflibercept are approved for DME, as opposed to the far less expensive bevacizumab? The approximate cost for a single intravitreous injection is €1,700 for aflibercept (at a dose of 2.0mg), $44 for bevacizumab (1.25mg dose), and $1,060 for ranibizumab (0.3mg).

“While aflibercept injections are significantly more costly than bevacizumab, potential improvements that can be anticipated offer a justification for conversion to the newer molecule. Further, you have to remember that DME is not AMD. The duration of the treatment regimen is not endless. Most patients need approximately four to five injections in the first year of treatment, two or three in the second year and only one or two in the third year. By the fourth year, most eyes are no longer receiving injections, so the investment in the superior molecules is worthwhile for this relatively short regimen,†Dr Schmidt-Erfurth pointed out.

Clearly, an absolute consensus has not yet been reached. While it is obvious that some patients respond less favourably than others to anti-VEGF treatment, it is at present impossible to predict treatment response in individual patients using conventional methods. “Currently, we only try something else when anti-VEGF treatment fails, but by then it’s often too late,†said Dr Bandello.

Surgical Options?

What about patients with epiretinal tissue and persistent DME, despite maximum medical and/or laser therapy? Is surgery an option?

Jan van Meurs MD, PhD, Department of Vitreoretinal Surgery in the Rotterdam Eye Hospital, The Netherlands, is not particularly enthusiastic about surgery for DME.

“There exists some wishful thinking regarding the role of vitrectomy for DME, but very few substantial studies to support these hypotheses. For example, it has been suggested that vitrectomy might improve posterior segment oxygenation, but it is more likely that the oxygen content of the infusion bottle was measured. There is substantial evidence from previous studies that vitrectomy for DME without traction does not improve visual outcomes. In patients with obvious epiretinal traction, it may be beneficial however, as suggested by the DRCRnet studies. What would be ideal is a trial in which patients with DME and obvious traction would be randomised to vitrectomy plus anti-VEGF treatment versus anti-VEGF only,†he said.

In The Pipeline

Looking ahead, several drugs are in the pipeline. Luminate® (Allegro Ophthalmics) is an integrin antagonist that blocks the integrin receptors on vascular endothelial cells that help mediate several angiogenic processes. Vasotide®, a peptidomimetic molecule, has been tested on three animal models in eye drop formulations. It has been shown to prevent VEGF from binding to both VEGF receptor-1 and neuropilin-1, both expressed by retinal vascular endothelial cells. Fovista® (Ophthotec), an anti-platelet-derived growth factor agent, has shown promise when added to an anti-VEGF regimen, as compared to anti-VEGF monotherapy.

It appears that we are on the cusp of a second wave of this second revolution. Angio-OCT might allow for more detailed analysis of the state of the retina, providing information on vascular patency without the burden of FA. At the same time, individualised treatment, based on pathogenetic and phenotypic differences between various types of DME, will produce results that we can currently only hope for and imagine.

Francesco Bandello:
bandello.francesco@hsr.it

Ursula Schmidt-Erfurth:
ursula.schmidt-erfurth@meduniwien.ac.at

Marc de Smet:
doctors@retina-uveitis.eu

Jan van Meurs:
J.vanmeurs@oogziekenhuis.nl