Changing Treatment Paradigms in Diabetic Macular Edema

New therapies expand therapeutic options for DME patients.

BY VIRGINIA PICKLES, CONTRIBUTING EDITOR

By all accounts, 2014 was a watershed year in the retina community and clinicians are still adapting. Three drugs, two of them sustained-release corticosteroids, became available for treating diabetic macular edema (DME), creating opportunities for individualized therapy and the potential for lessening the treatment burden for patients. “It was like a bounty, a windfall!” says Seenu M. Hariprasad, MD, Shui-Chin Lee Professor of Ophthalmology and Visual Science at the University of Chicago. “All of a sudden, we went from having just one FDA-approved product, ranibizumab (Lucentis, Genentech), to four FDA-approved products.”

On the heels of these approvals came word from FDA in early 2015 that it was expanding the approved use of Lucentis and aflibercept (Eylea, Regeneron) to include treatment of diabetic retinopathy in patients with DME. And seemingly just in the nick of time, in Q1 2015, the much-anticipated 1-year Protocol T results from the Diabetic Retinopathy Clinical Research Network were published, providing guidance for the use of Eylea, bevacizumab (Avastin, Genentech) and Lucentis for DME.¹

“More than any single study outside of the large phase 3 clinical trials for Lucentis, Protocol T has shaped how physicians think about anti-VEGF therapy in DME,“ says John W. Kitchens, MD, Lexington, Ky. “Now, for the first time ever, we can actually compare the three most commonly used anti-VEGF medications against one another in this context. Protocol T opened everyone’s eyes to just how effective these therapies are.”

In light of the expanded treatment options and newly released study data, we asked Dr. Hariprasad and Dr. Kitchens, as well as Howard F. Fine, MD, MHSc, NJ Retina, and Allen C. Ho, MD, Mid Atlantic Retina, to discuss their current approaches to DME treatment: where they start, when they switch or add therapies and the thought processes that drive their decisions.

INITIAL THERAPY: ANTI-VEGF

Thanks to ongoing research into the pathophysiology of diabetic eye disease, multiple potential therapeutic targets have been identified, with VEGF the primary one at this time. “Anti-VEGF injectables are the mainstay in first-line therapy for DME, because they’re safe and they’re the most efficacious monotherapy,” Dr. Ho says. “They’ve been clearly shown to be superior to other standards of treatment in the past, including focal laser, and they’re a welcome addition because many patients often improve significantly, gaining 2 or 3 lines of visual acuity.”¹

Dr. Kitchens concurs: “Without a doubt, an anti-VEGF agent will continue to be my first-line treatment in almost all cases of DME that don’t have a surgical indication, such as vitreous traction, or areas of focal edema outside the fovea, where focal laser treatment would be indicated.”

Dr. Ho notes the anti-VEGF agents are safe in eye and also systemically. “Patients with diabetes are theoretically at risk for microvascular disease, and, to date, we haven’t seen any real outliers in terms of increased incidence of thrombotic events,” he says. “I do believe, however, that injecting even small amounts of these medicines can have a systemic impact, based on pharmacokinetic studies that have been published recently,² as well as my own observations of a bilateral effect on the DME after injecting one eye with the drug, suggesting some systemic exposure. I think we still need to be careful in this group of patients, but to date, we haven’t seen any increase in systemic safety signals.”

Although the choice of initial anti-VEGF agent may be influenced by third-party payers, Dr. Kitchens does have a preference. “If all treatment options are completely open to me and I have no restrictions based on insurance, I use Eylea as first-line therapy,” he says. “Protocol T showed us that Eylea works best in eyes with the worst visual acuity; therefore, I want to use it, even in patients with good vision, to give them the best chance to have the driest maculas and the best possible outcomes.”

Another advantage of Eylea is the potential for extended dosing intervals as demonstrated in the VIVID and VISTA trials.³ “Of all the diseases we deal with in retina, the need for more durable and effective treatment is greatest in diabetic macular edema,” Dr. Hariprasad says. “When Lucentis was our only option, I embraced it because it helped patients see better, but not one of my patients could comply with the monthly injections that RISE and RIDE mandated.⁴ And if a patient had bilateral disease — 60% of patients do^4,5 — then all bets were off. Being able to reduce the number of injections required over a 2-year period from 24 to 12 or 13 with Eylea is extremely beneficial to patients, many of whom struggle to get to our offices because they’re already burdened with so many other doctor visits for their diabetes. Having more durable treatments is a godsend for them.”

ADJUNCTIVE THERAPY: CORTICOSTEROID

A frequently discussed topic among clinicians treating DME is when to declare an eye nonresponsive to initial treatment and consider switching or adding a therapy. “I think it’s fairly well accepted that DME is a multifactorial disease, involving VEGF and inflammatory processes,” Dr. Hariprasad says. “Unfortunately, at this time, we have no way of knowing in any given eye which process is in play. So we try one agent and if that doesn’t work, we switch to another agent, and if that doesn’t work, we may try a combination of the two. The latest rationale is to use a multi-pronged treatment approach with anti-VEGF and corticosteroids, either concurrently or sequentially.”

Delaying treatment with a corticosteroid is a missed opportunity, Dr. Kitchens says. “Since learning the Protocol T results, I typically administer three monthly Eylea injections, and if the response is adequate, I continue with Eylea until the edema has resolved,” he says. “If I observe less than a 50% improvement in edema after the first three injections, I consider switching to an intravitreal steroid, rather than trying a different anti-VEGF agent, which I may have considered in the past. In my opinion, significant edema that persists despite multiple anti-VEGF injections may be more inflammatory in nature, and by not switching to a steroid earlier, we potentially miss an opportunity to resolve the edema sooner.”

Dr. Ho holds the same opinion. “It’s my belief that we often don’t go to the other approved pharmacologic injectables for DME soon enough,” he says. “Specifically, I’m referring to the dexamethasone intravitreal implant (Ozurdex, Allergan), which releases drug for about 3 to 4 months, and the longer-acting (up to 3 years) fluocinolone intravitreal implant (Iluvien, Alimera Sciences), as well as off-label triamcinolone. Many of us stay with the anti-VEGF agents too long, looking for a response, and not all patients will have a response. I’m guilty of it myself, but I’m starting to understand some of the new literature and some of my own clinical experience.”

With regard to safety, Dr. Ho notes that corticosteroids, as a group, don’t meet the standards of the anti-VEGF agents for ocular safety. “All of the corticosteroids will cause cataracts with repetitive exposure,” he says, “and a small percentage of patients will develop steroid-induced ocular hypertension or glaucoma, so patients must be monitored for these complications. However, I believe these steroids pose little risk to vasculopathic diabetic patients, because steroids aren’t likely to cause systemic problems and the theoretical risk that anti-VEGFs do.”

Dr. Hariprasad recommends addressing a suboptimal response to anti-VEGF therapy within the first 4 to 6 months, or earlier if no improvement is seen, either switching to a different class or, his preference, adding a different agent. “Using combination therapy, we may increase efficacy and durability, which lessens the treatment burden for patients, while decreasing costs and improving the overall safety profile,” he says. “For example, instead of administering 12 Lucentis injections in a year, per the RISE and RIDE protocol,⁴ we may be able to achieve the same efficacy with six Lucentis injections and one Ozurdex implant during that time.”

When Dr. Kitchens sees an inadequate response to initial therapy, he chooses Ozurdex as his second-line treatment. “I always switch to Ozurdex first, because Iluvien is indicated for patients who were previously treated with corticosteroids and did not have a clinically significant rise in intraocular pressure,” he says.

FIGURE 1. Diabetic retinopathy as seen with fluorescein angiography (California ultra-widefield imaging by Optos).
Image courtesy of Paulo Stanga, MD

According to Dr. Hariprasad, not only does Ozurdex have the advantage of being less costly than the Iluvien (approximately $1,200 for Ozurdex versus $8,800 for Iluvien), but per the MEAD study, only 4 to 5 injections of Ozurdex are required in 3 years.6 “We’re learning that using Ozurdex either as monotherapy or in combination with Eylea is a very powerful treatment, in terms of managing patients with DME, particularly those who are suboptimal responders to anti-VEGF monotherapy,” Dr. Hariprasad says.

Another consideration in favor of Ozurdex as a first-choice corticosteroid is its relatively short-term effect on IOP, Dr. Kitchens says. “If a patient is a steroid responder, the resulting IOP rise need only be treated for 3 or 4 months and then it often returns to normal.”

Once a patient’s status as a steroid nonresponder is confirmed, he may receive the Iluvien implant. “I believe a number of patients who are recalcitrant to some of our therapies actually have a mixed mechanism to their DME, where it’s both VEGF-mediated and inflammatory,” Dr. Kitchens says. “Iluvien will address the inflammatory-mediated mechanism for 2 to 3 years. If the edema recurs during that time, I can add an anti-VEGF agent, and treat the patient with it in either a PRN or treat-and-extend style to determine the appropriate treatment interval, in an attempt to obtain and maintain the driest possible macula.”

ADJUNCTIVE THERAPY: LASER

Once the only treatment option for diabetic macular edema, laser photocoagulation remains an important consideration in the treatment algorithm, according to Dr. Fine. Which diabetic patients are candidates for laser in the anti-VEGF era? “I believe panretinal photocoagulation (PRP) laser remains the gold standard for treating proliferative diabetic retinopathy (PDR), particularly because it lasts a lifetime,” Dr. Fine says. “The most noncompliant patients in my practice are diabetic patients with PDR, so anti-VEGF therapy without PRP is a recipe for disaster if they don’t return. I will turn to anti-VEGF therapy in PDR for stubborn cases of persistent neovascularization despite thorough PRP laser.

“For patients with focal leakage, typically microaneurysms with circinate lipid, focal laser can still be very effective and should not be overlooked, and it can reduce the treatment burden in these often young, working-age individuals,” Dr. Fine continues. “Micropulse laser can be applied in these cases, and it also can be used to treat more diffuse edema. I often use a combination approach with anti-VEGF ± micropulse laser ± steroid in suboptimal responders and in patients with poor prognoses.”

With the advent of micropulse laser, Dr. Fine says he is using laser therapy in diabetic patients more often than he had been 1 or 2 years ago. “My experience with micropulse laser is that it can provide efficacy similar to traditional focal/grid laser, but with a better safety profile,” he says. “In a sense, it’s gentler on the macula. Some small studies support this notion.”

Vujosevic and colleagues⁷ found micropulse laser as effective as traditional macular laser but with superior retinal sensitivity as measured by microperimetry. Lavinsky and colleagues⁸ showed superior outcomes in DME with micropulse compared with traditional macular laser.

“I think the potential for micropulse laser in DME is not only to displace traditional ETDRS laser therapy but also to expand the number of DME eyes we treat with laser because of an improved safety profile,” Dr. Fine says. “In this anti-VEGF era, we deal with numerous patients who are incomplete responders as well as those who present with severe disease that may respond best to combination therapy.”

SURGICAL INTERVENTION

“For me, and I think for a large percentage of vitreoretinal surgeons, the surgical management of DME has decreased dramatically in the last 5 or 6 years,” Dr. Kitchens says. “We are much more effective at treating DME with anti-VEGF therapy, so we don’t have to resort to surgery in as many cases. Surgical treatment for DME is usually reserved for mechanical causes of the edema.”

Dr. Kitchens believes surgery for diabetic retinopathy is decreasing, although not quite at the same rate as for DME. “With anti-VEGF therapy, we’re regressing more retinopathy and preventing it from becoming proliferative disease,” he says.

Advances in imaging have also contributed to the reduced need for surgery, Dr. Kitchens says. “With ultra-widefield angiography, I find we’re catching more areas of nonperfusion and neovascularization earlier, enabling us to treat them with the laser and avoid emergent situations requiring surgery.”

There are still some indications for surgery, Dr. Kitchens notes, such as vitreomacular traction or traction retinal detachment causing macular edema. “In those cases, certainly, we want to try to alleviate anatomical causes of the swelling,” he says. “Surgical options include vitrectomy with detachment of the posterior hyaloid, if traction is present, and peeling of any associated epiretinal membranes, with or without internal limiting membrane removal.”

LOOKING AHEAD

Anti-VEGF therapy has set a high bar in retina, Dr. Kitchens says, which may be the reason why some investigational drugs for age-related macular degeneration seem to be faltering in phase 2 and phase 3 trials. “In the distant future, we may see combinations of anti-VEGF agents with different inhibitors of other factors, possibly delivered via subcutaneous injection versus an eye injection,” he says. “Currently, Genentech is working on an extended-release device for Lucentis, which could be a real game-changer if it shows the efficacy that we hope for.”

In the meantime, retina specialists are looking forward to further guidance from studies, particularly those conducted by the DRCR Network. “We anxiously await 2-year data for Protocol T,” Dr. Hariprasad says. “This is so critical, because we want to see if the spread in efficacy, safety and durability that sets Eylea apart widens or narrows compared with the other two anti-VEGF agents.”

Also expected in the next year are data from the DRCR Protocol V and Protocol S studies. “Basically, the objective of Protocol V, known as the ‘good vision’ study, is to determine if patients who have 20/32 or better visual acuity should be treated with laser or anti-VEGF therapy or observed,” Dr. Kitchens says. “It’s tough right now for me to convince a patient whose OCT shows edema to undergo injections in his eye when he is asymptomatic and has 20/20 visual acuity. Hopefully this study will provide some guidance.”

In Protocol S, the focus is on proliferative diabetic retinopathy. Researchers are comparing the effects of anti-VEGF therapy plus deferred PRP with standard prompt PRP.

“Although we know the benefits of regression of retinopathy from the phase 3 trials, it will be beneficial to learn the results of the DRCR’s study on the effect of anti-VEGF therapy on retinopathy and to gain some clinical pearls on how to dose, what to watch for and so on,” Dr. Kitchens says.

RAPID EVOLUTION

“Our field is evolving rapidly,” Dr. Hariprasad says. “Having so many treatment options of different durability, costs and side-effect profiles is beneficial for patients, clinicians, caregivers and payers, and it allows us to practice the art of retina to individualize therapy for each patient.”

Dr. Kitchens concludes: “This is the golden age of retina, and we are in a unique and wonderful position to make a profound difference in our patients’ lives.” ❖

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