DIABETIC MACULAR EDEMA

A Multifaceted Approach to Treating DME

Ozurdex is the go-to choice for targeting the inflammatory pathway

BY DESIREE IFFT, CONTRIBUTING EDITOR

Image courtesy of Seenu Hariprasad, MD

The person who modified the Hippocratic Oath to include the idea that practicing medicine is art as well as science easily could have had diabetic macular edema (DME) in mind. Diabetic eye disease is complex and multifactorial. It involves many mediators, including vascular endothelial growth factor (VEGF)¹ and inflammatory cytokines.^2,3 Although effective treatments are available, when and how to use them for each individual patient is not well defined. “It’s very rare that an eye would have DME driven by just one mechanism,” says Tarek S. Hassan, MD, professor of ophthalmology at Oakland University William Beaumont School of Medicine and senior partner with Associated Retinal Consultants in Royal Oak, Mich. “It’s up to the doctor to determine what is the most significant mechanism driving the disease.”

INITIATE TREATMENT AND MONITOR RESULTS

Given their track record of success in DME, it’s appropriate to use an anti-VEGF agent as first-line therapy, Dr. Hassan continues. “Start with what you think is the most effective agent for that patient and be sure to follow up in a timely manner (in 4 weeks at most) to determine whether there is a good response. If you don’t see one early enough, consider what other mechanisms are at play. Inflammation may be a factor, so you may want to add a steroid. There may be a tractional aspect, which a vitrectomy could relieve. If ischemia is present, laser may be helpful.”

If overproduction of VEGF is a factor in a patient’s DME, Dr. Hassan expects to see at least some response within a few weeks of one injection. If that is achieved, he expects two or three more injections to lead to a more significant reduction of the edema. If not, he says, it’s not unreasonable to try a different anti-VEGF agent. However, he emphasizes, “First you would have had to demonstrate at least some response to one anti-VEGF agent. You’ll never see a patient who has no response to one agent have a huge response to another. Based on the Protocol T results,⁴ I start with aflibercept (Eylea, Regeneron) most often, and, if the response is unsatisfactory, I may consider trying another anti-VEGF agent, even though I think it’s unlikely that switching will improve the edema very much.”

Rahul Khurana, MD, who practices with Northern California Retina Vitreous Associates and is a clinical associate professor of ophthalmology at the University of California, San Francisco, has a similar view of switching from one anti-VEGF agent to another. He says, “Although Protocol T showed differences among the three available agents, notably that Eylea and ranibizumab (Lucentis, Genentech) have greater effects on retinal thickness than bevacizumab (Avastin, Genentech), I personally haven’t seen a dramatic difference when switching between the agents.”

MOVING ON FROM FIRST-LINE THERAPY

Dr. Khurana gives a minimum of six anti-VEGF injections before considering a change in treatment regimen. “Three injections, in my mind, is too early to assess improvement in macular edema based on OCT and stabilization (and hopefully improvement) in visual acuity,” he explains. “A loading dose of three injections was incorporated from our collective experience using anti-VEGF therapy in neovascular age-related macular degeneration; however, the burden of injections is much higher in DME, especially in the first year. My loading dose is six injections, based on DRCR Protocol T, which started with four injections up front and then usually two more. And the VIVID⁵ and VISTA⁵ studies of Eylea started with five injections up front. After seeing the effectiveness of all three anti-VEGF agents in Protocol T, and knowing that even patients with persistent macular edema did well over 3 years in the Protocol I study,⁶ I’m more confident in — and patient with — anti-VEGF therapy.”

Dr. Hassan prefers to consider a treatment change after three anti-VEGF injections if he isn’t satisfied with the improvement in vision or the reduction in edema. “If you get a suboptimal response, you’re demonstrating that more than the VEGF mechanism is at play. So, the next logical step is to treat the inflammatory pathway,” he says. “Steroids are excellent in this situation, used more often in combination with anti-VEGF agents rather than in place of them.”

Data from EARLY,⁷ a post-hoc analysis of Protocol I that was supported by Allergan and presented during the 2015 meeting of the American Academy of Ophthalmology, may help retina specialists as they decide which treatment is best for each DME patient. The results suggest that a poor visual acuity response to Lucentis after three injections may predict outcomes at 3 years. “The concern is that patients who do not respond well early may leave vision on the table with continued anti-VEGF therapy,” Dr. Khurana says. “I look forward to learning more about EARLY once it is published.”

SUSTAINED-RELEASE STEROID IMPLANTS

Once Drs. Hassan and Khurana decide to augment or replace anti-VEGF therapy with a steroid, they choose the sustained-release dexamethasone 0.7 mg implant (Ozurdex, Allergan) most frequently. “The ability to use Ozurdex makes it much more palatable for me to use steroids as part of the treatment regimen,” Dr. Hassan says. “We’ve learned a great deal about steroids as time has gone on, and the pharmacodynamics of Ozurdex are more favorable than those of triamcinolone. To me, that translates into us seeing less IOP elevation with more consistent release of the steroid. The success we’ve had with Ozurdex highlights that there are two distinct, yet somewhat connected, pathways in DME, and we can target both by using anti-VEGF agents and steroids. I’m definitely more of an ‘and’ guy than an ‘or’ guy, and if DME is severe, particularly if it’s cystic-appearing, I’m more likely to use Ozurdex earlier in the course of treatment.” Dr. Khurana favors Ozurdex over other steroid options as well, noting that he’s more comfortable with its IOP elevation profile compared with that of triamcinolone. He also points out that in the MEAD trial⁸ of Ozurdex, 22% of patients experienced a ≥15 letter improvement in vision from baseline at 3 years. “Although the vision gains were not as robust as in the anti-VEGF clinical trials, the outcomes were good, and patients needed only four treatments over a 3-year period,” he says.

In addition to using Ozurdex in DME cases where an anti-VEGF agent doesn’t produce the desired outcome, Dr. Khurana uses the implant for patients who don’t want a heavy injection burden in the first year of treatment; in cases he’d rather avoid an anti-VEGF agent due to concern about a potential thromboembolic event; and for pregnant women, so as not to expose the fetus to the anti-VEGF medication. He also finds Ozurdex useful for diabetic patients who develop pseudophakic cystoid macular edema (PCME) after cataract surgery. Dr. Khurana and colleagues⁹ reported favorable results from a prospective, interventional case series in which Ozurdex was used to treat patients with diabetes who developed PCME following uncomplicated cataract surgery despite ongoing prophylactic treatment with topical anti-inflammatory agents.

The use of Ozurdex in vitrectomized eyes involves more than one consideration. Dr. Hassan says he often uses the implant in vitrectomized eyes because of its longer duration of action compared with an intravitreal injection in this scenario.¹⁰ Dr. Khurana, on the other hand, uses triamcinolone in vitrectomized eyes if he has any concern about the Ozurdex implant migrating to the anterior chamber and causing permanent corneal edema.¹¹

Another sustained-release steroid implant, fluocinolone acetonide 0.19 mg (Iluvien, Alimera Sciences), is also available for the treatment of DME. Iluvien is designed to deliver 36 months of continuous, low-dose corticosteroid with a single injection. Dr. Khurana says this implant can be a sensible choice for pseudophakic patients who require regular steroid therapy and would benefit from a longer-lasting agent. He says he would also use it for patients with chronic DME (≥3 years), pointing out that in a subgroup analysis from the FAME trial, 34% of patients who reported DME duration of ≥3 years at baseline gained ≥15 letters of vision at 3 years.¹² In the study overall, 28.7% of patients experienced a ≥15-letter improvement in vision from baseline to 3 years.

HOW FUTURE TREATMENT PARADIGMS MAY EVOLVE

In considering what additional information would be helpful as he manages his DME patients, Dr. Khurana says, “I would like to see a clinical study that randomizes patients who have responded poorly to anti-VEGF monotherapy to either continued anti-VEGF treatment or steroid to ultimately determine the optimal management in these challenging cases.” Dr. Hassan thinks help may come from another direction as well: “In the future, we’ll have more sophisticated ways to measure cytokines and determine which chemicals are most at play in each specific case of DME. In the meantime, the doctor has to determine which mechanisms are driving the disease by utilizing all of the available treatment options when necessary.” NRP

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