Diabetic Macular Edema – Considering Pathogenesis in Treatment Selection

Welcome to this special edition of the Ophthalmology Times® EyePod, recorded in conjunction with PER [Physicians’ Education Resource]. This podcast examines how key therapies for treating diabetic macular edema—anti-VEGF agents and corticosteroids—address the underlying pathophysiology of the condition to effectively and safely treat it. In this podcast, ophthalmologists J. Fernando Arevalo, MD, PhD, FACS, FASRS; Peter Kaiser, MD; and Nathan Steinle, MD, share their insights to help clinicians optimize care for their patients with this common diabetes-related eye disease.

Faculty:

• J. Fernando Arevalo, MD, PhD, FACS, FASRS
  The Johns Hopkins University School of Medicine
  Baltimore, Maryland
• Peter Kaiser, MD
  Cleveland Clinic
  Cleveland, Ohio
• Nathan Steinle, MD
  Sanford School of Medicine
  San Luis Obispo, California

Host:

To start us off, Dr. Arevalo how do you explain the treatment goals and expectations to a patient with DME?

Dr. Arevalo (00:36):

J. Fernando Arevalo, MD, PhD, FACS, FASRS

What I tell my patients with diabetic macular edema is this is a long-term treatment. I want to set the expectations from the start very clear at the beginning. The treatment is going to be very intensive with anti-VEGF therapy. Probably the patient will need, if they respond well, about nine to 10 injections the first year, but then the injections will be reduced to maybe five or six the second year, maybe four or three injections the third year, a couple of injections in year four, and in year five they may not need any more injections. So even though this is a long-term treatment and very intensive at the beginning, I tell my patients that there is a light at the end of the tunnel.

I tell them also that my goal is to improve vision and decrease central macular thickness. I follow the DRCR Net guidelines and I'd like to see at least five letters of visual acute improvement and 20% of reduction of central fill of thickness in the central macular. And if I get that, then I call that a responder. If I don't get it, then it may be a non-responder that may need something else to treat this diabetic macular edema.

Host (02:06):

Thank you, Dr. Arevalo. Dr. Kaiser, we know that anti-VEGF agents and corticosteroids are standard therapies used to manage DME. How established and robust are the data supporting use of anti-VEGF therapies for treating DME and what are the treatment limitations?

Dr. Kaiser (02:27):

Peter Kaiser, MD

So the gold standard treatment for diabetic macular edema has been established in multiple pivotal phase three clinical studies with anti-VEGF agents. And in these studies they went up against the previous gold standard which was focal laser treatment. And in those studies, the use of anti-VEGF injections improved visual acuity more so than what we saw with laser treatment. So because of that, we use anti-VEGF as the gold

standard. Now, not all patients will respond to anti-VEGF injections. There are patients who we call non-responders. And in these patients, despite anti-VEGF agents, we may consider other agents. In addition, even between the different anti-VEGF agents, we actually have clinical studies from the DRCR, for instance, that have compared the outcomes amongst the three major anti-VEGF injections, that were at the time of that study, bevacizumab, aflibercept, and ranibizumab.

And based on the baseline characteristics of the patient's macular edema, their visual acuity and their retinal thickness, one may consider one anti-VEGF agent over another. So there are many factors that come into play, but if we look at the data supporting the use of anti-VEGF in DME, there's excellent level one evidence to support its use.

Host (04:03):

Dr. Arevalo, what do you consider for a patient with DME who does not respond as expected to anti-VEGF therapy?

Dr. Arevalo (04:11):

When I get a patient that is a non-responder with anti-VEGF therapy, then I turn to corticosteroids. What I turn to is intravitreal dexamethasone. That's my preferred corticosteroid selection. It's something that I start after three or six injections depending on the response to anti-VEGF, and then keep the patient on injections every three to four months for several injections. Patients may respond well to that or may need supplementary injections with anti-VEGF. We have to remember that diabetic macular edema is multifactorial. It may be VEGF driven, those are the ones that will respond to anti-VEGF very well, but it may be inflammatory driven and those will respond to corticosteroids better. But it may also be combined both VEGF driven and inflammatory cytokines driven macular edema and those will need probably a combination therapy.

Host (05:25):

Thank you. Dr. Arevalo. Dr. Steinle, how effective are intravitreal steroids for DME and what kind of visual acuity outcomes have been observed in those clinical trials?

Dr. Steinle (05:38):

Nathan Steinle, MD

The answers are incredibly effective. I think that we all wish we'd probably reach for them more quickly than we do. I think most of us here in the United States, we reach for anti-VEGF agents first for diabetic macular edema, and after one or two or three injections if we're just not getting the response we want or the duration of response we want, we then will reach for a corticosteroid. And almost to a person, I'm always

really impressed by how well these corticosteroids work. They work best in patients that are already pseudophakic, but they also work well in patients that are phakic. And what we really see in those patients who have diffused edema across the entire macula, sometimes we call it almost an inflammatory DME or inflammatory diabetic macular edema picture, where they really have a lot of vascular leakage and diffuse spongy edema across the entire macula, it's about the only thing that can work in these patients are these long-term steroid injections for patients.

Host (06:34):

Thank you, Dr. Steinle. Some experts feel that often clinicians wait too long to switch to corticosteroids. What do you think are the reasons for this?

Dr. Steinle (06:45):

Even in my own clinics, I fault myself for this. Why am I not reaching for my corticosteroids more quickly in the treatment of my diabetic macular edema patients, especially those who aren't responding well or suboptimally to their anti-VEGF injections? And the answer really comes down to the fact that, first off I think most of us think the anti-VEGF is pretty darn safe. And so then when you reach over for corticosteroids, there's the two main side effects that are well-documented. Number one is cataract formation and cataract progression, and then number two is a small percentage of patients can get intraocular pressure rises. And both those are controllable factors, so if a person does get a cataract then of course cataract surgery is a pretty common procedure now in America. And then as far as the pressure rises, it's pretty rare that you'll get to the point where you'll need some type of incisional surgery for these patients.

Sometimes you will have to start a short-term drop or even a long-term drop on these patients or consider SLT laser in these patients with IOP rises with corticosteroids, but it's pretty rare that you'll have to move on to actually incisional glaucoma procedures for these patients. But the answer for why we are sometimes not reaching more quickly to corticosteroids comes a little bit down to the side effect profile of corticosteroids and also just comes down to our own kind of busy clinics. My busy clinic, it's sometimes easier to do what I did last time than to think about a new treatment algorithm and perhaps get a benefits investigation and move the patient to a different treatment. But I'm really kind of doing my patients a disservice and I try and obviously give every patient the best possible service.

And so I know from protocol I, from the DRCR Net, that after three injections of anti-VEGF if patients weren't responding well or were suboptimal responders, no matter how many injections you gave them of anti-VEGF, they really kind of stayed in their swim lane. And so those patients who are early non-responders or suboptimal responders on anti-VEGF, I've been really trying to be more conscientious about moving to corticosteroids especially after three anti-VEGF injections if I'm not seeing the response I want.

Host (08:49):

Thank you. Dr. Kaiser, how should the differential effects of various corticosteroids be factored into selection of therapy for DME?

Dr. Kaiser (09:00):

So when you talk about corticosteroids, especially when we're using it for the treatment of diabetic macular edema, it's important to understand that all steroids are definitely not created equal. Some are very potent very quickly but they don't last very long. Others have a lower potency but because they're insoluble will last for a very long time. And the goal of our treatment then is to balance these effects for the patient that we have in front of us. Now, if you were to inject a patient with dexamethasone, which you certainly could do, that's not going to last a very long time but it's going to be a very powerful steroid effect. And because of that, dexamethasone has been put into sustained release implants to allow us to get that effect over a long period of time.

Contrast that with the injection of triamcinolone acetonide, now that's a very insoluble steroid. It's going to last a very long time but the potency of triamcinolone compared to dexamethasone is not the same. So when you say you're going to use a steroid for diabetic macular edema, you really need to understand what's your goal with that treatment both in the short term and the long term, because steroids are not created equal

Host (10:16):

With several intravitreal corticosteroids available, what are your tips to clinicians for how to select among them?

Dr. Arevalo (10:25):

I would like to start when anti-VEGF does not work with the dexamethasone implant because it's more potent and the duration is shorter so I can see a good response. But if there is any complications that we know that can occur with steroids it would be also short term. Steroids can be associated with increasing intraocular pressure and affected patients they may develop a cataract. So a short term steroid will be associated with less complications and I can assess if the patient will respond to that corticosteroid. Usually, depending on the patient, we may use several injections. Some patients are different and may tolerate more injections even every three to four months, but some others want something more longer acting than the dexamethasone implant and then I would turn to the fluocinolone implant. And the fluocinolone implant can potentially last up to three years. And that can be used in patients that need multiple dexamethasone implant injections and have no intraocular pressure issues.

Host (11:51):

Dr. Steinle, what safety and tolerability concerns should clinicians be aware of for anti-VEGF agents and corticosteroids?

Dr. Steinle (12:01):

First, we'll talk about the safety profile of anti-VEGF agents, and this really came about in 2004 and 2005 when we started using broad stream these VEGF-A inhibitors, and we've been doing that now for almost 20 years in ophthalmology and so we have a pretty good feel for how these agents work. The real side effect profile of these are mostly related to the injection itself. A small risk of endophthalmitis in the order of one and two or 3000 injections gets endophthalmitis. We worry about a PVD creation or a posterior vitreal detachment creation in these patients, especially in younger diabetic patients who have formed vitreous and just that current of fluid at the injection can create a PVD so you watch for retinal tears and perhaps even retinal detachments. Those are rare. We watch for cataract formation, if you're not careful with your needle technique and making sure you're really aiming posteriorly.

And then finally, there's this theoretical risk of these arterial thrombolic events or ATEs and that's been in the literature for a long time, that these are at risk patients that are diabetic patients who already have baseline vasculopathy. And so you always want to talk to them about it, if they've had a recent stroke or heart attack and maybe not reaching for an anti-VEGF for a little while but perhaps switching over to a corticosteroid, at least in the short term if not in the long term, because there's not that risk of the arterial thrombolic events.

And then next I'll talk about the safety profile of corticosteroids. And corticosteroids we've also been using for about 20 years now very regularly in ophthalmology, starting with triamcinolone, then moving over to dexamethasone and then moving over to fluocinolone, and so we have a very good feel for how these agents work in the eye. And the main profile that we worry about here from a side effects profile is just cataract and also IOP elevations. And in general I think about a third of the population can be steroid responders. But I think it's important to note that just because you have a steroid responder does not mean you have glaucoma changes. And so you can have the increased intraocular pressure but have a normal nerve and have no visual functional loss.

And so yes, I don't love to have my patients have high pressure, but I always have to remind myself that I'm really following them for changes to the optic nerve and actual visual function loss rather than just high IOP. And as far as the cataract progression goes, I don't love it in patients that are under the age of 45 or so because those patients of course can still accommodate, but after the age of 45 if a person has a cataract or at risk for cataract progression, I'm less concerned for that because I have wonderful cataract colleagues here and anterior segment colleagues that can certainly help patients out. And sometimes it's almost a benefit to them because we can now have such great pseudophakic treatment algorithms that we can offer patients as far as different types of multifocal lenses and a different type of postoperative monovision or toric vision afterwards to try and minimize any refractive error.

So we really have gotten really great with the refractive options for our patients, even if they might be, say, 55 or so years old. And then finally, we mentioned for any type of intravitreal injection, we worry about that small risk of endophthalmitis with steroids as well. And then finally, PVD creation, just because you're putting some type of object in the eye and that of course could elicit a release in the posterior highlight so you have to watch for any types of horseshoe tears or any types of peripheral detachments.