Breakthroughs in Treating DME
Retina specialists update endocrinologists on the latest therapies.
Dr. Boyer: Let’s bring the endocrinologists on our panel up to date with advances in treating diabetic eye disease. When I started practicing, laser was the treatment of choice, the gold standard, for diabetic macular edema (DME). The Early Treatment of Diabetic Retinopathy Study (ETDRS) demonstrated that focal or grid laser photocoagulation reduced the risk of moderate vision loss in patients with clinically significant macular edema by about 50%, but visual acuity improvement was observed in less than 3% of cases.1 Today, we can achieve visual acuity gains in 30% to 40% of cases with the use of the vascular endothelial growth factor (VEGF) inhibitor ranibizumab (Lucentis; Genentech), as demonstrated in two pivotal, randomized Phase 3 clinical trials.2
Dr. Gonzalez, you were one of the first retina specialists to use an anti-VEGF agent, pegaptanib (Macugen; Eyetech, Inc.), which is not approved for the treatment of DME. Please provide some background for Dr. Handelsman and Dr. Peters.
Dr. Gonzalez: One of the most important breakthroughs in retina was the identification and cloning of VEGF-A by Dr. Ferrara and colleagues in 1989.3 They found that VEGF protein plays a critical role in physiological and pathological angiogenesis and contributes to conditions that can stimulate neovascularization. At the Joslin Diabetes Center in Boston, Aiello and colleagues took vitrectomy samples from patients with diabetes and demonstrated that VEGF increases in diabetic retinopathy; the more severe the retinopathy, the higher the levels of VEGF.4
The first VEGF antagonist to be developed was pegaptanib, an aptamer that binds specifically to VEGF165. It’s indicated for the treatment of neovascular age-related macular degeneration (AMD). Ranibizumab, a humanized monoclonal antibody fragment designed for intraocular use, is indicated for treating neovascular AMD, macular edema following branch retinal vein occlusion, central retinal vein occlusion and, most recently, DME.
Early on, we were able to demonstrate in clinical trials the ability to control diabetic retinopathy and reduce the need for laser treatment with pegaptanib specifically.5 Later, our group did some work using pegaptanib to treat proliferative diabetic retinopathy. The trial demonstrated an obvious benefit in terms of disease regression6 and laid the groundwork for larger studies.
A more recent study was performed by the Diabetic Retinopathy Clinical Research Network (DRCRnet), which is funded by the National Eye Institute of the National Institutes of Health. In that trial, we randomly assigned patients with center-involving DME to the drug ranibizumab and immediate or delayed (6 months) laser.7 Patients in the two groups who received ranibizumab had significant improvements in visual stability, visual acuity (3-line gains) and quality of vision versus those treated with laser only. Particularly noteworthy was the fact that the outcomes were the same in both laser groups, indicating the benefit was derived from the drug.
Dr. Schwartz: I want to emphasize that the evidence Dr. Gonzalez has been discussing includes the highest level, randomized, pivotal, phase 3 clinical trial results, which have been replicated over and over again by the National Institutes of Health, by industry, by academic centers and by busy academic-type practitioners such as David Boyer. There’s no question that VEGF is the culprit protein. Other mechanisms are in play, but when you block the activity of this protein, the retinopathy resolves.
Dr. Boyer: With these new anti-VEGF therapies, we now we have a nondestructive means of treatment, enabling us to treat earlier and achieve better visual results.
Dr. Handelsman: What anti-VEGF agents are currently available to treat DME?
Dr. Schwartz: On-label for the treatment of DME, ranibizumab, the antibody fragment, is most commonly used. It binds the target and is extraordinarily powerful. Another drug, aflibercept (Eylea; Regeneron Pharmaceuticals Inc.) is in trials for DME. In addition, some retina specialists use off-label bevacizumab (Avastin; Genentech), a full-length anti-VEGF antibody approved for treating patients with some metastatic cancers.
Dr. Handelsman: Why would you use an off-label drug?
Dr. Schwartz: That decision has to do with the cost of the drug. A dose of bevacizumab costs about $50, while a dose of ranibizumab costs $1,700 to $2,000. It is important to note, however, that the manufacturer has various access programs to help with the cost of ranibizumab. In my experience, ranibizumab is not only safer, but also far more effective. (For more of the panel’s discussion on the safety of anti-VEGF therapies, see “Common Side Effects of Anti-VEGF Agents.”)
Dr. Peters: Let’s talk about vision gains in terms my patients can understand. When a person has macular edema, what does he see on the eye chart?
Dr. Schwartz: Let’s say his visual acuity is 20/50. That means at 20 feet, he sees what a person with normal vision can see at 50 feet. In real-world terms, it means he has issues accurately dosing insulin or identifying medications, he can’t read comfortably and he can’t drive legally. After anti-VEGF therapy, he should be able to recognize faces, read his insulin syringe and drive. Visual quality of life can be dramatically improved, particularly with early detection and treatment.
Dr. Peters: You’re talking about the difference between functioning and not functioning in life.
Dr. Gonzalez: Yes, but that type of outcome depends on when we first see those patients which is why it’s so important for us to see patients early. If at their first visit, they can see only the big E, a 3-line improvement won’t have the same impact it would have if we’d seen them before their vision deteriorated.
|Common Side Effects of Anti-VEGF Agents|
Dr. Peters: Are there safety concerns for people with diabetes who are treated with an anti-VEGF agent?
Dr. Schwartz: In clinical trials of ranibizumab in diabetic macular edema, the most common ocular side effects included conjunctival hemorrhage, cataract, increased intraocular pressure and vitreous detachment. The most common nonocular side effects included nasopharyngitis, anemia and nausea. A small percentage of people with diabetes have an increased incidence of stroke or heart attack, which is associated with some of the anti-VEGF agent migrating out of the eye into the systemic circulation. That appears to be more frequent with bevacizumab as opposed to ranibizumab.1
Dr. Peters: Would a patient have a stroke or a heart attack during treatment?
Dr. Boyer: That is not likely. During the clinical trials, the higher dose of 0.5 mg ranibizumab seemed to yield better results in retinal vascular occlusive disease and wet macular degeneration. For diabetic eye disease, however, there was no real difference in outcomes between the 0.5 mg and 0.3 mg dosages, so the lower dose of 0.3 mg was approved. In many cases, patients need treatment in both eyes, and using the lower dose reduces the total exposure to the drug.
I want to emphasize that ranibizumab (and aflibercept, which is not approved for diabetic retinopathy) have been modified to have a short duration of action for use in the eye. Bevacizumab must be prepared at a compounding pharmacy for use in the eye at 1/400th of the usual dose for the treatment of certain cancers. (For more of the panel’s discussion of compounding, see “The Complexities of Drug Compounding.”)
1. Tolentino M. Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease. Surv Ophthalmol. 2011;56:95-113.
Dr. Peters: We know that anti-VEGF agents are administered via intravitreal injection. How many treatments are required before a patient gets better?
Dr. Gonzalez: The RISE and RIDE trials demonstrated that patients receiving monthly injections of ranibizumab continue to improve for up to 1 year.8 After the first year, patients who continue to receive treatment tend to mantain.
Dr. Handelsman: Do you continue treating after the first year?
Dr. Schwartz: Yes. I go from monthly injections in year 1 to PRN injections in year 2 and beyond. I have found that in many cases, I can reduce the number of injections, from a mean of seven per year to about two per year.
Dr. Gonzalez: The DRCRnet performed a study similar to the RISE and RIDE trials. We treated monthly for the first year. After the second year, we treated some patients as needed, and we were able to significantly reduce the number of injections required.
Dr. Handelsman: Suppose a patient hits all of her targets. Her glucose is perfect, her blood pressure is perfect, her lipids are perfect. After 1 year, would she need to continue treatment?
Figure 1. For many patients, a 3-line gain in visual acuity can mean the difference between functioning and not functioning in life.
Dr. Schwartz: Yes. She would need to continue PRN.
Dr. Handelsman: Why would she need to continue if there is no more DME?
Dr. Boyer: It is a continuous process. The DME will get better with tight control, but patients will still have DME for a long time before they get better, even though they’re “not diabetic” based on their A1c Hgb.
Dr. Schwartz: Remember, too, that what happens in the eye reflects glucose control from 3 to 5 years ago. The damage doesn’t manifest as center-involving macular pathology until year 2 or 3.
Dr. Boyer: There’s something else we should emphasize. In these studies, there was a marked improvement in the grade of diabetic retinopathy. We may find that we don’t have to treat forever, but we do have to follow patients forever.
Dr. Handelsman: What can you tell us about patients with high levels of VEGF who don’t improve?
Dr. Schwartz: The percentage of nonresponders is low. I’d like to make a couple of points. In these studies, we’re talking about patients who have center-involving macular edema from diabetes — not just a little bit of swelling. In other words, not all of your patients will receive injections. That’s number one.
Number two, we’re assessing many factors in addition to retinal thickness. Retinal thickness is a good surrogate for vision, but perfusion, vitreoretinal traction and other issues affect vision. When patients don’t respond to anti-VEGF therapy, we can turn to other drugs, such as steroids. We can also go to surgery. We can look at the vitreomacular interface. There are many other avenues we can try to improve vision; however, those cases can present some difficult management issues.
WHAT PATIENTS NEED TO KNOW
Dr. Gonzalez: When you talk to your patients, it’s important to explain what they can expect from anti-VEGF treatment and why this injection is better than laser. Simply put, as long as a patient is undergoing treatment, the chance that he will develop proliferative diabetic retinopathy nearly goes away.
Dr. Schwartz: Another way to explain it is: “If you go to the retina specialist and do what he says, you’re not going to go blind.” That’s almost always the case now. You can basically say that to every patient.
Dr. Gonzalez: One other important fact is that, in the past, patients’ complaints weren’t always that they were going blind. They often complained that they lost some vision after treatment with the laser. The beauty of these drugs is that we avoid that. In fact, we’re getting ready to publish some interesting work, showing that the functional ability of these patients is significantly improved and maintained without the loss of peripheral or central vision.
Dr. Handelsman: These facts should get more visibility in our guidelines, because when we talk to our patients about retinopathy, we primarily say go to the ophthalmologist because he will have some laser magic for you and you will be fine. The fact that you now have a disease-modifying treatment is important and will give a different dimension to our guidelines.
Dr. Boyer: At the present time, the DRCRnet is performing a study to compare panretinal photocoagulation therapy versus anti-VEGF therapy and deferred laser for the treatment of proliferative diabetic retinopathy. In another study (protocol T), which is currently recruiting participants, the DRCRnet will evaluate the comparative effectiveness of intravitreal aflibercept, bevacizumab, and ranibizumab for DME (NCT01627249).
These studies will give us additional information to help guide our treatment decisions. For example, we think that certain anti-VEGF agents dry the retina better than others. Now, we want to see if this translates to a difference in vision 1 year later. Fortunately, patients don’t experience the tremendous vision loss with DME as they do with wet AMD when fluid is present. In patients with DME, visual acuity may be 20/20, even though a small amount of fluid may be present.
Dr. Schwartz: That’s right. These studies are also valuable because of what they reveal about safety issues. For example, in a head-to-head study of ranibizumab and bevacizumab for wet AMD, at the end of 1 year, they were deemed to be noninferior, but there was a safety difference. Many predicted that the safety signals with bevacizumab were a fluke that would even out at year 2, but it didn’t, and, in fact, the safety difference was still there and difficult to explain.9
The study was not powered for safety, but the observation was still there. I predict — and this is a prediction without much data at this time, certainly no high-level data — that the bevacizumab safety data will extrapolate to diabetes and be magnified. I also predict that in the absence of something else, anti-VEGF treatments are better than laser alone.
|The Complexities of Drug Compounding|
Dr. Boyer: As we’ve mentioned, some retina specialists use bevacizumab as an off-label treatment for retinal vascular disease. This drug is indicated for the treatment of certain cancers. It must be repackaged by a compounding pharmacy into small doses appropriate for ocular use.
Dr. Schwartz: Compounding is a complex process, but it has been commoditized to the lowest common denominator and is now taken for granted. After a horrific outbreak of fungal meningitis traced to a compounding pharmacy in New England this year, the laws around compounding are changing. Furthermore, clinical experience strongly suggests that ranibizumab is far more effective than the generic compounded bevacizumab for the treatment of DME. There’s just very little question.
Dr. Handelsman: If my patient asks me about these two drugs, should I advise him to request ranibizumab if he can pay for it?
Dr. Schwartz: Definitely. Certainly, the government programs cover it, and the corporate sponsor has various access programs (http://www.genentech-access.com/lucentis/patients) to assist with the cost. I will tell you that my use of bevacizumab has plummeted, and I’m having it compounded at UCLA, which I consider one of the premier compounding pharmacies in the country. We’re filtering and culturing every batch, but I’m migrating away from its use. One should always recommend the on-label drug, in my opinion.
AN EYE IN THE SKY APPROACH
Dr. Schwartz: The DRCRnet treatment paradigm has tremendous value, but I’m a proponent of a slightly different treatment approach when it comes to managing complex diabetic retinopathy. Dr. Gonzalez and Dr. Boyer have also espoused our treatment patterns. We use an all-inclusive multimodal imaging approach centered on what you might call a “Google Earth” or “eye in the sky” perspective. Specifically, ultra-wide field angiography provides a very wide view of the retina, so we can assess perfusion of the entire retinal vascular tree as well as assessing vitreomacular traction and macular edema with SD-OCT. Then, based on these results, patients can have their diabetic eye disease approached in a manner that addresses not just macular edema, but also retinal vascular perfusion (which is closely tied to VEGF production). By combining gentle, precise and targeted laser photocoagulation with anti-VEGF therapy, we feel we can reduce not only the acute VEGF burden but also diminish VEGF upregulation over time, thus providing a more comprehensive treatment of eyes with DME.
Dr. Boyer: It takes a long time for laser alone to show an effect on macular edema. Therefore, you must use anti-VEGF drugs to get an improvement early and then the laser will hopefully be effective in reducing the injection frequency.
Dr. Schwartz: Correct, I employ a multimodal imaging workup and a combination anti-VEGF and laser treatment strategy. The DRCRnet studies are good studies, but have not yet been able to incorporate state-of-the-art peripheral retinal vascular imaging, and that is where the culprit protein, VEGF, is most likely sourced.
Dr. Boyer: We have some concerns in this vasculopathic population of using anti-VEGF agents. Some studies have shown bevacizumab lasts up to 21 days in the serum. It reduces the systemic VEGF level significantly to the point where it may cause an increase in serious systemic adverse events (SAEs). I think the safety question needs to be answered in the future for all anti-VEGF agents.
We can reassure you that with timely referrals and the new drugs that are available, we can reduce the incidence of vision loss from diabetic eye disease and improve patients’ quality of life, while at the same time reducing the economic burden on the entire population.
— David Boyer, MD
Dr. Boyer: This has been a valuable forum. From a retina specialist’s point of view, I feel I have a better understanding of the challenges faced by diabetologists. I know that we need to communicate with the doctors who manage diabetes patients and we must provide them with more information about the patients that we share. We can also help patients better understand why the targets you set for them are so important by showing them what diabetic eye disease looks like, explaining how it can affect their vision and reinforcing what must be done to preserve their sight. As you pointed out, if blindness is what they fear most, they’ll be willing to change many things to avoid blindness.
We can also reassure you that with timely referrals and the new drugs that are now available, we can reduce the incidence of vision loss from diabetic eye disease and improve patients’ quality of life, while at the same time reducing the economic burden on the entire population.
Dr. Schwartz: I always learn something new when I talk to endocrinologists, and today was no exception. As a retina specialist, I feel privileged to have the opportunity to positively impact vision. Often, the most meaningful interaction is motivating patients to comply with your recommendations. For the doctors who work with diabetes patients, I hope we have begun to convey the dramatic improvements now available in the evaluation and management of diabetic eye disease.
Dr. Gonzalez: I would echo that sentiment and add that I think it’s important for us to provide you with the latest information about the therapies we’re using. Then you will understand why we’re so enthusiastic. Anti-VEGF therapy is a game changer. We can now go beyond just preserving vision and help patients recover vision, which will keep them functional for a very long time.
Dr. Peters: This discussion has helped me tremendously. I now have a better understanding of anti-VEGF therapy — the long-term treatment plan and the expected outcomes — so that I can convey that information to my patients and make sure they follow through when I refer them to you. The more I know about what you expect my patients to do, the better. By the same token, I appreciate your involvement as a consultant and a care partner who will reinforce my instructions to our patients.
Dr. Handelsman: I believe in interdisciplinary discussions on any level, especially in diabetes. Although we learned about diabetic eye diseases years ago, we need to renew our studies and re-establish those discussions. Not only will it benefit us, it will benefit our patients.
Dr. Boyer: I agree that these types of discussions should be ongoing. My hope is that we can expand upon this topic and talk about other new drugs in the near future.
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3. Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989;161:851-858.
4. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480-1487.
5. Cunningham ET Jr, Adamis AP, Altaweel M et al; Macugen Diabetic Retinopathy Study Group. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 2005;112:1747-1757.
6. Gonzalez VH, Giuliari GP, Banda RM, Guel DA. Intravitreal injection of pegaptanib sodium for proliferative diabetic retinopathy. Br J Ophthalmol 2009;93:1474-1478.
7. Elman MJ, Bressler NM, Qin H, et al; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118:609-614.
8. Tolentino M. Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease. Surv Ophthalmol. 2011;56:95-113.
9. Martin DF, Maguire MG, Fine SL, et al; CATT Research Group. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 212;119:1388-1398.