Integrated CROSS-DISCIPLINARY APPROACHES to the MANAGEMENT OF DIABETIC EYE DISEASES

EVENT DATE: October 19, 2014LOCATION OF EVENT: ChicagoRELEASE DATE: March 1, 2015EXPIRATION DATE: February 29, 2016

THIS EDUCATIONAL ACTIVITY IS JOINTLY PROVIDED BY

SUPPORTED BY AN UNRESTRICTED EDUCATIONAL GRANT FROM

ALLERGAN AND REGENERON

2 INTEGRATED CROSS-DISCIPLINARY APPROACHES TO THE MANAGEMENT OF DIABETIC EYE DISEASES

INTENDED AUDIENCE The target audience is retina specialists and fellows, diabetologists, including endocrinologists, primary care physicians, fellows and registered dieticians.

LEARNING OBJECTIVESUpon completion of this activity, the participant should be able to: Describe what constitutes an effective

integrated cross-disciplinary referral pattern Discuss the implications of the growing

diabetes epidemic and its impact on eye care practice

Discuss available and emerging treatments for diabetic eye diseases, including safety and efficacy from clinical trials and real-world experience

Discuss the various ocular imaging modalities and their roles in the diagnosis and management of diabetic eye diseases

Discuss the role of the retina specialist in the diagnosis, treatment and management of diabetic eye diseases.

STATEMENT OF NEED Diabetes is the leading cause of new cases of blindness among working-age adults in the United States.1 The volume of U.S. patients with vision-threatening diabetic eye diseases is rapidly increasing and projected to triple between 2005 and 2050.2 Because diabetes is a multifactorial disease, patients may seek care from multiple specialists, underscoring the importance of integrating treatment and management strategies. What’s more, retinopathy progresses more slowly in patients who successfully manage their diabetes with systemic treatment versus those who do not, suggesting that outcomes could be maximized when ophthalmologists and diabetologists coordinate management approaches.3

Therapeutic options for the treatment of diabetic retinopathy and diabetic macular edema have expanded, and advancements in medical imaging technologies provide greater options for efficient, accurate and reproducible diagnosis and monitoring of ocular conditions. Likewise, diabetes management guidelines and strategies, including pharmacologic treatments and devices, have also evolved in recent years, underscoring the importance of cross-disciplinary education and communication.

1. Centers for Disease Control and Prevention. National Diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S Department of Health and Human Services, Centers for Disease Control and Prevention, 2011.2. Saaddine JB, Honeycutt AA, Narayan MV, et al. Projection of diabetic retinopathy and other major eye diseases among people with diabetes mellitus. United States 2005-2050. Arch Ophthalmol. 2008;126:1740-1747.3. Bloomgarden ZT. Diabetes: An update for the ophthalmologist. Adv Stud Ophthalmol. 2008;5:9-15.

METHOD OF PARTICIPATION This activity should take approximately 1 hour to complete. Participants should first read the objectives and other introductory CME information and then proceed to the educational activity. To receive credit for this activity, participants must complete the online post-test with a passing score of 80% and then complete the evaluation. Credit is provided through February 29, 2016. No credit will be given after this date. There is no fee to participate in this activity.

In the event you have questions about this activity or are unable to retrieve the certificate, please e-mail cme@dannemiller.com and a certificate will be emailed within 2 weeks.

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ACCREDITATIONThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Dannemiller and PentaVision. Dannemiller is accredited by the ACCME to provide continuing medical education for physicians.

Dannemiller designates this enduring activity for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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FACULTYDAVID M. BROWN, MD, is clinical professor of ophthalmology at Baylor College of Medicine, and in private practice at Retina Consultants of Houston.

SEENU M. HARIPRASAD, MD, is chief of the vitreoretinal service at the University of Chicago and professor of ophthalmology.

PETER K. KAISER, MD, is the Chaney Family Endowed Chair in Ophthalmology Research at the Cleveland Clinic Lerner College of Medicine.

TAMER H. MAHMOUD, MD, is an associate professor of ophthalmology at the Duke University Eye Center and the program director of the vitreoretinal surgery fellowship.

LOUIS PHILIPSON, MD, PHD, is professor of diabetes metabolism and endocrinology, and director of the Kovler Diabetes Center at the University of Chicago.

DISCLOSURES In accordance with the Accreditation Council for Continuing Medical Education (ACCME), Dannemiller requires that any person who is in a position to control the content of a CME/CE activity must disclose all financial relationships they have with a commercial interest.

Full disclosure of faculty/planners and their commercial relationships, if any, follows.

DAVID M. BROWN, MD: Served as a consultant/advisory board member and investigator for Allergan, Genentech, Novartis and Regeneron; served as a consultant/advisory board member for Bayer.

SEENU M. HARIPRASAD, MD: Served on the speakers’ bureau and as a consultant/advisory

board member for Alcon, Allergan, Genentech and Regeneron; served as a consultant/advisory board member for Bayer and Optos; served as a consultant/advisory board member for and is a stockholder of Clearside, Ocular Therapeutics and OD-OS.

PETER K. KAISER, MD: Served as a consultant/advisory board member for Alcon, Aerpio, Bayer, Genentech, Kanghong, Novartis, Ohr, Ophthotech and Regeneron.

TAMER H. MAHMOUD, MD: Served as a consultant/advisory board member for Alcon, Alimera and Allergan.

LOUIS PHILIPSON, MD, PHD: Served as an investigator for NovoNordisk and Pfizer; served as a consultant/advisory board member for Quest.

Leslie Goldberg, Angela Jackson and Virginia Pickles, content reviewers, and Erin Fletcher, Dannemiller project manager, have no financial relationships with commercial interests.

To resolve identified/potential conflicts of interest, the educational content was fully reviewed by a member of the Dannemiller Clinical Content Review Committee who has nothing to disclose. The resulting certified activity was found to provide educational content that is current, evidence-based and commercially balanced.

OFF-LABEL STATEMENT This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by FDA. The opinions expressed in the educational activity are those of the faculty. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Further, participants should appraise the information presented critically and are encouraged to consult appropriate resources for any product or device mentioned in this program.

DISCLAIMER The content and views presented in this educational activity are those of the faculty and do not necessarily reflect those of Dannemiller, PentaVision LLC, Allergan, Inc., or Regeneron Pharmaceuticals, Inc. This material is prepared based upon a review of multiple sources of information, but it is not exhaustive on the subject matter. Therefore, healthcare professionals and other individuals should review and consider other publications and materials on the subject.

DAVID M. BROWN, MD (MODERATOR): We are facing an emerging global epidemic of diabetes, with approximately 347 million people worldwide who have the disease.1 In the United States, more than 29 million people — 9.3% of the population — have diabetes, which puts them at risk for numerous serious systemic complications, including diabetic retinopathy.2 Diabetic retinopathy is the leading cause of new cases of legal blindness among adults aged 20 to 74 years in the United States.3 Researchers estimate the prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy will triple by 2050.4 Clearly, ophthalmologists have a critical role in caring for patients who have diabetes.

We will explore the role of the retina specialist in the diabetes care team, which may include diabetologists, endocrinologists, primary care physicians, dietitians, podiatrists, cardiologists and nephrologists. Although each individual specialty is its own island, collaboration is critical to ensure that patients receive optimum care and consistent reinforcement of their health goals at each encounter.

ACCESS TO SPECIALTY CARE

DR. BROWN: For the ophthalmologists at the table, to whom do you refer your patients for diabetes care?

TAMER H. MAHMOUD, MD: We are fortunate to have a team of endocrinologists at the Duke Medical Center, as well as two large endocrinology groups in the community to whom we can refer patients. At least 80% of my patients who have diabetes are already in our system, enabling me to easily access their information, which is a huge advantage.

SEENU M. HARIPRASAD, MD: Likewise, at the University of Chicago, we have excellent endocrinologists, and our primary care team is exceptional.

PETER K. KAISER, MD: The Cleveland Clinic is similar in that we have a team approach to diabetes care that involves endocrinology, primary care, internal medicine, cardiology, podiatry, nephrology and ophthalmology. In the primary care offices, patients who have diabetes often get fundus photographs that are sent to our department to decide if additional evaluation is required. With access to each patient’s entire medical record through EMR, every physician involved has access to the most current details of each patient’s health status.

DR. BROWN: I have access to both Baylor and Methodist hospitals, but I also care for patients whose insurers don’t allow access to those institutions. It can be difficult for me to locate an endocrinologist or a primary care physician to whom I can refer patients. Sometimes I see patients who need help to manage their disease — they may not even know what their hemoglobin A1c is — yet many of the internists and primary care physicians in the community are overwhelmed with patients, and endocrinology is not accessible. That’s something our society must address. We have to find out who is willing to take these people under their wing and help them gain control of their disease.Dr. Philipson, I think we’d all like to hear your

perspective as a diabetologist.

LOUIS PHILIPSON, MD, PHD: In the United States, over 29 million people have diabetes, but because there are so few endocrinologists, I would estimate about 80% to 90% of people with diabetes are receiving care from general practitioners, family physicians or other generalists. Access to specialty care is limited, which is why diabetologists are trying to educate primary care physicians to be more aggressive — not to be satisfied with an A1c of 8, and certainly not double digits — and to understand when to refer a patient to a specialist.

DR. BROWN: Dr. Philipson, when would you refer a patient to a retina specialist?

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DR. PHILIPSON: I first establish the type of diabetes. Generally, I believe evaluation by an ophthalmologist can be deferred for children or young people with type 1 diabetes until about 5 years from their diagnosis. The presumption is that their blood pressure and cholesterol levels are good, and they don’t smoke. If a patient has type 2 diabetes, even if his blood sugar is apparently good, I refer him for an eye examination immediately, preferably with a retina specialist.

RETINA EXAMINATIONS AND IMAGINGDR. BROWN: The American Academy of Ophthalmology recommends that people who have diabetes and no retinopathy have a dilated eye examination every year. What are your thoughts on the frequency of eye examinations for patients with diabetes and the role of those examinations?

DR. KAISER: I agree that a patient whose diabetes is well controlled and who has no retinopathy can be seen yearly, but we need to be careful to generalize the recommendation. For example, a patient who is newly diagnosed with diabetes and whose hemoglobin A1c level is extremely high, should probably be seen sooner than next year, even though he has no retinopathy. The more concerned I am about disease progression, the more likely I am to bring a patient back sooner for evaluation.

DR. BROWN: When you see a new patient referred to you with a diagnosis of diabetes, how do you proceed? What imaging studies do you perform?

DR. MAHMOUD: We don’t know a great deal about the eye before microaneurysms or diabetic changes become apparent on physical examination, but spectral domain optical coherence tomography (SD-OCT) and enhanced-

depth optical coherence tomography may show early changes in the retina and choroid that can serve as baseline for follow up and future studies.5 Therefore, I think it’s important to obtain such images at baseline. If I don’t see diabetic retinopathy, I recommend that the patient see an ophthalmologist in our comprehensive service on a yearly basis. If early diabetic changes are detected, the patient will be referred back to me. If diabetic retinopathy is detected, I like to get widefield color images and widefield fluorescein angiography in addition to OCT. We have been focused on diabetes as a posterior pole disease, but many of the changes can be peripheral, and the degree of peripheral nonperfusion needs to be assessed at baseline and may influence treatment decisions.

DR. HARIPRASAD: I agree. Just because a patient is diagnosed with diabetes without diabetic retinopathy doesn’t mean there are no subclinical changes. I suspect VEGF levels in those eyes are elevated. If we could take a biopsy of the vessels and examine them carefully, I believe we would see pericyte loss and microangiopathy. Ultrawidefield angiography would likely show peripheral changes and ischemia. Furthermore, future imaging technologies, such as adaptive optics, may show changes in the retina long before we can detect them clinically.

DR. KAISER: I agree with imaging a patient when I see diabetic retinopathy, but I always examine a new patient clinically before deciding whether or not to obtain imaging studies. If I see no retinopathy, I generally don’t obtain any imaging studies. In terms of choroidal changes with no observable retinopathy, I’m not sure we are at the level of science to recommend that in all new patients.

DR. BROWN: If a patient has diabetic retinopathy, I like to obtain a widefield angiogram, because sometimes what it reveals is surprising. An eye that appears quiet may show profound peripheral ischemia. What’s more, using

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6 INTEGRATED CROSS-DISCIPLINARY APPROACHES TO THE MANAGEMENT OF DIABETIC EYE DISEASES

the widefield angiogram, I can show a patient the microaneurysms and explain how his diabetes is causing that to happen all over his body (Figure 1).

In my practice, we always perform OCT. Fluorescein angiography is a variable, depending on what I see during the examination. Dr. Hariprasad, do you always perform angio-graphy and OCT?

DR. HARIPRASAD: If I suspect early proliferative disease or worse, I obtain a fluorescein angiogram. If a patient has recalcitrant diabetic macular edema (DME) or a suboptimal response to therapy, I also obtain an ultrawidefield fluorescein angiogram. I don’t perform OCT on every patient unless there is a history of DME, but I have a low threshold for performing OCT if there’s any suspicion of macular disease or if the vision isn’t as good as it should be.

DR. BROWN: Dr. Kaiser, what imaging studies do you obtain when you first see a patient who has diabetes?

DR. KAISER: If a patient has evidence of retinopathy at the initial visit, I use OCT to assess the retinal microarchitecture. We can’t see ischemia on an OCT, so I also perform widefield fluorescein angiography. In the past, I would have obtained a standard fluorescein angiogram, but I now use widefield angiography, even at baseline, to evaluate for peripheral nonperfusion. Unfortunately, I frequently see extensive nonperfusion and even early neovascularization on widefield angiograms.

DR. BROWN: What imaging do you perform during a patient’s course of treatment?

DR. KAISER: As I’m treating patients for DME, I generally monitor them with OCT. I don’t feel I need to repeat fluorescein angiography at every visit. However, if a patient isn’t responding to therapy as well as I would like, I repeat the widefield angiography to determine, for instance, if I need to perform targeted panretinal photocoagulation to areas of nonperfusion, which may improve an eye’s response to treatment.

EFFECTIVE COMMUNICATIONDR. BROWN: Dr. Philipson, what sort of interactions do you and your patients have with retina specialists? What are the challenges to effective communication?

DR. PHILIPSON: Some challenges are related to the psychology of diabetes management. As an example, often when a retina specialist tells a patient he has background diabetic retinopathy, the patient doesn’t hear “background” and is likely to call me in tears, saying, “My eye doctor told me I’m going to go blind.” When I receive the retina specialist’s report, it says: “background; nonproliferative; stable; come back in a year.” So part of my job is to interpret that report, which can be delivered to my patients in a fairly succinct fashion.

DR. BROWN: What can we do to help?

Figure 1. In addition to its clinical utility for revealing the peripheral retina, widefield fluorescein angiography is also helpful for educating patients.

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DR. PHILIPSON: Part of my plea to the ophthalmologists and the ophthalmology subspecialists is to be aware of the impact of their communications to patients and referring doctors. When someone hears a diagnosis or prognosis that he believes is potentially career-threatening and life-altering, he needs help to process that information. Sometimes a phone call, in addition to a letter, to the referring physician can be helpful. That’s also part of the reason why we encourage ophthalmologists to locate either an endocrinologist or a diabetes-oriented center where patients can follow up on recommendations.

DR. BROWN: Do retina specialists frighten your patients and create more work for you, or do we help when we tell patients they need to work on their hemoglobin A1c levels because it’s worth the effort?

DR. PHILIPSON: Patients’ reactions are varied. Some are immediately remorseful and promise to “clean up my act.” Unfortunately, that enthusiasm often fades. Some people give up, thinking, “Well, this is the end. I already need dialysis, and now I’m going to be blind.” Some patients who are undergoing treatment for diabetic eye disease see me between injections, literally crying about what they think may or may not happen. When someone is about to start therapy or exhibits a danger sign, a quick phone call to the primary care physician or whomever is managing the patient’s diabetes, in addition to a letter, may be critical in terms of support.

DR. BROWN: Dr. Mahmoud, how do you educate patients at the initial visit?

DR. MAHMOUD: At the first visit, I discuss the process, especially if they are newly diagnosed. I tell them that working on diabetes requires teamwork on their part and mine. I emphasize prevention, but I tell them if they don’t control their blood sugar and reduce their hemoglobin A1c levels, they can go blind. I also explain that diabetes doesn’t affect only their eyes, and I warn them about the risks for stroke, heart disease and renal failure. I explain that treatment for diabetic eye disease entails many visits to my office for injections, laser therapy or possibly a surgical procedure (Figure 2). I want them to think about how this will affect their lives, their work and their bodies. I may be scaring them initially, but they need to realize what can happen if they don’t start taking their disease seriously and become an integral and active part of the management. I also try to end the conversation on a positive note, particularly if they will undergo treatment. I explain that even if their vision worsens, we have many treatment options that can save vision, and I emphasize compliance with visits and the treatment plan.

Figure 2. Patients must be made aware that treatment for diabetic eye disease entails many visits to a retina specialist for injections, laser therapy or possibly a surgical procedure.

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DR. PHILIPSON: My most interesting interactions with retina specialists and general ophthalmologists are concerning people who require good vision for their employment. One of my more memorable cases was a thoracic surgeon who presented to the ophthalmologist with decreased vision. He was diagnosed with advanced proliferative retinopathy and had an A1c of 10. That case is not unusual in that many people with type 2 diabetes will have had diabetes for at least 5 years before diagnosis.6 This underscores the need for the general internist or the family practitioner to refer patients for a dedicated retina examination when they initiate care for diabetes. That first visit could be critical to a patient’s understanding of the depth of his problem.

DR. BROWN: Dr. Hariprasad, how do you educate patients?

DR. HARIPRASAD: I routinely see more than 65 patients a day, so I may have only a few minutes to talk to a patient. I supplement one-on-one education with brochures from the American Academy of Ophthalmology and nonbranded brochures from eye care companies that patients can take home and share with family members. Given my time constraints, my goal is to get the educational ball rolling.

DR. BROWN: How do you inform a patient’s primary care physician or endocrinologist about the patient’s status?

DR. HARIPRASAD: EMR has been a godsend for this type of communication. With a few clicks, I can send Dr. Philipson an EMR e-mail and a copy of my note, so that when he sees the patient, my note is in front of him. EMR really has facilitated communication. I know which patients are plugged into the system and which patients aren’t. One day, I believe these EMR systems will be cross-office compatible, so that even our community doctors will have this information available to them.

TREATMENT OPTIONS FOR DME

DR. BROWN: After years of the status quo in treatment options, we now have several agents approved for treating DME: ranibizumab (Lucentis, Genentech), an antibody fragment against VEGF; aflibercept (Eylea, Regeneron), a fusion protein of two VEGF receptors; dexamethasone intravitreal implant (Ozurdex, Allergan), a long-acting steroid; and fluocinolone intravitreal implant (Iluvien, Alimera Sciences), a longer-acting steroid. Have these new agents replaced laser therapy, which was our standard of care for many years?

DR. HARIPRASAD: Laser photocoagulation still has a place in my treatment armamentarium. In carefully selected patients who have discrete leaking microaneurysms, focal laser can be effective.

DR. KAISER: I completely agree. I still consider laser a very good treatment for DME. In extrafoveal DME cases, laser treatment works well, especially in patients with good vision and defined areas of leakage; and it has a durable effect (Figure 3).

DR. BROWN: Let’s discuss the two anti-VEGF agents approved for treating DME.

DR. HARIPRASAD: Ranibizumab is an efficacious drug, but the treatment burden is high. In the RISE and RIDE trials, patients received 36 injections in each eye over 3 years, and as we know, the bilaterality of DME is upwards of 60%.7 Therefore, if we follow the RISE and RIDE protocol, some patients could require 72 injections over 3 years.

Aflibercept has the advantage of placental growth factor inhibition, and its durability was found to be better than laser photocoagulation in the clinical trials.8 Therefore, there may be some advantages in terms of treatment burden.

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We look forward to the results of the Diabetic Retinopathy Clinical Research Network’s Protocol T trial, which will provide us with data comparing ranibizumab, bevacizumab and aflibercept for the treatment of DME.

DR. BROWN: We also have new options for corticosteroid treatment, including novel drug delivery systems. What is your opinion of these agents?

DR. HARIPRASAD: The dexamethasone intravitreal implant 0.7 mg is an excellent advance in terms of decreasing the treatment burden. In the MEAD trial, the mean number of treatments administered over 3 years was fewer than 5 injections,9 although it has been suggested that patients were undertreated in this trial. As we begin to use the dexamethasone implant in the real world, we’ll have a better idea of the number of treatments required. In any case, the difference between the number of injections required in the MEAD trial compared with the number needed in the anti-VEGF trials was significant.

The fluocinolone intravitreal implant has durability for up to 3 years.10 Among its disadvantages are that it induces a high rate of cataract formation as well as intraocular pressure (IOP) elevation; however, these effects can be mitigated with careful patient selection.

DR. BROWN: Dr. Mahmoud, walk us through your thought process for using a steroid.

DR. MAHMOUD: When I see patients for the first time, I look at their systemic risk factors. In most cases, because of what we’ve learned from the evidence-based

clinical trials, I start with an anti-VEGF agent. If an eye is going to respond, I will likely see a response within the first 3 months of treatment. If a patient is doing well after 3 months of treatment and the vision has improved more than 2 or 3 lines, I continue on the same course and decide if I want to treat and extend. If there is no response at 3 months, particularly if the patient is losing vision and the hemoglobin A1c is high, I know I must try a different approach. I may switch to a different anti-VEGF agent or to a steroid, or I may use a combination treatment.

DR. BROWN: Dr. Kaiser, do you use intravitreal triamcinolone when treating patients who have DME?

DR. KAISER: Intravitreal triamcinolone acetonide for intravitreal injection is usually my first choice when I use steroids in patients with DME. Steroids work well in these patients because there’s a dramatic inflammatory component to DME that anti-VEGF agents don’t address. Adding a steroid often triggers a response in an eye that was previously not responding to anti-VEGF therapy.

Figure 3. In eyes with extrafoveal diabetic macular edema, especially those with good vision and defined areas of leakage, focal laser photocoagulation works well.

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DR. BROWN: When do you consider a steroid implant?

DR. KAISER: If an eye is not responding to anti-VEGF therapy and I believe it requires more frequent or longer-acting steroids, I consider using a steroid implant. I like to use triamcinolone first to ensure the patient is not a steroid responder. If they respond favorably to the steroid injection and have no adverse IOP rise, then I’m much more likely to use a steroid implant in the future. In my opinion, however, these implants should not be used in young patients because of the risk of steroid-induced cataract formation. I try to use steroids sparingly in younger patients. That said, however, I think there’s absolutely a role for steroids in treating DME and I use them often.

DR. BROWN: Is there ever a time when you’d use a steroid as initial therapy?

DR. KAISER: I don’t consider steroids as first-line therapy for DME. If you look at the visual acuity results from steroids — in particular the dexamethasone implant for which we have the best data — versus anti-VEGF therapy, the patients receiving anti-VEGF therapy have better visual acuity gains and fewer adverse events. Thus, in my opinion, anti-VEGF agents are first line and steroids are second line.

NEW AGENTS FOR DIABETES TREATMENTDR. BROWN: Dr. Philipson, I have a diverse population of patients who have diabetes. Some are seeing their primary care physicians, some of whom haven’t changed their diabetes care protocols in 10 years. Others are being managed by

COST CONCERNS WITH ANTI-VEGF THERAPY

DR. BROWN: Of the three anti-VEGF agents available to us — two that are FDA-approved and the less costly bevacizumab (Avastin, Genentech), which is used off-label — do you see a role for one over another? Is cost ever a factor when you choose a therapy?

DR. HARIPRASAD: This is a complicated and controversial question. Ranibizumab has set the bar at a very high level in terms of outcomes in treating DME, but the treatment burden is high. Recent news reports about the Diabetic Retinopathy Clinical Research Network’s Protocol T study, which compares the efficacy and safety of aflibercept, bevacizumab and ranibizumab, suggest aflibercept’s durability may be slightly better, and improvements in visual outcomes may be significantly better while safety is similar.11 Obviously, we’re at the edge of our seats waiting for these data to be published in greater detail.

DR. KAISER: I agree. Protocol T will be interesting, because until the release of those data, my opinion was that I would start all patients on bevacizumab and then switch them if I felt their response was suboptimal. Given our current healthcare system, I believe we have to take costs into account. Until now, no study showed any differences in safety between these drugs, and as such, I based my decision on cost. If Protocol T indeed shows a significant difference in efficacy or safety, I will need to rethink that algorithm.

DR. MAHMOUD: While cost is a factor to consider, there are assistance programs available that can help alleviate some of the financial burden.

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cutting-edge, university-based endocrinologists who are using the latest agents. How has the management of diabetes changed in recent years?

DR. PHILIPSON: Just as the retina world has seen the introduction of exciting new agents, similarly a host of new agents are available for diabetes management. Although we still see some patients who are using metformin, sulfonylurea, and even NPH insulin, generally those days are long gone. Some older classes, such as the glitazones, are still on the market, but I have not written a prescription for them in quite a long time because of their systemic side effects.

Today, there are about 15 different classes of diabetes medicine, including a whole new set of oral agents, such as the sodium-glucose cotransporter 2 (SGLT2) inhibitors. There are also new classes of injectables, including several noninsulin drugs, administered once a day or once a week, that can also be used for weight loss and blood sugar management.

DR. BROWN: Suppose I have a patient who isn’t improving, his eye health is at risk, and I’m concerned he’s not being treated as aggressively as he could be. What should I do?

DR. PHILIPSON: That’s a concern. I think you have to gently suggest that the patient discuss this situation in detail with the physician managing his diabetes treatment. Obviously, referral practices can be very sensitive, and in the real world, it may be difficult to suggest to a patient that his primary care physician, or whomever is taking care of his diabetes, is not aggressive enough. Patients can be given educational material from the American Diabetes Association, the American Association of Family Practice and the Diabetes Educators Association to enlighten them about the current standard of care. Depending on a patient’s age and comorbidities, his hemoglobin A1c certainly should be less than 8, and for young, otherwise

healthy patients, it should be less than 7. How do you get there? You get there by way of a comprehensive diabetes program that addresses nutrition, exercise, medications and psychological needs.

I would urge ophthalmologists to push back and encourage primary care physicians, internists or even endocrinologists who may not be as aggressive as the current guidelines recommend, to use the new therapies, or to refer your patient to someone else in the community who is known to be more aggressive.

DR. BROWN: I hear from my endocrinology colleagues that no one is using glitazones any more, but I see many patients who are using glitazones. Is that just in Houston?

DR. HARIPRASAD: No, I see this in Chicago as well, and I think retina specialists, general ophthalmologists, optometrists and endocrinologists need to be aware that we may see new-onset or a worsening of macular edema in patients who are using glitazones.12

DR. MAHMOUD: There have been conflicting reports that DME can worsen with glitazones, and I don’t believe there’s been a randomized prospective clinical trial. Whenever I see a patient who is using a glitazone and whose DME is not improving, I ask his endocrinologist if there are any other options for the patient.

DR. BROWN: Dr. Philipson, do you use specific management strategies to protect the kidneys when a patient has concomitant hypertension and hyperglycemia?

DR. PHILIPSON: If a patient doesn’t have hypertension, the idea of instituting angiotensin-converting enzyme inhibitor (ACEI) therapy for renal protection before demonstrated renal disease has virtually been eliminated. This is because data from randomized controlled trials shows there is no advantage to starting ACEI unless there is already renal disease.13 Once

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a patient becomes hypertensive, however, aggressive intervention is critical. We may use as many as five agents to control hypertension.

DR. KAISER: I become very concerned when a patient tells me she doesn’t know what her hemoglobin A1c is and that her blood pressure isn’t well controlled. From the retina perspective, we all know this patient will not do well, even with our excellent treatments. So even though some studies have shown good results were achieved despite high hemoglobin A1c levels,8 my primary concerns are controlling blood pressure and blood sugar and referring the patient to an endocrinologist.

DR. PHILIPSON: Studies have shown that even for other complications of diabetes, control of hypertension and hyperlipidemia trumps the A1c.14 So the emphasis on A1c may, in fact, be misguided if a patient’s blood pressure is 180/110 and her low-density lipoprotein is 190. I think controlling those two factors and also gradually reducing the A1c may be the most successful strategy in preventing or ameliorating complications of diabetes, including eye diseases.

NEW INITIATIVES IN DIABETES CAREDR. BROWN: Dr. Philipson, what are your thoughts on the differences between the complexities of patients with type 1 diabetes, who in my clinic have the sickest eyes, compared with those with the more variable type 2 diabetes?

DR. PHILIPSON: In my institution, we are seeing what seems to be a large number of women in particular in their mid-20s to mid-30s with advanced type 1 diabetes. They’re already undergoing dialysis, their 5-year life expectancy is poor, and in many cases, they’re blind. The time to intervene has long passed. We feel there needs to be a comprehensive analysis, not only

with insulin management in the case of type 1 diabetes, but also an aggressive move to pumps and continuous glucose monitors. Support for the concept of the diabetes e-clinic is growing. In other words, instead of seeing a physician in the office every 3 months, patients have weekly consultations with an endocrinologist or diabetes educator.

That intensity of effort is also making its way into type 2 diabetes with the idea that someone who has had type 2 diabetes for 20 years, who may be taking multiple oral agents and insulin, could benefit from aggressive care, including intermittent continuous glucose monitors and/or insulin pumps. It’s a growing notion. Many people are still wrapping their heads around it. The combination of aggressive care with psychological intervention is critical. In Houston, for example, Barbara Anderson-Thomas, PhD, is leading the way to bridge the gap between what we tell our patients to do and how we can help them do it.

We know that not everyone will develop every complication. Some people may be predisposed to retinopathy, while others will have mostly neuropathies. It behooves the practitioner, the generalist, the internist or the endocrinologist to be sure to touch all of these bases. We need to treat patients’ feet as intensively as their eyes and not miss one for the other.

DR. BROWN: I’m affiliated with Methodist and Baylor hospitals, but I also have clinics in Livingston, Texas, and rural East Texas where the closest endocrinologist is at least a 2-hour drive away. What do you recommend to help underserved communities?

DR. PHILIPSON: I wish there were a simple answer to that question. In Chicago, we work closely with some of our colleagues who are involved with a project called “Improving Diabetes care and outcomes on the south side of Chicago,” (http://southsidediabetes.com) which helps serve a primarily underserved, underprivileged, socioeconomically challenged

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community. We’re also affiliated with some of the federally qualified health centers (FQHCs) in the area. That means putting an endocrinologist in an FQHC environment as a consultant to primary care physicians who are available to see more complicated cases. We’re trying to educate patients and practitioners, as well as educators. The staff includes nurses, pharmacists and dieticians, who see patients frequently, often in classroom environments, which can be cost-effective. This type of education can help reinforce the importance of self-care.

DR. BROWN: Obviously, lifestyle issues are important to manage diabetes. Are there challenges related to medications, as well?

DR. PHILIPSON: It can be extremely challenging from one month to the next to understand what medicine a patient is taking. Health insurance keeps changing in front of our eyes, and the costs of medicines are increasing. I’m sure many of you are having similar experiences.

I think the bottom line is, we don’t yet have a viable system to manage the underserved. A system whereby general practitioners could manage patients and a diabetologist could see them from time to time would be great.

This is probably one of those areas where the more basic interventions with optometry can make a difference. We are trying to partner with whomever can do the most basic analysis under the theory that some health care is better than no health care.

DR. BROWN: Dr. Kaiser, tell us about the photoscreening program at your institution.

DR. KAISER: At the Cleveland Clinic, we’re actively promoting the idea of remote screening for diabetic eye changes. We’ve placed right-angle photography machines in the offices of our endocrinologists and our primary care physicians, and we’re planning to add OCT and other noninvasive modalities. The photographs and OCT images are evaluated at the Cole Eye

Institute. If we see any evidence of diabetic retinopathy, or any other abnormality for that matter, we inform the primary care physician or the endocrinologist and schedule the patient for a complete retinal examination at the Cole Eye Institute.

Using this technique, we’ve been able to dramatically increase our reach to find patients with diabetic retinopathy. Often, these patients don’t even know they have a problem and haven’t seen an ophthalmologist, so we’re able to initiate treatment considerably earlier with this easy-to-use technique.

DR. BROWN: Do you feel this type of program would be useful in underserved areas?

DR. KAISER: Yes. I think photoscreening could be very useful for underserved or indigent populations. The challenge would be to secure funding to offset the costs of the imaging machines and transmission to a central site for evaluation. It certainly increases the reach of ophthalmologists without requiring a visit unless abnormalities are detected.

CONCLUSION

DR. BROWN: This has been a very open and informative panel discussion, highlighting the communication required between eye specialists and the other physicians and care providers who collectively treat and educate our patients who have diabetes. Although we as retina specialists have experienced game-changing breakthroughs in the management of many aspects of diabetic eye disease, it’s a shallow victory if we see patients too late or other comorbidities limit the benefits that the new retina therapies offer. In closing, I’ll ask each panelist to summarize a key point in the team-oriented approach to managing diabetes patients.

DR. HARIPRASAD: Undoubtedly, the optimal

14 INTEGRATED CROSS-DISCIPLINARY APPROACHES TO THE MANAGEMENT OF DIABETIC EYE DISEASES

management of diabetic eye disease requires a cross-disciplinary approach. What we see in the eye is a reflection of systemic disease. By optimizing systemic variables, we help the patient at so many levels and likely improve their response to our ocular therapies.

DR. KAISER: We have entered a new era in diabetic therapy. In the past, laser photocoagulation was used to prevent loss of vision. With anti-VEGF agents and steroids, we now can offer patients improvement in vision. Hopefully, in the future, we can build on this success and provide patients with durable improvements in vision and possibly even improve the diabetic retinopathy with our therapeutic agents.

DR. MAHMOUD: Diabetic retinopathy is part of a systemic disease with many confounding variables, such as treatment options and approaches, possible complications, and significant economic issues. A custom approach to each patient’s presentation and situation is key, with multidisciplinary involvement for best success. Evidence-based information from randomized, prospective clinical trials can help guide our treatment approaches, but real-life experiences and economics also help refine our treatment modalities. Comprehensive management of this complex disease will continue to evolve as new drugs and delivery approaches become available.

DR. PHILIPSON: This conversation highlights the importance of interactions among retina specialists and diabetologists. Despite many advances in therapies over the last few decades, eye disease leading to decreased vision and blindness remains a life-changing complication of diabetes. Close communication can help ensure that individuals with diabetes benefit from early intervention and state-of-the-art management and treatment.

REFERENCES1. Danaei G, Finucane MM, Lu Y, et al; Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Blood Glucose). National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet. 2011;378(9785):31-40.

2. Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. Atlanta, GA: US Department of Health and Human Services; 2014.

3. Fong DS, Aiello L, Gardner TW, et al; American Diabetes Association. Diabetic retinopathy. Diabetes Care. 2003;26 Suppl 1;S99-S102.

4. Saaddine JB, Honeycutt AA, Narayan KM, Zhang X, Klein R, Boyle JP. Projection of diabetic retinopathy and other major eye diseases among people with diabetes mellitus: United States, 2005-2050. Arch Ophthalmol. 2008;126(12):1740-1747.

5. Yiu G, Manjunath V, Chiu SJ, Farsiu S, Mahmoud TH. Effect of anti-vascular endothelial growth factor therapy on choroidal thickness in diabetic macular edema. Am J Ophthalmol. 2014;158(4):745-751.

6. Harris MI, Klein R, Welborn TA, Knuiman MW. Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis. Diabetes Care. 1992;15(7):815-819.

7. Brown DM, Nguyen QD, Marcus DM, et al; RIDE and RISE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013;120(10):2013-2022.

8. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247-2254.

9. Boyer DS, Yoon YH, Belfort R, et al; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10):1904-1914.

10. Pearson PA, Comstock TL, Ip M, et al. Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology. 2011;118(8):1580-1587.

11. EYLEA (aflibercept) injection demonstrates significantly greater gains in visual acuity than both bevacizumab and ranibizumab in NIH-sponsored diabetic macular edema study (press release). Tarrytown, NY; Regeneron Pharmaceuticals, Inc.: October 17, 2014. http://newsroom.regeneron.com/releasedetail.cfm?releaseid=876732. Accessed December 16, 2014.

12. Idris I, Warren G, Donnelly R. Association between thiazolidinedione treatment and risk of macular edema among patients with type 2 diabetes. Arch Intern Med. 2012;172(13):1005-1011.

13. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Am J Kidney Dis. 2014;64(4):510-533.

14. American Diabetes Association. Cardiovascular disease and risk management. Sec. 8. In Standards of Medical Care in Diabetes—2015. Diabetes Care. 2015;38(Suppl 1):S49–S57.

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1. According to the American Academy of Ophthalmology, if someone has diabetes and no retinopathy, how frequently should he or she have a dilated eye examination?

a. every 5 years b. annually c. twice a year d. every 2 years

2. Which of the following imaging modalities, although still in its infancy, will help retina specialists visualize ischemia?

a. widefield fluorescein angiography b. ultrawidefield fluorescein angiography c. enhanced-depth optical coherence

tomography d. OCT angiography

3. Stressing how important it is for family practitioners and other generalists to refer patients to retina specialists upon initial diagnosis of diabetes, Dr. Philipson notes many people with type 2 diabetes will have had the disease for at least how long before diagnosis?

a. 5 years b. 6 years c. 10 years d. 2 years

4. In the RISE and RIDE trials of ranibizumab, how many injections did patients receive in each eye over 3 years?

a. 12 b. 24 c. 36 d. 48

5. In the MEAD trial, which evaluated the dexamethasone intravitreal implant 0.7 mg, what was the mean number of treatments administered over 3 years?

a. <3 b. <4 c. <5 d. >5

6. Among the pharmacologic treatments approved for treating diabetic macular edema, which agent has shown durability for up to 3 years?

a. aflibercept b. ranibizumab c. dexamethasone d. fluocinolone

7. Citing studies, Dr. Philipson notes control of which of the following “trumps” hemoglobin A1c control?

a. hypertension and hyperlipidemiab. BMI and inactivityc. hyperthyroidism and sugar intaked. pregnancy and fat distribution

8. Although there have been conflicting reports and no randomized prospective clinical trials, which of the following has been implicated in new-onset or worsening of diabetic macular edema?

a. metformin b. sulfonylurea c. NPH insulin d. glitazones

INTEGRATED CROSS-DISCIPLINARY APPROACHES TO THE MANAGEMENT OF DIABETIC EYE DISEASES

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