Setting Our Sights on Diabetes
Three diabetic eye disease gurus discuss prevention, detection, diagnosis, and treatment – and explain why it’s important to consider the future
Meet the Gurus
Neil Bressler is the James P. Gills Professor of Ophthalmology at the Wilmer Eye Institute, Johns Hopkins University School of Medicine in Baltimore, USA.
“I specialize in diseases of the retina, including diabetic retinopathy (DR). When I started my career, definitive benefits of laser treatment for diabetic macular edema (DME) had just been reported in 1985 by the Early Treatment Diabetic Retinopathy Study Group. There were no substantial improvements in treatment until publications regarding anti-VEGF therapies for DME in 2010 followed anti-VEGF for proliferative diabetic retinopathy in 2015 by the NIH-sponsored DRCR Retina Network, which I was fortunate to Chair from 2006 through 2012.”
Andrew Schimel is a retina specialist at the Center for Excellence in Eye Care in Miami, Florida, USA. He has published numerous peer-reviewed papers and book chapters.
“I have been researching, diagnosing and treating patients with diabetic retinopathy in both academic and private practice settings for over 10 years. The changes that we have seen in this field over such a short period of time are remarkable. When I began 10 years ago, I often operated on three or more patients a week to repair complications from diabetic retinopathy, whereas now I may operate on one such patient every few weeks. And that’s because our treatments have moved us from the operating room to the clinic, and our understanding of disease and our armamentarium has rapidly expanded and improved. This is a very exciting field – especially right now.”
Heeral Shah practices ophthalmology at Ramesh R. Shah in Joplin, Missouri, USA, specializing in retinal diseases. She is a co-founder of the International Society for the Advancement of Medical Retina.
“I practice in southwest Missouri, in a smaller city surrounded by a multitude of farming communities. A large percentage of our patients have uncontrolled diabetes, and are uneducated in the disease process. Though they have implicit trust in their doctors, keeping appointments and medical compliance is an issue. Therefore, we find ourselves treating diabetic retinopathy aggressively to prevent vision loss.”
What are the main lessons you have learned while working with patients with diabetes?
Andrew Schimel: Diabetic retinopathy is the number one cause of vision loss in American adults aged 20-74 years. The most important specific lesson in the treatment of diabetic retinopathy is that most patients do not lose permanent significant vision with appropriate follow-up and treatment. With the right screening, monitoring and treatment, we should be able to prevent the majority of DR patients from losing any significant vision. The old adage could not be more true: an ounce of early prevention and treatment saves a pound of later expensive treatment, surgery, and disability costs to the system.
Heeral Shah: Unfortunately, patients who have diabetic retinopathy usually developed it due to poor compliance with medications over many years. The same factors make it increasingly difficult to treat their retinopathy, as they now have to deal with other comorbidities, including nephropathy and peripheral neuropathy. the prevention and treatment of diabetic retinopathy.
How important is prevention of diabetic eye diseases, and what can ophthalmologists do to help?
Heeral Shah: In my opinion, this is an area that is largely in need of improvement. As the complications from diabetes are delayed years after diagnosis, far too many patients spend years with poorly-controlled diabetes, without realizing the repercussions of their actions until it is too late. Technological advances such as telemedicine can now be used to screen patients, even in the most rural of settings, from their primary care doctor’s office. The wide use of electronic medical records can aide in improving coordinated efforts between primary care physicians and ophthalmologists. And last but certainly not least, aggressive public service announcements via social media can help reach the younger generation of diabetic patients.
Andrew Schimel: I was so excited that you approached me to address this issue as there is so much potential for us to do better in this field. We have access to the tools necessary to screen and treat the ever-growing population of diabetics, which now includes over 30 million Americans, and over 80 million more pre-diabetics. Unfortunately, there are no great public service efforts to help these patients and their primary physicians to understand their disease. Though there are some more recent attempts to improve this effort from insurance carriers, including Medicare in the US, most healthcare entities are not doing a great job. We need a more unified approach, where patients are motivated to get screened, where hospital systems and primary care providers are driven to get their diabetic patients evaluated and treated, and where ophthalmologists and retinal specialists are motivated to coordinate care appropriately.
How has the diabetic eye disease picture changed over the last few decades?
Andrew Schimel: There has been a massive evolution in the treatment of diabetic retinopathy over the past few decades. The DRCR.net (DRCR Retina Network) and others have done incredible work to demonstrate that not only can we treat patients with diabetic retinopathy, but we can also reverse damage in patients with moderate and even advanced disease in many cases. In the 1980s, we discovered that using laser on these patients reduced the risk of major vision loss by half (ETDRS study). By 1994, research demonstrated that the hypoxic retina produced excessive vascular endothelial growth factor (VEGF) that would eventually lead to diabetic macular edema, proliferative diabetic retinopathy with neovascularization, vitreous hemorrhage, and tractional retinal detachments with severe vision loss. Remarkably, only 10 years later, we had our first approved anti-VEGF medication (Pegaptanib for wet macular degeneration) and a decade after that (2014) we had three more powerful anti-VEGF therapies with bevacizumab, ranibizumab, and aflibercept to treat diabetic macular edema. In the past five years, we have proven that appropriate treatment with these anti-VEGF medications can reverse diabetic retinopathy altogether in many patients. There appears to be a strong trend towards earlier clinical treatment in moderate and slightly advanced disease with anti-VEGF injections to prevent vision loss and complications before they occur. And indeed, such action has been shown to maintain and improve quality of life in these patients, which is what it should be all about.
Heeral Shah: Fortunately, the introduction of insulin pumps, phone apps, and newly released equipment using non-invasive glucose monitoring technology have significantly improved disease control over the past few years. In my opinion, we should see a decrease in the degree of diabetic retinopathy in the next few decades due to this. In terms of retinal disease, with the use of anti-VEGF injections, steroid implants, and exciting upcoming treatments, patients have much better long-term visual outcomes now than they did a few decades ago.
Bearing the Burden
Our experts discuss the economic burden of diabetes and diabetic eye disease – and how it has changed over the last few decades.
Andrew Schimel: The economic burden of treating diabetic eye diseases is large, with some estimates placing the number over $500 million a year in the USA. There is the cost of medical care for the diabetic patient directly, but also the secondary cost, which is loss of productivity and, in the case of blindness, the high cost of caring for someone who has lost their vision. Treating these patients earlier on in the course of their disease to prevent late stage complications that require significantly more expensive surgical management – and the enormous secondary costs involved – provides great promise. Unfortunately, around 50 percent of patients with diabetic retinopathy still do not receive appropriate eye care and another 50 percent of those being treated do not follow up appropriately, which greatly limits our potential to relieve this economic burden. We need to further educate and incentivize those at every step of the process, to reduce these large costs.
Heeral Shah: The economic burden of diabetes and diabetic retinopathy is huge. In our current healthcare system, we see the large numbers of patients who present with several comorbidities related to diabetes, and the chronic nature of these diseases is significant. Their diabetic retinopathy often results in an inability to work and drive, which results in a further burden on their family members and friends. It becomes a cycle. I previously worked at the Veterans Hospital in Tampa, Florida, where the burden was identical.
What are the current and emerging detection/diagnosis options for diabetic eye diseases?
Neil Bressler: “Diabetic eye disease” is a very broad term – I would argue that it is too broad when communicating among healthcare professionals – for example, cataracts are associated with diabetes, as is neovascular glaucoma, or – even more commonly – diabetic retinopathy, which also may be best stratified into non-proliferative or proliferative diabetic retinopathy, either of which may have diabetic macular edema. All of these conditions might be considered “diabetic eye diseases,” but it seems better for healthcare communication if one uses more precise terms like proliferative diabetic retinopathy instead of “diabetic eye disease.”
For diabetic macular edema (DME), the gold standard for detection is optical coherence tomography (OCT), in which abnormal thickening of the retina, as well as subretinal fluid or cystoid abnormalities, are coupled with confirmation on ophthalmoscopy or fundus images that indicate that these features are indeed associated with diabetic macular edema, and not other causes of edema, such as a branch retinal vein occlusion. It is predicted that home OCT devices or detection of DME via automated analyses (such as deep learning algorithms of artificial intelligence) of fundus images that match OCT detection will facilitate detection of DME outside of the ophthalmologist’s office where OCT devices currently exist.
For non-proliferative and proliferative diabetic retinopathy, fundus photographs (seven standard stereo fields, or four wide field images, or one ultrawide field image) are the gold standard for detecting abnormalities. Of course, the images must be of adequate quality in terms of clarity and field to maximize the possibility of obtaining the correct diagnosis by an expert in the interpretation of these images. Several investigators around the world have shown that deep learning algorithms can allow computers to provide interpretations of these images that match human experts, so that these approaches likely can be incorporated in future management.
Andrew Schimel: All diabetic patients need to have a dilated retinal examination at least once a year. Currently, this is most often accomplished through evaluation by an optometrist or ophthalmologist, who screen these patients for diabetic retinopathy. Ideally, once DME or proliferative diabetic retinopathy begin, these patients are referred to a retina specialist for further treatment. Alternatively, patients can get retinal photographs that are individually reviewed and referred appropriately.
Typically, physicians diagnose diabetic eye disease, but there is a great deal of excitement around emerging technologies. For example, artificial intelligence (AI) systems have recently emerged that who great promise in screening retinal photographs for diabetic retinopathy – and systems can be placed in convenient locations. But there are significant concerns that current AI technologies are not perfect and often only screen for diabetic retinopathy. If these patients have any other ocular diseases, such as glaucoma, retinal tears, choroidal nevi, and so on, they would be missed by current AI systems. As a result, the patients, who assume they are getting their eyes examined regularly, could lose significant permanent vision. As AI technology improves, the hope is that it can screen for most common ocular diseases to address this concern.
Heeral Shah: The current techniques include OCT and fluorescein angiography. Widefield angiography has been extremely helpful in determining the areas of nonperfusion, and therefore helping select areas to treat with pan-retinal photocoagulation. OCT angiography is another emerging tool, which I believe will eventually prove to be very beneficial.
What are the most important treatment trends and how are they likely to evolve in the future?
Neil Bressler: Treatment of DME has been guided over the past decade by important clinical trials from the government (NIH) sponsored DRCR Retina Network, industry-sponsored trials for registration of new drugs, as well as investigations by others around the world. These trials have shown that intravitreous anti-VEGF agents as first-line treatments are superior to intravitreous corticosteroids, and surpassed the previous gold standard, which was focal/grid laser treatment (from 1985 until 2010). Proven regimens (not including consideration of conbercept which is currently only available in China) have included monthly treatments for at least three years (ranibizumab), five monthly injections followed by bi-monthly injections (aflibercept), or the DRCR Retina Network’s PRN regimen (aflibercept, bevacizumab, or ranibizumab). The DRCR Retina Network’s PRN regimen typically starts with six monthly injections followed by focal/grid laser treatment for residual, stable edema with stable visual acuity, and resumption of injections for any subsequent worsening of DME or worsening visual acuity from DME until stable visual acuity and central subfield thickness on OCT again are attained. The DRCR Retina Network treatment regimen is associated with increasing visit intervals as great as every four months, and decreasing mean number of injections, with almost 50 percent of patients avoiding injections each year after reaching stability, and without a clinically relevant decrease in visual acuity, even among eyes with persistent but stable, residual DME. The treatments, on average, are quite effective, with a majority of patients maintaining visual acuity 20/32 or better when starting with visual acuity 20/32 or worse. The percentage of patients receiving focal/grid laser at six months or beyond can differ depending on the anti-VEGF agent used, and for eyes with initial visual acuity of 20/50 or worse, the vision outcomes over 1–5 years also can differ, depending on the agent used. Regardless of the agent used, when following the DRCR Retina Network regimen, fewer than five percent of patients will lose two or more lines of visual acuity over five years from DME diagnosis.
For patients with visual acuity of 20/25 or better and DME involving the center of the macula, no differences in outcome, on average, at two years have been detected, whether starting with a strategy of monthly aflibercept, or focal/grid laser followed by aflibercept for the approximately one-quarter of eyes that develop visual acuity loss (defined as at least one but less than two lines at two consecutive monthly visits, or at least two lines at one visit) or observation followed by aflibercept for the approximately one-third of eyes that develop visual acuity loss. Observation with aflibercept rescue may be a reasonable strategy for these eyes. There are no current data available to know definitively whether rescue with bevacizumab or ranibizumab would provide similar results.
For patients with DME not involving the center, observation until edema involves the center appears to be a reasonable strategy, given the success, on average, of the management of patients with visual acuity of 20/25 or better when DME subsequently involves the center of the macula.
Pan-retinal photocoagulation (PRP) or anti-VEGF therapy, for example, using the DRCR Retina Network’s treatment regimen for proliferative diabetic retinopathy, are viable treatments to reduce the risk of vision loss. Each of these treatments has advantages and disadvantages.
For PRP, advantages include benefits proven across multiple randomized clinical trials for decades, with visits typically every four months in the first two years rather than every month or so with anti-VEGF therapy, no chance of endophthalmitis or other complications of intravitreous injections if not needed subsequently for DME, and a management typically considered cost-effective in developed countries such as the US in the absence of concurrent DME with vision loss necessitating anti-VEGF therapy. The disadvantages include a greater loss, on average, of peripheral visual field, a greater likelihood of developing DME with vision loss necessitating initiation of anti-VEGF therapy, and a greater likelihood for vitrectomy for complications of PDR, such as non-clearing vitreous hemorrhage or traction retinal detachment threatening or involving the macula.
For anti-VEGF, advantages include less peripheral visual field loss on average, less likelihood of developing diabetic macular edema with vision loss necessitating initiation of anti-VEGF therapy, an acceptable incremental cost effectiveness ratio for eyes that have concurrent diabetic macular edema with vision loss in developed countries such as the US, and a decreased likelihood for vitrectomy complications of PDR, such as non-clearing vitreous hemorrhage or traction retinal detachment threatening or involving the macula. Disadvantages include more frequent visits, especially within the first two years after initiating therapy, increased risk of endophthalmitis and other risks associated with intravitreous injections, and an incremental cost-effectiveness ratio that is far greater than is considered acceptable by most developed countries for eyes that do not have DME with vision loss.
It is unknown at this time whether combining PRP with anti-VEGF therapy can maintain the advantages of each of these therapies while avoiding most of the disadvantages. It also is unknown whether bevacizumab provides similar results to those obtained with either aflibercept or ranibizumab when used for PDR.
Though anti-VEGF agents in eyes with moderate to severe non-proliferative diabetic retinopathy can result in less likelihood of developing DME and can result in improved diabetic retinopathy severity levels as determined by fundus photographs, it is unknown if this approach leads to better visual acuity outcomes over time. Such an investigation is the objective of Protocol W by the DRCR Retina Network. The role of other anti-VEGF agents, such as brolucizumab, or other delivery systems, such as the port delivery system, may change the management outlined above.
Deep learning algorithms of AI may be incorporated in telemedicine in the future, where imaging devices are brought to the patient, outside of the ophthalmology office, to determine if referral for further management or treatment in the ophthalmologist’s office is warranted. The role of OCT angiography, if any, in the management of diabetic macular edema, non-proliferative diabetic retinopathy, and proliferative diabetic retinopathy, is under active investigation at this time.
Heeral Shah:The most valuable information that we now have is that anti-VEGF therapy does, in fact, result in improved vision in the long run. Also, knowing that while pan-retinal photocoagulation is necessary in many patients, limiting laser to nonperfused areas may help preserve their vision in the future. It is a huge paradigm shift, considering the value of anti-VEGF therapy in combination with laser. Furthermore, the ability to reduce the severity of diabetic retinopathy with anti-VEGF therapy is something we have never had before. As new biologics are introduced, their future role in the treatment of diabetic retinopathy is something that may change the way we treat diabetic retinopathy even now. Telemedicine should be a significant resource, most importantly in underserved areas.
We work with endocrinologists, internists, and optometrists closely. I believe that educating the patients and providers will result in the best outcomes for patients. Such integrated care has the best chance of working in this healthcare system with the nature of our current EMRs, and requirements from EMR and insurance companies to keep primary care doctors and endocrinologists notified of the patient's retinal status.
Andrew Schimel:There needs to be a more integrated care system for our diabetic patients. Whether we use screening with AI or old-fashioned retinal photographs reviewed by a reading center is less important as actually getting more of our diabetic patients screened and treated appropriately. The largest impediment is money. Each part of the necessary team wants a greater proportion of the money involved and is worried about how much they will lose if a more perfect system is created. Medicare and insurance companies want to pay less to get more. Hospital systems and primary care physicians want to keep all of the incentives for getting their diabetic patients screened. Ophthalmologists and optometrists are concerned about losing the reimbursement that comes from screening the patients that actually do come to see them. Retina specialists wonder where the patients who are found to have disease will be referred and whether they will be paid appropriately to treat them. Finally, the companies who are developing the AI software want the majority of the money involved.
Everyone involved can do better if the system remains efficient. All diabetics should get an annual photograph that is reviewed for disease. These photographs should be taken in a convenient location, such as where the patients get their HbA1c lab work drawn. The photographs should be reviewed by a fully trained and experienced retina specialist who understands the disease, its treatment, and appropriate referrals of these patients. I am certain that these could be reviewed with nearly 100 percent accuracy for less than the click fee on the newly-available and less-than-perfect AI cameras. Patients should be referred appropriately to ophthalmologists if disease exists but does not require treatment at that time or to a retina specialist if the disease requires treatment. Patients with advanced disease should be treated early and aggressively to reverse significant active disease, and should be managed appropriately according to the available literature. Patients with clean photographs should get repeat photographs annually.
With a system like this, hospital systems and primary care physicians would be financially rewarded as they would reach higher benchmarks with more of their diabetic patients screened annually. Medicare and insurance companies would save a great deal of money as they would avoid the massive costs associated with patients being discovered to have late stage disease, requiring significantly more expensive surgeries and treatments. Approximately 50 percent of patients with diabetes are not currently being seen by eye care professionals, so estimates suggest that ophthalmologists would be even busier and would actually be able to bill higher for monitoring patients with diabetes rather than negative screening exams. Retina specialists would cut down on time spent with patients who have disease that does not require treatment (as these patients would be referred to the general ophthalmologists) and so could spend more time performing money-making and sight-saving procedures. Most importantly, patients could be conveniently screened, sent to the correct physician the first time and appropriately treated to prevent losing significant vision and quality of life.
Breakdown of the retinal vasculature is a critical event underlying diabetic retinopathy and loss of vision that few physicians talk about. The great question is whether there can or will be a treatment that can reverse this retinal non-perfusion. Though anti-VEGF medications seem to begin the process of reperfusion, targeting this process with a new molecule, combination therapy, or a new generation of anti-VEGF medication would be very helpful. I am further excited and hopeful as development of new pharmaceuticals targeting anti-VEGF as well as angiopoietin 2 and the TIE2 pathway may take us to the next level in both efficacy and durability perspectives.
Could you share best practice tips for treating patients with diabetes?
Andrew Schimel: My best advice: keep up to date on the latest literature from the DRCR.net and other reputable sources – and follow the data. It troubles me that several recent studies demonstrate that physicians are not treating diabetic retinopathy appropriately despite all of the incredible data we have on best practices. We must inject patients with visually significant diabetic macular edema early and regularly to obtain optimal visual outcomes. The data is clear, there is a direct visual correlation with frequency of anti-VEGF injections once vision declines. We are not doing the patients any favors by allowing them to come in only when it is convenient for them. Our current treatments are remarkable in their ability to maintain the precious retinal vascular bed, but once it is gone, it is unclear if we can ever get it back.
Heeral Shah:As I mentioned previously, many diabetic patients develop complications due to their lack of education with the disease process. I strongly believe that empowering them with information is our responsibility. With each patient, I sit down and show them the fundus photos, fluorescein angiography, and OCT findings, and explain what we are aiming to obtain with treatment, as well as the treatment options. I explain which options provide short-term improvements, and which ones longer-term. And with each visit, we discuss how much progress we are making, and how we can further this improvement. If the patients don’t understand why they are frequently coming in for treatment, eventually they will give up. It is our responsibility to educate them.
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