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Earlier referrals, advanced treatments help fight vision loss related to diabetes
The growing incidence of diabetes is becoming a public health crisis of global proportions. According to estimates from the World Health Organization, the number of people with diabetes mellitus worldwide is expected to rise to 360 million by 2030, heavily involving developing countries due to dietary changes, sedentary lifestyle and obesity.
Type 2 diabetes has assumed epidemic proportions in Asia, which accounts for nearly 60% of the world’s diabetic population. India is already home to more than 62 million people with diabetes, bases on the ICMR-INDIAB study results published in 2011.
“Asian Indians tend to develop diabetes at a younger age and with lower body mass index than Caucasians. Ocular consequences are a major cause for concern, with approximately 12 million Indians who already have diabetic retinopathy (DR),” Ramachandran Rajalakshmi, MBBS, DO, FEDD, PhD, head of medical retina at Dr. Mohan’s Diabetes Specialties Centre and Madras Diabetes Research Foundation (MDRF) in Chennai, India, said.
Image: Rajalakshmi R
Late referral and underscreening are some of the major challenges in DR management. With early detection, DR can be treated with modalities that can decrease the risk of severe visual impairment.
“The biggest hurdle faced by most developing countries like ours is the lack of resources and trained manpower to both screen and treat the large number of people with DR,” Rajalakshmi said.
To overcome these challenges, models of mobile DR screening and treatment aided by the use of telemedicine are becoming popular.
“For patients in remote areas and villages who don’t have access to a retina specialist for fundus examination, teleophthalmology is a boon. The MDRF/WDF Rural India Diabetes Prevention Project, carried out by our center, is a rural community outreach program which serves a cluster of 42 villages in the Kanchipuram district,” she said.
Pharmacotherapies are the first-line treatment in Western countries.
In areas of the world where diabetes is better controlled, about 20% to 30% of people affected will have DME, with a potentially severe decrease in vision in half of the cases, Anat Loewenstein, MD, head of ophthalmology at Tel Aviv University, Israel, said.
“The good side of it is that today we do have a treatment, with multiple options to choose from and possibly combine,” she said.
New pharmacotherapies, namely anti-VEGFs and steroids, can be effective in preventing the detrimental consequences of DME on vision.
“Laser, which was standard of care for many years, does not improve vision. It stabilizes it, except in a small percentage, about 15%. But anti-VEGFs and steroids can incrementally improve vision by more than two lines and in more than two-thirds of the patients. Only a small number have a decrease in vision if they have a good compliance with the treatment,” Loewenstein said.
Of the three anti-VEGFs currently used for the treatment of DME, only Lucentis (ranibizumab, Genentech/Novartis) has been granted approval for this indication by the U.S. Food and Drug Administration.
The DRCR.net Protocol I trial was the first to clearly demonstrate that ranibizumab yields superior anatomic and visual acuity outcomes over 3 years in eyes with center-involved DME and vision impairment when compared with the previous gold standard of focal/grid laser photocoagulation, as well as with triamcinolone plus focal/grid laser, Susan B. Bressler, MD, the Julia G. Levy, PhD, Professor of Ophthalmology at Wilmer Eye Institute, Johns Hopkins University School of Medicine, in Baltimore, U.S.A., said.
The DRCR.net Protocol T trial is currently comparing the effectiveness of intravitreal Eylea (aflibercept, Regeneron/Bayer), Avastin (bevacizumab, Genentech/Roche) and ranibizumab for DME.
“The study will tell us whether or not one of the three drugs is superior to the others in regards to efficacy, and it may provide insights into potential safety concerns or total treatment burden,” Bressler said “It will be helpful to all of us when it comes to make the decision of what drug to choose and how to use it.”
In the absence of evidence-based criteria, the choice is often made on the basis of cost and reimbursement policies for anti-VEGFs in individual countries.
“From a logistical standpoint, we are able to offer Lucentis or Avastin to most of our patients with DME,” Bressler said, because they are both covered by most insurances. Eylea is not reimbursed and therefore rarely used.
“In my country, we use Avastin for the first three injections; otherwise, the patient will never be reimbursed for any other drug. If there isn’t a good enough response, we switch to Lucentis or Eylea. If I have a patient for whom reimbursement is not an issue, I go immediately for either Eylea or Lucentis. They both seem to be excellent drugs for DME and comparable for their efficacy,” Loewenstein said.
Steroids have also shown efficacy in the treatment of DME. Not all ophthalmologists, however, accept steroids as a treatment option. The risk of cataract development and the exacerbation of macular edema after cataract surgery should be a concern, according to Bressler. Steroids also increase IOP and can lead to glaucoma complications.
“I consider them an option for only the most refractory eyes, and in my experience, I have very few eyes that are refractory if aggressively managed with anti-VEGF therapy and laser,” she said.
According to Loewenstein, the main advantage of steroids is that less frequent treatments are needed compared with anti-VEGFs.
“In most cases, anti-VEGFs are my first choice because they are a registered therapy for DME in my country. However, if a patient has already had cataract surgery, I might consider steroids, particularly if there are impediments to come for regular visits to my office and have the at least six injections that are needed monthly to start with. I make sure that IOP is measured by a local ophthalmologist at 1 week and 1 month,” she said.
Increasing availability in India
Laser photocoagulation is still the gold standard treatment for proliferative diabetic retinopathy (PDR) and fresh DME in India.
“It is my first choice of treatment for patients with PDR and DME when the patients have a good vision as it is a simple, safe and painless outpatient procedure. Patients who maintain good glycemic and lipid control and have fresh DME respond well to laser photocoagulation,” Rajalakshmi said.
However, in patients with a decrease in vision due to severe DME, intravitreal anti-VEGF injections are becoming first choice. Major limitations are the cost of the treatment, the need to administer it under sterile conditions and the need for repeated injections. Anti-VEGF therapy is mainly used in urban areas and has not reached the rural population. However, some patients living in rural areas are screened by teleophthalmology and travel to urban eye hospitals to be treated.
Until recently, ranibizumab was only available in major eye hospitals due to the cost. Recently, however, the cost has been brought down significantly, leading to more widespread use. Intravitreal bevacizumab is used both as aliquots, maintaining the cold chain, or in multiple patients with DME on the same day.
“Injections are given on the same day to six to 10 patients, so that the cost of the drug is divided between them,” Rajalakshmi said.
Steroids such as triamcinolone, which is relatively cheaper than bevacizumab or ranibizumab, and implants such as Ozurdex (dexamethasone intravitreal implant, Allergan) are also currently used as intravitreal injections for the treatment of persistent severe DME, mainly in pseudophakic patients only.
Outreach programs
In areas where they have been implemented, telescreening programs are showing to be a cost-effective, accurate and reliable method for screening for DR. All diabetic patients are screened annually, and those who have sight-threatening DR are referred for further investigation.
“In our project, we found that less than 5% of the screened rural diabetic patients needed referral to our main center in Chennai for further treatment. This reduces traveling costs for the patients and provides regular monitoring for the underprivileged who lack accessibility to major diabetes eye care centers. It also reduced the burden of ophthalmologists in the tertiary care center, where more time can be given to the patients who are selected for treatment,” Rajalakshmi said.
Projects such as “Nayana” in Karnataka have moved one step ahead in making laser photocoagulation mobile. A van equipped with a fundus camera and Nd:YAG laser travels from town to town in some areas of Karnataka, south India, providing local ophthalmologists with a facility for diagnosis and treatment of DR. Patients can be treated locally, unless they need intravitreal injections or vitreoretinal surgery.
“Training more ophthalmologists in administering intravitreal injections under aseptic conditions is another goal we should be able to reach,” Rajalakshmi said.
Illiteracy and lack of awareness about DR are barriers that need to be overcome, she said. Neglected diabetes, undetected retinopathy at the nonproliferative stage, lack of periodic follow-up as advised by the ophthalmologist, poor review after laser photocoagulation and intravitreal injection treatment are some of the reasons for progression of DR and vision loss.
The World Health Organization is working toward the implementation of Vision 2020 in India, especially in rural areas, with a primary focus on community participation. Outreach programs are primarily aimed at fighting diabetes-related blindness and visual impairment by increasing the awareness about DR in the community. – by Michela Cimberle
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For more information:
Susan B. Bressler, MD, can be reached at Wilmer Eye Institute, Johns Hopkins Hospital, Maumenee 706, 600 North Wolfe St., Baltimore, MD 21287, U.S.A.; +1-410-955-3648; email: sbressler@jhmi.edu.
Anat Loewenstein, MD, can be reached at Tel Aviv Sourasky Medical Center, Department of Ophthalmology, 6 Weizmann St., Tel Aviv, Israel 64239; email: anatlow@tasmc.health.gov.il.
Ramachandran Rajalakshmi, MBBS, DO, FEDD, PhD, can be reached at Dr. Mohan’s Diabetes Specialties Centre and Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India; email: drraj@drmohans.com.
Disclosure: Bressler’s university receives grant support from Novartis, Genentech, Regeneron and Bayer. Loewenstein is a consultant for Notal Vision, Allergan, Novartis, Alimera, Bayer and Roche. Rajalakshmi has no relevant financial disclosures.
Is the timing of treatment in DME as crucial as in AMD?
Early initiation of therapy can maximize visual benefit, reduce risk of visual loss
DME is one of the most important causes of visual loss in patients with diabetes mellitus. The natural history of DME is poor without treatment, as the Early Treatment of Diabetic Retinopathy Study has demonstrated that more than 30% of eyes with DME will have moderate visual loss at 3 years. In the past, macular laser photocoagulation has been the standard treatment for DME because it can prevent visual loss. However, the benefit of macular laser treatment is limited to visual stabilization with minimal visual improvement after treatment. Over recent years, anti-VEGF therapy has become the new gold standard treatment for both neovascular AMD and DME because various clinical trials have shown that prompt treatment can result in long-term visual gain. As with neovascular AMD, treatment with anti-VEGF agents in DME with central involvement should be initiated early because deferring anti-VEGF treatment might result in additional visual loss. Many patients with DME frequently have a delay in diagnosis and, therefore, might already have permanent structural damage to the macula, causing irreversible visual loss.
The recently published 3-year data from the RISE and RIDE studies demonstrated that patients who were delayed for 2 years in receiving ranibizumab treatment were much less likely to gain vision to the same extent as those who were treated early. Therefore, if treatment is not initiated early, the potential for visual gain will be impaired due to macular damage associated with chronic macular edema. Moreover, visual acuity is likely to worsen without treatment, with progressive atrophy of the retinal pigment epithelium, loss of photoreceptors and formation of foveal exudates. The RISE and RIDE studies also found that patients who were not treated initially with ranibizumab were two times more likely to develop moderate visual loss of 15 letters or more compared with patients who were treated early. Because many patients with DME are in the working age group, it is important that anti-VEGF therapy for DME should be initiated early so that patients can have improved vision as soon as possible, optimizing their visual function.
References:
Brown DM, et al. Ophthalmology. 2013;doi:10.1016/j.ophtha.2013.02.034.
Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmol. 1985;doi:10.1001/archopht.1985.01050120030015.
Fong AH, et al. Clin Interv Aging. 2013;doi:10.2147/CIA.S36811.
Timothy Y.Y. Lai, MD, FRCS, FRCOphth, is a honorary clinical associate professor at the Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, and a director at 2010 Retina & Macula Centre, Hong Kong. Disclosure: Lai has received honorarium for consultancy and lecture fees from Alcon, Allergan, Bayer HealthCare, Heidelberg Engineering and Novartis.
DME management requires a comprehensive systemic, ocular approach
DME is a complication of diabetes, a chronic metabolic disease, and DME develops slowly, usually over a long duration from the onset of diabetes. Early-stage or mild DME with exudation and edema within the macula region but still far from the foveal center most often presents asymptomatically in patients who are screened and reviewed for diabetic retinopathy. Thus, there is often time to discuss the natural history and consequences of DME as well as the range of treatment options, including the risks and benefits. While anti-VEGF therapy is now considered the first-line therapy for moderate or severe DME with center involvement and visual impairment, milder forms of DME may not need anti-VEGF treatment. For example, in patients with mild DME with no center involvement or in eyes with good vision, it remains possible to consider focal/grid laser treatment. There is no need to rush to inject the patient when DME is diagnosed in such scenarios. Even if anti-VEGF therapy is considered, the natural history of DME is a slower progression of visual loss, which is evident in the placebo arms of large clinical trials. Furthermore, because patients with DME often have poor systemic control of glucose, blood pressure and lipids and may have multiple medical problems (eg, nephropathy and kidney disease), a comprehensive approach that tackles the systemic aspects is equally important as the ocular treatment. Consideration may be given to the use of fenofibrate, for example, which has been found to be beneficial to DME. Finally, because DME patients are at high risk of vascular diseases, including stroke and heart disease, the physician should adequately explain the potential systemic effects of anti-VEGF therapy.
In contrast, the urgent treatment of wet AMD is based on a more aggressive natural history, often accompanying severe loss of vision, the lack of alternative therapies such as laser, and the lack of significant systemic comorbidity of the patients (at least in comparison to a diabetes patient with DME). Thus, most physicians offer to inject the patient early rather than later.
References:
Cheung N, et al. Lancet. 2010;doi:10.1016/S0140-6736(09)62124-3.
Cheung N, et al. Prog Retin Eye Res. 2008;doi:10.1016/j.preteyeres.2007.12.001.
Lim LS, et al. Lancet. 2012;doi:10.1016/S0140-6736(12)60282-7.
Mitchell P, et al. Am J Ophthalmol. 2014;doi:10.1016/j.ajo.2013.11.012.
Wong TY, et al. Am J Ophthalmol. 2012;doi:10.1016/j.ajo.2012.03.013.
Wong TY, et al. Ophthalmology. 2008;doi:10.1016/j.ophtha.2007.03.008.
Tien Y. Wong, MD, MPH, PhD, is an OSN Asia-Pacific Edition Assistant Editor, a professor and chairman at the Department of Ophthalmology, National University of Singapore, chief of ophthalmology at the National University Hospital, and a senior consultant and deputy medical director at the Singapore National Eye Center. Disclosure: Wong is on advisory boards and has been a consultant for Allergan, Bayer, Novartis and Pfizer.