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New pharmacotherapies fight global emergency of diabetes-related vision impairment
Diabetic macular edema is still the leading cause of blindness in working-age people in developed countries. According to estimates from the World Health Organization, the number of people with diabetes worldwide is expected to rise to 360 million by 2030, heavily involving developing countries due to dietary changes, sedentary lifestyle and obesity.
The growing rate of type 2 diabetes, which accounts for about 90% to 95% of all diagnosed cases of diabetes, is becoming a global concern. Ocular manifestations are consequently also on the rise. Data from the Wisconsin Epidemiologic Study of Diabetic Retinopathy stated that the 10-year cumulative incidence of macular edema was 20.1% among people with type 1 diabetes and 25.4% among those with type 2 diabetes.
“Even though today diabetes is much better controlled, about 20% to 30% of the people affected will suffer from 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.”
According to Anat Loewenstein, MD, both anti-VEGFs and steroids have advantages and disadvantages in DME, and the treatment should be tailored to the individual patient.
Image: Loewenstein A
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.
Szilárd Kiss
Laser treatment still has a role, according Szilárd Kiss, MD, director of clinical research and associate professor at Weill Cornell Medical College, particularly in patients with focal, well-defined areas of leakage and exudate. Furthermore, fewer treatments are needed than for anti-VEGFs and steroids. However, Kiss sees the role of laser in treating diabetic retinal disease as “shrinking.”
“I predict within the next 3 to 5 years, laser is going to have a minimal role as we figure out where steroids fit into the anti-VEGF realm,” Kiss said.
Anti-VEGFs as first-line treatment
There are three anti-VEGF agents and three steroids currently used for the treatment of DME. Lucentis (ranibizumab, Genentech) is the only anti-VEGF approved for this indication, and the fluocinolone acetonide intravitreal insert Iluvien (Alimera Sciences) has received marketing authorization approval in several European countries. In March, Alimera resubmitted a new drug application for Iluvien to the U.S. Food and Drug Administration.
“When we come to choose between anti-VEGFs and steroids, there is no study that has results on the head-to-head comparison of the two options. When we look at separate studies, it seems that both therapies are very beneficial. There are advantages and disadvantages to each of them,” Loewenstein said.
The DRCR.net Protocol I trial was the first to clearly demonstrate that ranibizumab, with either prompt or deferred laser, 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, said.
Susan B. Bressler
Ranibizumab was given every 4 weeks for at least four doses and often six consecutive doses. In the deferred laser group, more than half of the eyes did not require any focal/grid laser. Prompt laser treatment in combination with ranibizumab injection proved to be no better and was possibly worse in terms of visual outcomes.
Kiss said that the Protocol I trial successfully influenced his choice of treatment for patients with DME: “The DRCR.net Protocol I really changed the first choice for diabetic macular edema, and that first choice became anti-VEGF therapy. … The question of which one is the better anti-VEGF is yet to be determined.”
The DRCR.net Protocol T trial is currently comparing the effectiveness of intravitreal Eylea (aflibercept, Regeneron), Avastin (bevacizumab, Genentech) 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.
“When we look at DME, my choice is always Lucentis because that is what is FDA approved,” Kiss said. “Perhaps protocol T will give us a better sense of which anti-VEGF therapy is going to be best if there is a difference among the three.”
In the United States, Eylea is not approved by the FDA for DME.
“Since the drug is costly and not presently reimbursed, there are limits on how much we can use it off label for DME,” Bressler said.
Lucentis is approved by the FDA for DME management and covered by most insurance companies. Avastin is less expensive, covered by some insurances and used off label for DME.
“From a logistical standpoint, we are able to offer Lucentis or Avastin to most of our patients with DME,” Bressler said.
“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.
Advantages and limitations of steroids
Steroids have also shown efficacy in the treatment of DME.
“In 2014, the first line of treatment for DME is anti-VEGF therapy, but we must not ignore steroids in patients who have chronic DME, whether it is Ozurdex (dexamethasone intravitreal implant, Allergan) or Iluvien implants,” Kiss said.
“Triamcinolone is a drug I don’t use because the data show it has side effects. Ozurdex is an excellent drug for DME and the one I use more often. Iluvien is my drug of choice for very long-term, chronic, resistant DME. It is a good option for patients with long-standing diabetic macular edema resistant to other treatments,” Loewenstein said.
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. “Basically, having both options available nowadays, I tailor the treatment to individual patients.”
Although pharmacotherapy has become first-line therapy, laser still has a role in specific cases, according to Loewenstein and Bressler.
“I still do laser therapy in patients resistant to anti-VEGFs or steroids after a number of injections, between four and six. If I see a poor response, I do a fluorescein angiography, and if I see leakage, I do focal laser therapy. I also use laser as first-line therapy in a small number of patients with very limited center-involved DME and very distinct treatable lesions,” Loewenstein said.
“I only use laser in cases of persistent center-involved edema not responding to many months of anti-VEGF monotherapy,” Bressler said.
“In terms of DME, anti-VEGF therapy is my primary choice,” Kiss said. “I would consider steroids or a combination of anti-VEGFs and laser therapy if I am not satisfied with visual acuity results or what I see on optical coherence tomography. I would be hard pressed to invest in a laser technology at this point knowing how well pharmacotherapy with anti-VEGF and steroids works.”
India proactively addresses emergency
Type 2 diabetes has assumed epidemic proportions in developing countries. Asia accounts for nearly 60% of the world’s diabetic population, and India is home to more than 62 million people with diabetes, based on the Indian Council of Medical Research-India Diabetes 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 in Chennai, India, said.
Ramachandran
Rajalakshmi
The biggest hurdle is the lack of resources and trained manpower to both screen and treat the large number of people with DR, she said. To meet such a huge challenge, models of mobile DR screening and treatment aided by the use of telemedicine are becoming popular.
Although laser photocoagulation is still the gold standard treatment for proliferative DR and DME in India, anti-VEGF agents and steroids are becoming widespread
“Anti-VEGF agents like Avastin and Lucentis and steroids like triamcinolone and Ozurdex are currently used as intravitreal injections for the treatment of persistent severe DME. However, multiple injections may be required, which is a disadvantage. Intravitreal anti-VEGF combined with laser photocoagulation is the main treatment modality for severe recalcitrant DME,” Rajalakshmi said.
Some of the disadvantages of anti-VEGFs include the cost of the medicine, the need to be administered under sterile conditions and the need for repeated injections. They are mainly used in urban areas and have 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, and 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.
Triamcinolone is a cheaper option, mainly used in pseudophakic patients.
“Training more ophthalmologists in administering intravitreal injections under aseptic conditions will be essential,” she said “In the year 2013, 15,727 patients have been screened in our tertiary care diabetes center for retinopathy, of which 7,193 (45.7%) had DR. Increasing awareness amongst people and providing early diagnosis, properly scheduled treatments and regular follow-up are mandatory to prevent progression of DR and vision loss.” – by Michela Cimberle and Nhu Te
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Is the timing of treatment in DME as crucial as in AMD?
Anti-VEGF treatment should be initiated early for maximal benefits
Diabetic macular edema, defined as a retinal thickening involving or approaching the center of the macula, is one of the most important causes of visual impairment in diabetic retinopathy. It has been calculated that if left untreated, 25% to 30% of patients affected by DME experience a 15-letter decrease in visual acuity score within 3 years.
Stanislao Rizzo
The standard of care in DME consisted of laser photocoagulation since first results of the ETDRS were published in 1985. However, laser is mostly only able to stabilize vision. To date, there is indeed a need for therapies that restore visual acuity in DME. Advances in understanding DME pathophysiology have launched the investigation of pharmacological therapies, including those targeting vascular endothelial growth factor, which is upregulated in eyes with DME and is a major mediator of increased retinal permeability. Randomized clinical trials have demonstrated the efficacy of anti-VEGF agents and showed how it is important to start therapy with an anti-VEGF as soon as possible, highlighting how the recovery of visual acuity is lower in patients who started treatment later because of irreversible changes resulting from chronic macular edema.
In this regard, the RESTORE extension study showed an improvement in visual acuity could be observed also in prior laser-treated patients, but the visual acuity gained at month 24 (5.4 letters) in this group was less than that observed in the prior ranibizumab groups (prior ranibizumab, 7.9 letters; prior ranibizumab plus laser, 6.7 letters), suggesting that some patients may have lost potential for visual acuity gains because of irreversible changes resulting from chronic macular edema. These results support early initiation of ranibizumab injections in DME patients to achieve maximum visual acuity benefits.
In conclusion, anti-VEGF therapy should be initiated early in DME treatment to achieve rapid and maximal visual acuity benefits and should be continued based on individualized treatment criteria to maintain the gained vision.
Stanislao Rizzo, MD, is the chairman of the U.O. Chirurgia Oftalmica, Azienda Ospedaliero Universitaria Pisana, Department of Ophthalmology, University Hospital, Pisa, Italy. Disclosure: Rizzo has no relevant financial disclosures.
Early DME treatment not as crucial as early AMD treatment
Macular edema due to diabetes mellitus is a common phenomenon that mainly results from a breakdown of the blood-retinal barrier and consequent extracellular accumulation of both intravascular fluid and macromolecules such as lipids and proteins. On the other hand, choroidal neovascularization due to age-related macular degeneration appears as a neovascular sprout growing underneath or even through the retinal pigment epithelium layer. As these twigs mature, they develop a more organized vascular system stemming from a trunk of feeder vessels off the choroid, as well as fibrous tissue proliferation.
Albert J. Augustin
DME and CNV are both chronic recurrent diseases. However, the management of the early stages may not be the same for a number of reasons.
In early-stage AMD, enduring irreversible anatomical changes occur in the most sensible area of both the RPE and the photoreceptors. Anti-VEGF therapy targets both leakage and vessel growth but does not antagonize the inflammatory processes and/or the neovascular tissue that is already present. Therefore, an early treatment is mandatory.
DME results from a breakdown of the blood-retinal barrier in the inner retina. A persistent macular edema carries the risk of ultrastructural alterations only over a certain period of time. Anti-VEGF therapy targets the leakage by “repairing” tight junctions, at least in a temporary fashion.
There is also robust evidence that the control of systemic risk factors is crucial to the course of DME. Strict control of systolic blood pressure, blood lipid and blood sugar levels lead to a lower incidence of edema formation. The control of serum lipid level through pharmacologic therapies can not only slow down the progression of macular edema but also lead to reduction of intraretinal exudates and microaneurysm formation. Due to the reversibility of the changes that occur in the early stages of DME, an early treatment approach may be beneficial, but it is not as crucial as in AMD.
Albert J. Augustin, MD, is the chairman of the Department of Ophthalmology, Klinikum Karlsruhe, Karlsruhe, Germany. Disclosure: Augustin has no relevant financial disclosures.