Lindstrom's PerspectivePublication Exclusive

DME treatment plan should be customized for each patient

It is estimated that 8.3% of the U.S. population has diabetes, or about 26 million people. For these patients, diabetic macular edema is the most common cause of visual loss and can occur in association with both nonproliferative and proliferative diabetic retinopathy.

While the numbers vary from one source to another, by 10 years after diagnosis, at least 10% of patients with diabetes will manifest clinically significant DME, resulting in visual acuity of less than 20/40. Many more, as high as 30% in some sources, may manifest some edema on OCT or fluorescein angiography. We must always remember that careful glucose control, treatment of hypertension, cessation of smoking and reduction of obesity are important baseline treatments that can be reinforced by the ophthalmologist for all patients with diabetes.

The classic ocular treatment for DME, going back to the 1985 Early Treatment Diabetic Retinopathy Study, was focal or grid photocoagulation. In 2012, Lucentis (ranibizumab, Genentech) achieved FDA approval for the treatment of DME, and in 2014, Eylea (aflibercept, Regeneron) was approved for this indication. We also have Triesence (triamcinolone acetonide injectable suspension, Alcon), Ozurdex (dexamethasone intravitreal implant 0.7 mg, Allergan) and Iluvien (fluocinolone acetonide intravitreal implant, Alimera Sciences) as alternatives for intravitreal steroid delivery, and some studies have suggested a benefit from topical steroid and NSAID drops as well. Finally, some patients benefit from vitrectomy and epiretinal membrane or internal limiting membrane removal. Of course, these various therapies can be combined or utilized in sequence.

Most patients with DME are treated by retina specialists in collaboration with comprehensive ophthalmologists, optometrists and primary care physicians. Of note and worth repeating is the fact that most surveys confirm that less than 50% of patients with diabetes undergo the recommended annual dilated fundus examination by a skilled examiner. We must do better here because early treatment before significant vision loss drives the patient in for an examination is preferred and offers a better prognosis.

The ever-increasing alphabet of well-designed clinical trials in the retina literature now includes the DRCR.net Protocol T study, discussed in this issue’s cover story. The study, while not without criticism, supports Eylea as being more effective than Avastin (bevacizumab, Genentech) or Lucentis for improving vision in the patient with DME when the patient presents with a visual acuity of less than 20/50. In these patients with poorer vision, Avastin and Lucentis were equivalent in efficacy. For patients with DME who present with vision better than 20/40, Avastin, Lucentis and Eylea were equally effective.

All of the agents reduced DME as measured by OCT, but interesting to me was the fact that many patients had persistent DME despite monthly injection therapy for a year and significant visual improvement. In addition, it must be noted that the study data are only to 1 year, and most patients with DME will live with their diabetes and DME for decades.

In the increasingly complex modern world of medical care, it is necessary to look at cost and quality of life issues, as well as safety and efficacy. The cost-benefit analysis clearly favors Avastin over Lucentis or Eylea and Lucentis over Eylea, but superior efficacy in the face of equal safety comes first and should, in my opinion, trump cost. We physicians are constantly challenged to consider who is responsible for the cost and how our treatments will be compensated. While it is important to consider the total cost to society, for most physicians, including me, the classical doctor-patient relationship leads one to primarily represent the best interests of each patient one at a time.

In regard to quality of life (and cost as well), less frequent injections are preferable to more frequent injections. There is some evidence accumulating that Eylea may also require fewer injections, at least in the patient with exudative age-related macular degeneration. So, if it were me, my family or my patient, and insurance coverage were good to excellent and affordability high, I would prefer Eylea in the patient with DME when visual acuity is less than 20/50. I would also prefer Eylea in DME even with better than 20/40 vision if further studies confirm that it requires less frequent injections using a treat-and-extend approach. On the other hand, if I have a patient with a high deductible insurance plan that will simply not pay for Eylea, Avastin is clearly far superior to no treatment. The indications for Lucentis are less clear, as it is far more expensive than Avastin but demonstrated similar efficacy, safety and frequency of injections.

To be sure, one study, such as the DRCR.net Protocol T, cannot stand alone and must be considered in the context of many other clinical trials and each physician’s personal experience. Combination therapies with the addition of steroids, laser and surgery are also indicated in many cases. In addition, every patient deserves a plan customized to his own eye condition, life expectancy, personal financial status and lifestyle. It is clear to me that we still have much to learn, and it amazes me how fast our treatment options are expanding. As the complexity in the arena of intraocular injection of medications for retinal disease increases, I find myself ever more dependent on the advice of a well-trained and broadly experienced retina specialist.

It is hard for me to imagine how retina specialists will be able to keep up with the demand of delivering these drugs as the incidence and prevalence of disease grow with the aging population and indications for treatment expand. Decision making is becoming ever more complex, and I do not see how we can replace the experienced retina specialist’s clinical judgment as to how and when to treat. However, I am not as certain that specialists must personally provide all the treatments. Some form of telemedicine and use of care extenders to perform the injections will surely be required to bring the highest possible quality of care to our diverse and often rural population. Innovation is needed not only in our drug and device development, but also in the methods of their delivery.

It is estimated that 8.3% of the U.S. population has diabetes, or about 26 million people. For these patients, diabetic macular edema is the most common cause of visual loss and can occur in association with both nonproliferative and proliferative diabetic retinopathy.

While the numbers vary from one source to another, by 10 years after diagnosis, at least 10% of patients with diabetes will manifest clinically significant DME, resulting in visual acuity of less than 20/40. Many more, as high as 30% in some sources, may manifest some edema on OCT or fluorescein angiography. We must always remember that careful glucose control, treatment of hypertension, cessation of smoking and reduction of obesity are important baseline treatments that can be reinforced by the ophthalmologist for all patients with diabetes.

The classic ocular treatment for DME, going back to the 1985 Early Treatment Diabetic Retinopathy Study, was focal or grid photocoagulation. In 2012, Lucentis (ranibizumab, Genentech) achieved FDA approval for the treatment of DME, and in 2014, Eylea (aflibercept, Regeneron) was approved for this indication. We also have Triesence (triamcinolone acetonide injectable suspension, Alcon), Ozurdex (dexamethasone intravitreal implant 0.7 mg, Allergan) and Iluvien (fluocinolone acetonide intravitreal implant, Alimera Sciences) as alternatives for intravitreal steroid delivery, and some studies have suggested a benefit from topical steroid and NSAID drops as well. Finally, some patients benefit from vitrectomy and epiretinal membrane or internal limiting membrane removal. Of course, these various therapies can be combined or utilized in sequence.

Most patients with DME are treated by retina specialists in collaboration with comprehensive ophthalmologists, optometrists and primary care physicians. Of note and worth repeating is the fact that most surveys confirm that less than 50% of patients with diabetes undergo the recommended annual dilated fundus examination by a skilled examiner. We must do better here because early treatment before significant vision loss drives the patient in for an examination is preferred and offers a better prognosis.

The ever-increasing alphabet of well-designed clinical trials in the retina literature now includes the DRCR.net Protocol T study, discussed in this issue’s cover story. The study, while not without criticism, supports Eylea as being more effective than Avastin (bevacizumab, Genentech) or Lucentis for improving vision in the patient with DME when the patient presents with a visual acuity of less than 20/50. In these patients with poorer vision, Avastin and Lucentis were equivalent in efficacy. For patients with DME who present with vision better than 20/40, Avastin, Lucentis and Eylea were equally effective.

All of the agents reduced DME as measured by OCT, but interesting to me was the fact that many patients had persistent DME despite monthly injection therapy for a year and significant visual improvement. In addition, it must be noted that the study data are only to 1 year, and most patients with DME will live with their diabetes and DME for decades.

In the increasingly complex modern world of medical care, it is necessary to look at cost and quality of life issues, as well as safety and efficacy. The cost-benefit analysis clearly favors Avastin over Lucentis or Eylea and Lucentis over Eylea, but superior efficacy in the face of equal safety comes first and should, in my opinion, trump cost. We physicians are constantly challenged to consider who is responsible for the cost and how our treatments will be compensated. While it is important to consider the total cost to society, for most physicians, including me, the classical doctor-patient relationship leads one to primarily represent the best interests of each patient one at a time.

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In regard to quality of life (and cost as well), less frequent injections are preferable to more frequent injections. There is some evidence accumulating that Eylea may also require fewer injections, at least in the patient with exudative age-related macular degeneration. So, if it were me, my family or my patient, and insurance coverage were good to excellent and affordability high, I would prefer Eylea in the patient with DME when visual acuity is less than 20/50. I would also prefer Eylea in DME even with better than 20/40 vision if further studies confirm that it requires less frequent injections using a treat-and-extend approach. On the other hand, if I have a patient with a high deductible insurance plan that will simply not pay for Eylea, Avastin is clearly far superior to no treatment. The indications for Lucentis are less clear, as it is far more expensive than Avastin but demonstrated similar efficacy, safety and frequency of injections.

To be sure, one study, such as the DRCR.net Protocol T, cannot stand alone and must be considered in the context of many other clinical trials and each physician’s personal experience. Combination therapies with the addition of steroids, laser and surgery are also indicated in many cases. In addition, every patient deserves a plan customized to his own eye condition, life expectancy, personal financial status and lifestyle. It is clear to me that we still have much to learn, and it amazes me how fast our treatment options are expanding. As the complexity in the arena of intraocular injection of medications for retinal disease increases, I find myself ever more dependent on the advice of a well-trained and broadly experienced retina specialist.

It is hard for me to imagine how retina specialists will be able to keep up with the demand of delivering these drugs as the incidence and prevalence of disease grow with the aging population and indications for treatment expand. Decision making is becoming ever more complex, and I do not see how we can replace the experienced retina specialist’s clinical judgment as to how and when to treat. However, I am not as certain that specialists must personally provide all the treatments. Some form of telemedicine and use of care extenders to perform the injections will surely be required to bring the highest possible quality of care to our diverse and often rural population. Innovation is needed not only in our drug and device development, but also in the methods of their delivery.