New Paradigm in DME Treatment
RPS Presenters Identify More Effective Approaches.
■ Three presentations at this year's Retinal Physician Symposium highlighted recent advances in therapies for diabetic macular edema (DME). The presentations point to an emerging new paradigm in the treatment of DME, with the traditional first-line therapy, focal laser coagulation, now often being supplemented with intravitreal steroid injections and anti-VEGF drugs. In addition, ongoing studies are identifying potential new therapies and more effective approaches to treating the disease.
"Diabetic macular edema is a very complicated condition that often is nonresponsive to conventional therapies and can recur," said Diana Do, MD, in her presentation. "Therefore, it may be helpful to develop an algorithm approach, a step-by-step procedure for the evaluation of patients with diabetic macular edema."
Dr. Do suggested the following 6 steps:
► optimize metabolic control
► perform a complete ocular evaluation with appropriate imaging studies
► rule out other causes of treatable edema
► consider treatment with ETDRS laser
► follow the patient carefully to monitor response to treatment
► retreat with laser or consider other options.
Dr. Do emphasized the importance of metabolic control, noting that the vast majority of DME patients in her practice who did not respond to 2 or more laser treatments had an elevation in the hemoglobin A1C to above 7.5%. She said that the combination of strict medical therapy and laser treatment has proved effective in patients who initially presented with elevated hemoglobin A1C.
In regard to imaging, Dr. Do advocated the use of both fluorescien angiography (FA) and optical coherence tomography (OCT). She said FA is useful for identifying microaneurysms, capillary nonperfusion and severe macular ischemia, while OCT is a complementary tool that can help in monitoring response to therapy and in evaluating other treatable causes of macular edema, such as epiretinal membrane or vitreomacular traction.
Dr. Do presented the case for laser as first-line treatment, noting that, despite its limitations, laser "is the only proven treatment for diabetic macular edema. It decreases retinal thickening and reduces the rate of moderate vision loss." She also noted that there are no systemic side effects after laser photocoagulation.
Dr. Do said 2 alternative DME therapies currently available are intravitreal steroids and anti-VEGF drugs. She said steroids have shown some efficacy in retrospective anecdotal case reports but increase the risk of cataract progression and glaucoma. She noted that anti-VEGF therapies "make sense" as an effective treatment for DME because patients in the proliferative stage show increased levels of VEGF in affected eyes. She pointed to a 20-patient study at Johns Hopkins led by Quan Dong Nguyen, MD, and Peter Campochiaro, MD, in which ranibizumab injections over 7 months reduced retinal thickness and produced an average increase of 12.3 letters in visual acuity.
Dr. Do said more clinical studies using anti-VEGF agents and intravitreal steroids for the treatment of DME are needed. She also sees the potential for an increased role for combination therapies over the next few years.
In another presentation, David Boyer, MD, reviewed studies demonstrating the effectiveness — and limitations — of laser treatment and medical metabolic control for DME. He said that vitrectomy can be an effective treatment in advanced cases, though it carries increased risk of retinal detachment, cataract, vitreous hemorrhage, and glaucoma.
Dr. Boyer also reviewed preliminary data on the use of intravitreal steroids, steroid implants, and anti-VEGF drugs for the treatment of DME. He cited the impressive results achieved by Drs. Nguyen and Campochiaro in their 20-patient ranibizumab study.
Dr. Boyer then turned to more experimental therapies, one aimed at inhibiting advanced glycosylation end products (AGE), another targeting inhibition of growth-hormone release, and another whose goal is to reduce protein kinases. All 3 of these experimental therapies target factors that researchers see as contributing to neovascularization. In the area of potentially emerging therapies, Dr. Boyer pointed to Eli Lilly's investigational oral drug ruboxistaurin and the Novartis drug somatistatin, which is approved for acromegly, as 2 therapies that have demonstrated some level of effectiveness against DME in clinical trials.
In a third presentation on DME, Harry Flynn, MD, reviewed a list of current and planned clinical trials with the potential to have the greatest impact on how DME is treated in the future.
He first mentioned 2 recently completed studies. One looked at variations in OCT measurements and visual acuity among patients at specific times of the day. The differences were not statistically significant. A second study found only a weak correlation between macular thickness and VA.
In a pilot study of 263 patients that Dr. Flynn characterized as important, researchers compared laser treatment of all microaneurysms in areas of thickness to a grid-pattern laser treatment in areas demonstrated to be leaking.
"At 12 months after treatment, the modified macular grid technique was less effective at reducing OCT-measured thickening," reported Dr. Flynn. "However, VA changes were not substantially different."
As far as upcoming trial results, Dr. Flynn cited a current study of 1 mg and 4 mg intravitreal triamcinolone vs laser therapy.
"We're (soon) going to have 1-year data available," he noted. "It's going to be very interesting and exciting data because these are objective, randomized, prospective data with OCT and ETDRS vision that will evaluate it."
Another study currently enrolling will measure the effectiveness of vitrectomy for DME.
"This will really give us some objective data on how well these eyes do in terms of everything — progression of cataract, visual acuity, OCT measurement.
Other current studies mentioned by Dr. Flynn include one using peribulbar triamcinolone for DME, another involving patients with both proliferative diabetic retinopathy and clinically significant macular edema, and a phase 2 study using bevacizumab (Avastin) to treat DME. Impressive preliminary results from the bevacizumab study have encouraged researchers to proceed with a phase 3 study using ranibizumab.
Finally, Dr. Flynn noted that Eli Lilly would probably not proceed with ruboxistaurin in the United States after the FDA requested a second phase 3 trial. He said there was a possibility that international rights to the drug could be sold or licensed to a European company. RP