Defining the ‘ideal’ DME treatment

By Cheryl Guttman Krader

Reviewed by Baruch D. Kuppermann, MD, PhD

Irvine, CA-Despite the emergence of anti-vascular endothelial growth factor (VEGF) agents as treatment for diabetic macular edema (DME), corticosteroid and/or laser treatment is preferred for many patients.

“Injection of an anti-VEGF agent is certainly effective for treating DME in many patients, but not in all, and efficacy depends on the treatment protocol and frequency of repeat injections,” said Baruch D. Kuppermann, MD, PhD, professor of ophthalmology and biomedical engineering, and chief, Retina Service, Gavin Herbert Eye Institute, University of California, Irvine.

“Additionally, I have concerns about the treatment costs, burden, and systemic safety that I think are shared by many others,” he said. “While corticosteroids are not without side effects, they are a great option for [patients with] pseudophakia and better than anti-VEGF treatment for eyes with chronic DME. Furthermore, we should not forget about laser for focal DME where it can provide very good results for low cost and low treatment burden.”

At what cost?

Reviewing the evidence, Dr. Kuppermann noted that anti-VEGF treatment for DME carries a “huge” treatment and cost burden considering that maximizing the visual acuity improvement requires ongoing monthly injections. Whereas in the pivotal trials for exudative age-related macular degeneration, patients treated with an anti-VEGF agent achieved rapid vision gains that peaked after 3 monthly injections, in the phase III ranibizumab DME trials, visual acuity continued to improve over 2 years with ongoing monthly anti-VEGF injections.

In addition, it appears that a p.r.n. treatment approach may not be that effective for DME.

“Results from ranibizumab clinical trials show you have to be aggressive when treating DME to achieve good results,” Dr. Kuppermann said. “With ongoing monthly injections in RISE and RIDE, about 40% of [patients with] DME treated with ranibizumab 0.3 mg gained 3 or more lines of best-corrected visual acuity at 24 months. However, using a p.r.n. approach in a DRCR.net study, less than 30% of patients were three-line gainers at the end of year 2.”

Efficacy, safety

Results from 3 years of follow-up in RISE and RIDE also indicate that reduced efficacy in patients with chronic DME is another limitation of anti-VEGF therapy. Patients originally assigned to sham treatment in RISE and RIDE were crossed over to ranibizumab after 2 years years, but had only a meager response, he explained.

“In contrast, in the study of the fluocinolone acetonide intravitreal insert (Iluvien, Alimera Sciences), the patients with chronic DME were the most responsive, with 34% achieving a three-line improvement,” Dr. Kuppermann said.

Concerns about systemic safety of anti-VEGF treatment are heightened in the vasculopathic DME population. In the phase III RISE and RIDE trials that compared ranibizumab 0.3 and 0.5 mg, the higher dose was associated with more deaths without providing any efficacy advantage compared with the lower dose. Therefore, ranibizumab was approved for treatment of DME using the 0.3 mg dose.

“However, patients with bilateral disease will be getting higher doses and there is concern that these severe systemic side effects might be even greater with bevacizumab due to its longer systemic half life and the reduction in systemic VEGF levels noted with bevacizumab but not ranibizumab in the IVAN trial for wet AMD,” Dr. Kuppermann said.

Discussing alternatives, Dr. Kuppermann noted that in the DRCR protocol I study enrolling pseudophakic patients, efficacy outcomes were similar at 1 year in the group that received injections of triamcinolone every 4 months as needed compared with eyes receiving ranibizumab as often as monthly. Visual acuity results were also similar in the second year when injections for both agents were only given as needed, but more injections were given in the ranibizumab group.OT

FYI

Baruch D. Kuppermann, MD, PhD

E-mail: bdkupper@uci.edu

Dr. Kuppermann is a consultant and clinical investigator with Alimera, Allergan, Genentech, and Regeneron, manufacturers of intravitreal anti-vascular endothelial growth factor therapies (VEGF) and steroid therapies, either approved for diabetic macular edema (DME) or being investigated for DME. This article was adapted from Dr. Kuppermann’s presentation during Retina 2012 at the annual meeting of the American Academy of Ophthalmology, where he provided his perspective on whether anti-VEGF therapy is the ideal treatment for DME in an Oxford-style debate.