Steroid therapy for DME: Yes or maybe?

First-line treatment for diabetic macular edema (DME) is overwhelmingly anti-vascular endothelial growth factor (VEGF) drugs, with more than two-thirds of clinicians around the world prescribing them for this patient population.

Clinicians in Africa and the Middle East lead the way with 91% of clinicians prescribing anti-VEGF drugs as the primary treatment for DME followed by the United States at 87%, Central and South America at 64%, and European clinicians at 63%.

There is also a role for treatment with steroids for patients who are refractory to anti-VEGF therapy with an increase of only a few letters of vision and those with persistent edema among others, said Anat Loewenstein, MD, MHA.

However, the disease pathogenesis-which is complex and involves both the vascular and neural components-is enhanced by increased leakage of inflammatory cytokines, explained Dr. Loewenstein, professor of ophthalmology and deputy dean of the medical school, Sackler Faculty of Medicine, Tel Aviv University, and chairman of the ophthalmology division, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

"Steroids that inhibit these cytokines theoretically and potentially have a role in the management of DME," she said.

Steroid therapy: Yes

Dr. Loewenstein recounted the case of a 63-year-old man with DME who had received six injections of bevacizumab (Avastin, Genentech) without improvement in the visual acuity. He did have a marked positive response to the dexamethasone intravitreal implant (Ozurdex, Allergan) and the visual acuity increased from 20/100 to 20/40 by 4 months after the implant.

In light of this, it is noteworthy that 40% of the patients analyzed in Protocol I by the Diabetic Retinopathy Clinical Research group had persistent edema that was refractory to ranibizumab (Lucentis, Genentech) at treatment week 24 and the DME persisted at 3 years in 16% of these patients.

"These patients pay a price in the change in the visual acuity from baseline (+5 letters versus +12 letters, respectively) and the changes for a two-line improvement in the visual acuity (43% versus 60%, respectively) are lower than in patients without persistent DME through 3 years," Dr. Loewenstein said.

Similar results were seen in a post-hoc analysis of the visual acuity and retinal thickness data from Protocol I.
Dr. Loewenstein noted that at 12 weeks, 40% of patients had less than five letters of improvement (functional non-responders) and 35% had less than a 20% improvement in the central retinal thickness (anatomic non-responders).
Among the functional non-responders, the average additional gain in visual acuity after three injections was also small over 3 years in two-thirds of these eyes.

When patients were stratified anatomically by disease duration, Dr. Loewenstein reported that edema was present in one-third of eyes at almost every evaluation. When the stratification was based on the extent of the edema, the average thickness over 250 μm in quartile 4 was greater by a mean of 129 μm and minimal in quartiles 1 and 2.
Unadjusted comparisons showed that only the greater disease duration and not the greater extent of the edema was associated with significantly worse visual acuity outcomes at week 52 (6.3 versus 11.5).

However, when adjusting for potential confounders, a strong association was seen between both the duration of the DME and the extent of the edema and the long-term visual improvement, according to Dr. Loewenstein.

The Protocol T subanalysis highlighted the effect of persistent edema at 24 weeks. In these eyes, the visual acuity outcomes were worse in the presence of persistent edema compared with eyes without persistent edema.

Steroids also might be useful in patients who do not comply with their treatment regimens. In the case of a 48-year-old man with uncontrolled diabetes, the right and left eye visual acuities were 20/60 and 20/20, respectively. This patient was unwilling to report for monthly treatments and monitoring, and he responded well to the dexamethasone intravitreal implant.

Another case is that of a 35-year-old pregnant woman with type 1 diabetes who was pseudophakic. In the second trimester, the patient reported decreased visual acuity bilaterally with a hemoglobin A1C value of 8.2. She underwent application of panretinal photocoagulation and received the dexamethasone intravitreal implant and responded well.

Steroid therapy: Maybe

Dr. Loewenstein urged cautioned for clinicians when dealing with patients who had a recent stroke or myocardial infarction. Protocol T found that cardiovascular events were rare, but they did occur. She believes that a steroid can be considered to treat these patients.

Finally, the FAME study found that eyes with chronic edema responded better to fluocinolone compared with the total cohort. The BEVORDEX trial showed that eyes with substantial intraretinal lipids treated with steroids had more and rapid regression of the lipids from the foveal center and greater decreases in lipid area.

The lens status of a patient is also important, Dr. Loewenstein noted. In patients for whom steroid therapy is definitive and for whom steroid therapy is a possibility, the effects of the steroids are even stronger in pseudophakic patients.

Disclosures:

Anat Loewenstein, MD, MHA
E: anatl@tlvmc.gov.il
This article was adapted from Retina Subspecialty Day during the 2017 meeting of the American Academy of Ophthalmology. Dr. Loewenstein serves as a consultant to Allergan, Bayer Healthcare Pharmaceuticals, Notal Vision Inc., ForSight Labs, and Novartis Pharmaceuticals Corp.