Combined steroids, anti-VEGFs show promise in DME

Take home

For some patients with diabetic macular edema, treatment with anti-vascular endothelial growth factor agents may not be enough. Clinicians need to consider other options, including dexamethasone implants.

Dr. Maturi

By Michelle Dalton, ELS; Reviewed by Raj K. Maturi, MD

Indianapolis-Anti-vascular endothelial growth factor (VEGF) agents alone may not provide the optimal response for all patients with diabetic macular edema (DME).

This was evident with only 50% of the subjects in the Diabetic Retinopathy Clinical Research Network’s Protocol I monthly ranibizumab group achieving a 2-line improvement in visual acuity after 2 years.

Because steroids provide a different mechanism of action, combining steroids with anti-VEGFs “may be more efficacious than either treatment alone in those patients without a complete response,” said Raj K. Maturi, MD, in private practice at Midwest Eye Institute and with the Department of Ophthalmology, Indiana University School of Medicine, Indianapolis.

Protocol I also found 40% were unable to achieve macular flattening at year 2, despite the protocol-mandated monthly evaluation and treatment.

Protocol I (as well as the RISE/RIDE and RESTORE, the extension study for RISE/RIDE) “shows that if patients don’t get the required treatment over time, they will lose out. If they don’t come in consistently, they are losing out,” Dr. Maturi said. “RISE and RIDE mandated monthly ranibizumab treatment, but there was “a continued leakage on angiography at 12 and 24 months: 85% with continued leakage at month 12 and 74% with leakage at month 24.”

Optical coherence tomography (OCT) showed a continued thickening in a significant number of subjects at 12 months in both the ranibizumab arms (0.3 and 0.5 mg).

Dr. Maturi said an issue with the data is that the group “did not use a now-standardized definition of DME, which is typically more than 250 µm of central subfield thickness. What RISE/RIDE did was use center point thickness, where using 250 µm may be too liberal.

Potential role for steroid combinations

Dr. Maturi and colleagues-through a study supported by an Investigator Initiated Trial grant from Allergan-randomly assigned 40 eyes of 30 patients in a prospective, subject-masked, single-center study to evaluate the combination of dexamethasone and bevacizumab 1.25 mg (Group 1) versus bevacizumab 1.25 mg alone (Group 2).

In both groups, treatment was withheld if OCT was less than 250 µm and the acuity was better than 20/20. Both groups also received an initial bevacizumab injection.

Group 2 continued to receive monthly injections while Group 1 received dexamethasone intravitreal implant at month 1, 5, 10 and retreated with bevacizumab at other visits.

The main inclusion criteria included a best-corrected visual acuity (BCVA) score between 24 and 78 letters and the presence of DME, defined as time domain equivalent OCT >250 µm.

Subjects with two eligible eyes had one eye randomly assigned to one treatment arm and the second eye to the other treatment arm. Ninety percent of those in Group 1 (n = 21) and 95% of those in Group 2 (n = 19) had type 2 diabetes.

There were more female (n = 17) than males, and the subject group was overwhelmingly Caucasian (n = 28).

At baseline, OCT central subfield thickness was slightly greater in Group 2.

Both groups gained about 5 letters, but it’s the OCT changes that are “marked different between groups,” Dr. Maturi said.

“What we found was the edema resolution was much more complete in Group 1-volume is 10.4 mm³ vs. 11.3 mm³ in the bevacizumab-only arm,” Dr. Maturi said. “The dexamethasone intravitreal implant is most effective in the first 3 months after injection and less effective in the fourth month in reducing edema.”

Monthly additions of bevacizumab during the subsequent three months “did not seem to have much affect on the duration of response,” Dr. Maturi added.

For an example, see Figures 1 (a subject who was randomly assigned to Group 1, but her severe edema was unsuccessfully treated with anti-VEGFs and she required rescue with the dexamethasone implant).

In Figure 2, one patient with both eyes enrolled showed much better results in the combination arm than in the bevacizumab-only arm.

Dr. Maturi pointed out that the patients who had undergone the most bevacizumab injections prior to study enrollment gained the most vision when in the dexamethasone arm.

“There are some areas of caution with the use of dexamethasone (or other steroid),” Dr. Maturi said.  “Steroids can cause an increase in intraocular pressure (6 of the 20 eyes in the steroid arm needed topical treatment for pressure control), and cataract progression can occur-almost half the eyes in the steroid group had progression of cataract.

However, these are known and manageable complications that the patient and physician are generally quite aware of, Dr. Maturi noted.

“Clinicians need to know that the anti-VEGFs don’t work on everyone-about 30% will have continued edema despite 6 months or more of treatment,” Dr. Maturi said. “We need to think about other options for these patients and dexamethasone implants are an excellent choice.”

Dr. Maturi suggested these findings warrant a larger, phase III study.

Raj K. Maturi, MD

P: 317/817-1423

E: rmaturi@gmail.com

Dr. Maturi noted Allergan provided financial support for the study and had no control on the results or submission. The statistical analysis was performed by the DRCR group (Diabetic Retinopathy Clincal Research group at the JAEB Center, Tampa, FL).

Figure 1 One subject who was unsuccessfully treated with bevacizumab showed a marked improvement with the addition of dexamethasone. This patient was randomly assigned to the bevacizumab alone arm, but had to be rescued with dexamethasone implant at month 7.

Figure 2 A subject with both eyes in the study showed a much more complete resolution of edema in the left eye compared with the right. Visual acuity gain was similar. (Figures courtesy of Raj K. Maturi, MD)