Pro-permeability Factors in Diabetic Macular Edema; the Diabetic Macular Edema Treated With Ozurdex Trial

Abstract

Purpose: The Diabetic Macular Edema Treated with Ozurdex (DMEO) Trial measured aqueous pro-permeability factors (PPFs) in diabetic macular edema (DME) patients before and after injection of dexamethasone implant or vascular endothelial growth factor (VEGF)-neutralizing protein and correlated changes in levels with changes in excess foveal thickness (EFT) to identify potential PPFs contributing to DME.

Design: Prospective, randomized crossover clinical trial.

Methods: Twenty DME patients randomized to dexamethasone implant or VEGF-neutralizing protein had aqueous taps and spectral-domain optical coherence tomography (SDOCT) at baseline and every 4 weeks for 28 weeks. Aqueous levels of 55 vasoactive proteins were measured with protein array. Crossover at week 16 provided changes in protein levels after each intervention in all 20 patients.

Results: After dexamethasone implant there was significant correlation between changes in levels of 13 vasoactive proteins with changes in EFT, including 3 known PPFs: angiopoietin-2 (r = 0.40, P = .001), hepatocyte growth factor (HGF; r = 0.31, P = .02), and endocrine gland-VEGF (EG-VEGF, r = 0.43, P < .001). Reduction of prolactin, insulin-like growth factor binding protein-3, and matrix metalloproteinase-9 correlated with edema reduction after injection of a VEGF-neutralizing protein as well as dexamethasone implant, suggesting their modulation is likely secondary to changes in edema rather than causative.

Conclusions: Correlation of edema reduction with reduction in the PPFs angiopoietin-2, HGF, and EG-VEGF provides potential insight into the multifactorial molecular mechanism by which dexamethasone implants reduce edema and suggest that additional study is needed to investigate the contributions of these 3 factors to chronic DME.

Figure 1. Improvement in central subfield thickness (A) and best-corrected visual acuity (B) after injection of dexamethasone implant or anti-vascular endothelial growth factor injections in patients with diabetic macular edema

Patients were randomized to initially receive a dexamethasone implant or pro re nata (prn) anti-vascular endothelial growth factor (anti-VEGF) injections and then crossover at week 12. Mean (±standard error of the mean) change from baseline central subfield thickness (CST, A) and best-corrected visual acuity (BCVA, B) were improved after dexamethasone implant injection or during prn anti-VEGF injections.Mixed effects regression models with a random intercept for eyes to account for the correlation among the repeated measures from the same eye were used to determine whether BCVA or CST was different from baseline at each follow up visit.

Figure 2. Spectral domain-optical coherence tomography horizontal scans through the fovea at each study visit for patients with diabetic macular edema who had a good response to intraocular injection of an anti-vascular endothelial growth factor agent

Horizontal scans through the fovea at each study visit are shown for 5 patients who had a marked reduction of edema after intraocular injections of ranibizumab (RBZ) or bevacizumab (BVZ). These were the only patients in the trial who showed a good response with regard to edema reduction from anti-VEGF injections. After cross-over, these 5 patients received a dexamethasone implant (Dex) and had elimination of recurrent edema. Treatment (Dex, RBZ, BVZ, or sham injection) received at each visit is indicated in the lower right of each box. Central subfield thickness is shown in the upper left and best-corrected visual acuity in Early Treatment Diabetic Retinopathy Study letter score is shown in the upper right of each box. Blank boxes indicate a missed visit.

Figure 2. Spectral domain-optical coherence tomography horizontal scans through the fovea at each study visit for patients with diabetic macular edema who had a good response to intraocular injection of an anti-vascular endothelial growth factor agent

Horizontal scans through the fovea at each study visit are shown for 5 patients who had a marked reduction of edema after intraocular injections of ranibizumab (RBZ) or bevacizumab (BVZ). These were the only patients in the trial who showed a good response with regard to edema reduction from anti-VEGF injections. After cross-over, these 5 patients received a dexamethasone implant (Dex) and had elimination of recurrent edema. Treatment (Dex, RBZ, BVZ, or sham injection) received at each visit is indicated in the lower right of each box. Central subfield thickness is shown in the upper left and best-corrected visual acuity in Early Treatment Diabetic Retinopathy Study letter score is shown in the upper right of each box. Blank boxes indicate a missed visit.

Figure 3. Spectral domain-optical coherence tomography horizontal scans through the fovea at each study visit for representative patients with diabetic macular edema who showed substantial reduction in edema after injection of a dexamethasone implant, but little or no edema reduction from anti-vascular endothelial growth factor injections

Horizontal scans through the fovea at each study visit are shown for 5 patients (representative of the majority of patients in the trial) who showed a substantial reduction in edema after injection of a dexamethasone implant (Dex), but little or no edema reduction after ranibizumab (RBZ) or bevacizumab (BVZ). Treatment (Dex, RBZ, BVZ, or sham injection) received at each visit are indicated in the lower right of each box. Central subfield thickness is shown in the upper left and the best-corrected visual acuity in Early Treatment Diabetic Retinopathy Study letter score is shown in the upper right of each box. Blank boxes indicate a missed visit.

Figure 4. Proteins with a significant positive correlation between fold change(log2) in aqueous protein level and fold change(log2) excess foveal thickness after dexamethasone implant injection

Fold change(log2) from baseline protein level was plotted versus fold change(log2) from baseline excess foveal thickness (EFT) for each protein. The plots for 13 proteins (A, 8 proteins and B, additional 5 proteins) showed a significant positive Pearson correlation coefficient (r) after dexamethasone implant injection: 1) Insulin-like growth factor binding protein-1 (IGFBP-1), 2) Prolactin, 3) Matrix metalloproteinase-9 (MMP-9), 4) Endocrine gland-VEGF (EG-VEGF), 5) Endostatin, 6) Angiopoietin-2, 7) IGFBP-3, 8) Persephin, 9) Macrophage inhibitory protein-1α (MIP-1α), 10) Thrombospondin-2 (THSP-2), 11) Hepatocyte growth factor (HGF), 12) Interleukin-8 (IL-8), and 13) C-X-C motif ligand 16.

Figure 5. Proteins with a significant correlation between fold change(log2) in aqueous protein level and fold change(log2) excess foveal thickness during anti-vascular endothelial growth factor injections

Fold change(log2) from baseline protein level was plotted versus fold change(log2) from baseline excess foveal thickness (EFT) for each protein. The plots for 4 proteins showed a significant Pearson correlation coefficient (r) during anti-vascular endothelial growth factor injections: A) Insulin-like growth factor binding protein-3 (IGFBP-3), B) Prolactin C) Matrix metalloproteinase-9 (MMP-9) D) Vascular endothelial growth factor₁₆₅