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 cross-over clinical trial Methods Twenty DME patients randomized to dexamethasone implant or VEGF-neutralizing protein had aqueous taps and spectral domain-optical coherence tomography (SD-OCT) at baseline and every 4 weeks for 28 weeks. Aqueous levels of 55 vasoactive proteins were measured with protein array. Cross-over 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 three known PPFs, angiopoietin-2 (r=0.40, p=0.001), hepatocyte growth factor (HGF, r=0.31, p=0.02), and endocrine gland-VEGF (EG-VEGF, r=0.43, p<0.001). 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 multi-factorial molecular mechanism by which dexamethasone implants reduce edema and suggest that additional study is needed to investigate the contributions of these 3 factor to chronic DME.

Repeated Dexamethasone Intravitreal Implant for the Treatment of Diabetic Macular Oedema Unresponsive to Anti-VEGF Therapy: Outcome and Predictive SD-OCT Features

“…The dexamethasone intravitreal implant 0.7 mg (DEX implant, Ozurdex®, Allergan Inc., Irvine, CA, USA), a long-acting sustained-release corticosteroid [13], has been shown to be effective in treating DME [14-17]. Upon treatment with DEX implant, pro-permeability factors were reduced in aqueous samples [18]. …”

Clinical Decision-Making when Treating Diabetic Macular Edema Patients with Dexamethasone Intravitreal Implants

“…Overall, there are many factors that possibly contribute to DME, and their specific effects may vary among patients [33], adding another level of complexity to the treatment. DME treatment should first try to obtain good metabolic control in the patient, including glycemic control, lipid profile, and blood pressure [34].…”

“…These data suggest that anti-VEGFs alone may not be sufficient to produce an adequate decrease in inflammatory response and that other pro-permeability factors in addition to VEGF may contribute to DME. In this regard, other molecules such as HGF and ANGPT2 have been proposed to play a prominent role in DME [33]. …”

“…Hence, corticosteroids exert their function by inhibiting various cytokines, chemokines, and pro-permeability factors involved in DME (IL-6, IL-8, MCP-1, ICAM-1, TNF-α, VEGF, HGF, ANGPT2, etc.) [1, 24, 32, 33] and by regulating the activity of the Müller cells, which are essential to maintain the water balance in the retina. A sustained-release dexamethasone implant has proven to be an effective and safe alternative for DME treatment [2].…”

Intravitreal Steroids in Diabetic Macular Edema

“…Ozurdex intravitreal implants can be considered as the second-line treatment for DME in eyes unresponsive to anti-VEGF therapy [31][32][33] . However, data from the MEAD and BEVORDEX clinical trials and results from the CHAMPLAIN study suggest that Ozurdex can be considered as a first-line treatment option, especially in pseudophakic and vitrectomized eyes [30,34,35] .…”