Dexamethasone intravitreal implant in the treatment of diabetic macular edema

Figures & data

Table 1 Key inflammatory mediators driving BRB breakdown in diabetic macular edema

Mediator	Contribution to BRB breakdown
Leukocytes	Rich content of readily releasable mediators including cytokines, chemokines, superoxide, and proteolytic enzymes that perpetuate inflammation, damage underlying EC, promote BRB breakdown, and participate in tissue remodeling Expression of Fas ligand directly encourages EC death (neutrophils)
Growth factors (VEGF, TGFβ)	Phosphorylation of tight and adherens junctional molecules, leading to breakdown of BRB (VEGF) Activation of ECs, expression of ICAM-1 and VCAM-1, and leukostasis (VEGF) Vascular remodeling via multiple pathways (TGFβ in particular)
Oxidative stress (O2^−, H2O2,ONOO^−)	Radicals cause cell damage and vasodilation, while having inherent signaling qualities, including PKC activation Increases the formation of AGE and lipid mediators Activates production of pro-inflammatory mediators (superoxide/hydrogen peroxide)
Cytokines (TNF-α, IL-1β, IL-6, HMGB1)	Stimulate the production and release of further pro-inflammatory mediators Encourage reorganization of junctional proteins, leading to BRB breakdown (IL-6), sometimes in conjunction with leukocyte recruitment (TNF, IL-1β) High local concentrations promote cell death, including ECs and pericytes (TNF, IL-1β)
Chemokines (MCP-1, IL-8, SDF-1)	Induce VEGF expression (SDF-1) Direct recruitment of cellular mediators toward the retina, from both the blood and within the tissue (MCP-1, IL-8, SDF-1) Can also directly induce EC junctional reorganization and BRB breakdown (IL-8)
Adhesion molecules (ICAM-1, VCAM-1, P-selectin)	Allow attachment of blood leukocytes to ECs, initiating leukostasis and diapedesis
AGE	Act on RAGE receptors to initiate mediator production
Protein kinases (PKC)	Phosphorylate junctional molecules to induce BRB breakdown (PKC) Induce production/release of many other mediators (PKC)
Lipid mediators and eicosanoids (LTB4, PGE1, PGE2, PLA2)	Chemotactic for leukocytes (LTB4) Promote reorganization of EC junctional proteins, leading to BRB breakdown (LTB4, PGE1) Induce vasodilation (PGE2) Promote retinal VEGF, ICAM-1, and TNF-α expression (PLA2)
MMP (MMP9)	Digests basement membrane, releasing mediators and also weakening vascular support Proteolytically activate chemokines May aid the diapedesis of leukocytes but damage pericyte layer
Hypoxia (low pO2 and high metabolite levels)	Induces production of pro-inflammatory mediators and initiates angiogenesis, both of which encourage BRB breakdown

Abbreviations: AGE, advanced glycation end-products; BRB, blood–retinal barrier; EC, endothelial cell; HMGB1, high-mobility group box-1 protein; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; LTB₄, leukotriene B₄; MCP-1, monocyte chemoattractant protein 1; MMP, metalloproteinase; PGE, prostaglandin E; PKC, protein kinase C; PLA2, phospholipase A2; pO₂, partial pressure of oxygen; RAGE, receptor for AGE; SDF-1, stromal cell-derived factor 1; TGFβ, transforming growth factor-beta; TNF, tumor necrosis factor; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor.

Table 2 Comparative efficacy and safety of dexamethasone and fluocinolone acetonide intravitreal implants in diabetic macular edema

	Ozurdex^®	Iluvien^®
Active drug	Dexamethasone	Fluocinolone acetonide
Formulation	Biodegradable implant	Non-biodegradable implant
Dose	0.7 mg	0.19 mg
Duration of action (months)	≤6	24–36
FDA approval for DME treatment	2014	2014
Phase III clinical trial in DME	MEAD^Citation82	FAME^Citation92
Trial design	rand, db, mc, sham controlleda N=1,048	rand, db, mc, sham controlledb N=956
Efficacy (% patients)
≥15-ETDRS-letter BCVA gain at 3 years	18.4c 22.2e	28.7d 27.8f
Ocular safety (% patients)
Elevated IOP	34.1c 36.0e	37.1d 45.5f
Cataract-related adverse eventsg	64.1c 67.9e	81.7d 88.7f
Incisional glaucoma surgery	0.3c 0.6e	4.8d 8.1f

Notes:

a Rescue laser not permitted; repeat treatment permitted at ≥6-month intervals.

b Rescue laser permitted after 6 weeks; repeat treatment permitted at ≥12-month intervals.

c Dexamethasone intravitreal implant 0.35 mg.

d Fluocinolone acetonide low-dose intravitreal implant (0.2 µg/day).

e Dexamethasone intravitreal implant 0.7 mg.

f Fluocinolone acetonide high-dose intravitreal implant (0.5 µg/day).

g Phakic patients.

Abbreviations: BCVA, best-corrected visual acuity; db, double-blind; DME, diabetic macular edema; ETDRS, Early Treatment Diabetic Retinopathy Study; FDA, US Food and Drug Administration; IOP, intraocular pressure; mc, multicenter; rand, randomized; FAME, Fluocinolone Acetonide for Macular Edema.

Table 3 Summary of Phase II and Phase III clinical trials of dexamethasone intravitreal implant in diabetic macular edema

Study design	Duration	Patient characteristics	Treatments	Endpoints	Results
Phase II
Randomized, single-masked, multicenter (Haller et al^Citation77)	6 months	Persistent (>3 months) macular edema after laser/pharmacotherapy; BCVA 35–67 ETDRS letters; n=171	DEX implant 0.7 mg DEX implant 0.35 mg No treatment	Percent patients with ≥10-letter improvement in BCVA CRT change from B/L Percent patients with ≥2-level improvement in macular leakage	DEX implant 0.7 mg (33%) and 0.35 mg (19%) similar to no treatment (23%) at 6 months (P= NS) DEX implant 0.7 mg (mean –132.3 µm) superior to no treatment (+30.2 µm) at 3 months (P<0.001) DEX implant 0.7 mg (36.4%) and 0.35 mg (22.2%) superior to no treatment (5.4%) at 3 months (P≤0.01)
Open-label, multicenter, noncomparative (Boyer et al^Citation80)	6 months	Treatment-resistant DME; prior pars plana vitrectomy; BCVA 24–70 ETDRS letters; CRT ≥275 µm; n=55	DEX implant 0.7 mg	BCVA change from B/L CRT change from B/L Percent patients with macular leakage	Mean +3.0 ETDRS letters at 6 months (P<0.05) Mean −38.9 µm at 6 months (P=0.004) 96.4% at B/L vs 84.0% at 6 months
Randomized, double-masked, sham-controlled, multicenter (Callanan et al^Citation81)	12 months	Diffuse macular edema; BCVA 34–70 ETDRS letters; CRT ≥275 µm; n=253	DEX implant 0.7 mg + laser therapy Sham injection + laser therapy	Percent patients with ≥10-letter improvement in BCVA BCVA change from B/L (AUC approach) CRT change from B/L Macular leakage change from B/L	DEX implant + laser superior to laser alone at 1 month and 9 months (P≤0.007) DEX implant + laser superior to laser alone over 12 months (P<0.001) DEX implant + laser similar to laser alone at 12 months (P= NS) DEX implant + laser superior to laser alone at 3–12 months (P<0.05)
Phase III
Randomized, double-masked, multicenter; pooled analysis (Boyer et al^Citation82; Danis et al ARVO^Citation83)	3 years	BCVA 34–68 ETDRS letters; CRT ≥300 µm; n=1,048	DEX implant 0.7 mg DEX implant 0.35 mg Sham injection	Percent patients with ≥15-letter improvement in BCVA CRT: mean AUC change from B/L	DEX implant 0.7 mg (22.2%) and 0.35 mg (18.4%) superior to sham (12.0%) at 3 years (P≤0.018) DEX implant 0.7 mg (−111.6 µm) and 0.35 mg (−107.9 µm) superior to sham (−41.9 µm) at 3 years (P≤0.001)

Abbreviations: ARVO, Association for Research in Vision and Ophthalmology; AUC, area under curve; B/L, baseline; BCVA, best-corrected visual acuity; CRT, central retinal thickness; DEX implant, dexamethasone intravitreal implant; DME, diabetic macular edema; ETDRS, Early Treatment Diabetic Retinopathy Study; NS, nonsignificant.

Figure 1 A 64-year-old male diagnosed with diabetic macular edema in the right eye.

Notes: Color and red-free fundus photographs of the RE indicate thickening of the fovea, as well as intraretinal small hemorrhages and microaneurysms (A and B). After ten monthly bevacizumab injections, optical coherence tomography indicates marked macular thickening, while fluorescein angiography fails to identify any treatable lesions (C and D). Intravitreal injection of dexamethasone implant reduces central macular thickness from a baseline (post-bevacizumab) level of 412 µm (BCVA 6/12) (E) to 286 µm (BCVA 6/10) at 6 weeks (F), 285 µm (BCVA 6/12) at 12 weeks (G), and 309 µm (BCVA 6/15) at 18 weeks postinjection (H). Images courtesy of Dr A Loewenstein.
Abbreviation: BCVA, best-corrected visual acuity.

Figure 2 A 62-year-old patient with cystoid macular edema in the left eye previously treated with three monthly injections of intravitreal bevacizumab.

Notes: Early- and late-phase fluorescein angiograms indicate diffuse leakage temporal to the fovea, and distortion of the foveal avascular zone with some non-perfusion (A and B). Optical coherence tomography images indicate a decrease in central macular thickness from a baseline (post-bevacizumab) level of 475 µm (C) to 235 µm at 3 months after dexamethasone implant injection (D), with improvement in BCVA from 20/60 to 20/40 over this period. Images courtesy of Dr A Loewenstein.
Abbreviation: BCVA, best-corrected visual acuity.

Table 4 Most frequently reported adverse events in Phase III studies of dexamethasone intravitreal implant in the treatment of diabetic macular edema

Adverse event	Incidence (% patients)
	DEX implant 0.35 mg	DEX implant 0.7 mg	Sham control
Cataract relateda	64.1	67.9	20.4
IOP elevationb	27.4	32.0	4.3
Conjunctival hemorrhage	25.9	21.0	12.9
Vitreous hemorrhage	13.1	6.9	7.1
Macular fibrosis	10.8	5.8	2.9
Conjunctival hyperemia	8.7	5.8	5.4
Vitreous detachment	6.7	4.9	2.3
Retinal hemorrhage	5.8	4.0	4.3
Dry eye	5.5	6.1	2.6
Conjunctival edema	5.0	4.3	1.1
Conjunctivitis	4.4	5.5	2.3

Notes:

a Cataract, cataract cortical, cataract subcapsular, cataract nuclear, or lenticular opacities.

b IOP ≥25 mmHg. Data from Boyer et al.⁸²

Abbreviations: DEX implant, dexamethasone intravitreal implant; IOP, intraocular pressure.

Figure 3 A 72-year-old patient with diabetic macular edema in the right eye previously treated with three monthly injections of intravitreal bevacizumab.

Notes: Color and red-free fundus photographs (A and B) and fluorescein angiograms (C and D) of the right eye show multiple microaneurysms, as well as leakage primarily in the temporal fovea, with accumulation in a cystoid pattern. Optical coherence tomography images indicate a central macular thickness of 525 µm on presentation (E), which transiently decreases to 269 µm at 1 month after dexamethsone implant injection (F) before returning to pretreatment levels (534 µm) at 3 months postinjection (G). Images courtesy of Dr A Loewenstein.

Figure 4 A 65-year-old female with regressed proliferative diabetic retinopathy in the right eye previously treated with three monthly injections of intravitreal bevacizumab.

Notes: Early- and late-phase fluorescein angiograms reveal significant leakage, with accumulation in a cystoid pattern, and multiple-scatter scars (A and B). Optical coherence tomography images indicate a decrease in central macular thickness from a baseline (post-bevacizumab) level of 846 µm (BCVA 6/30) (C) to a trough of 209 µm (BCVA 6/15) at 11 weeks after the first dexamethasone implant injection (D), with reversal of effect occurring by week 20 (CMT 752 µm; BCVA 6/15) (E). Consistent, marked reductions in central macular thickness to trough levels of 222 µm (BCVA 6/12), 209 µm (BCVA 6/30), and 235 µm (BCVA 6/15) were recorded 9–12 weeks after the second, third, and fourth dexamethasone implant injections, respectively (F–H). Images courtesy of Dr A Loewenstein.
Abbreviation: BCVA, best-corrected visual acuity.

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