Safety and Efficacy of Dexamethasone Intravitreal Implant Given Either First-Line or Second-Line in Diabetic Macular Edema

Figures & data

Table 1 Design and Results of Clinical Studies Involving Patients Affected by Diabetic Macular Edema Who Received Dexamethasone Intravitreal Implant

Study (First Author, RCT Name, Year)	Patients	Study Design and Study Groups	Follow-Up	Results Numerical Values Refer to the End of the Study Follow-Up Unless Stated Otherwise
RCTs supporting the use of DEX in DME
Kuppermann et al (2007)^Citation9	315 ME pretreated with laser or medical therapy	Study Design: Phase 2 RCT Multicenter Double-masked Groups: 105 DEX 0.7 mg 105 DEX 0.35 mg 105 observation	6 months	BCVA improvement ≥ 15 letters 18.1% DEX 0.7 mg (p<0.05 vs observation) 14.6% DEX 0.35 mg (p=0.02 vs observation) 7.6% observation Mean change in CRT -106.7 µm DEX 0.7 mg (p=0.02 vs observation) -53.2 µm DEX 0.35 mg (p<0.001 vs observation) +20.7 µm observation
Haller et al (2010)^Citation10	171 DME pretreated with laser or medical therapy	Study Design: Phase 2 RCT Multicenter Single-masked Sham-controlled Groups: 57 DEX 0.7 mg 57 DEX 0.35 mg 57 observation	6 months	BCVA improvement ≥ 10 letters 30% DEX 0.7 mg 19% DEX 0.35 mg 23% observation (p=0.4 vs DEX groups) Mean change in CRT -132.3 µm DEX 0.7 mg (p<0.001 vs observation) -42.6 µm DEX 0.35 mg (p=0.07 vs observation) +30.2 µm observation
Boyer et al, MEAD (2014)^Citation11	1048 DME treatment naïve, or pretreated with laser or medical therapy	Study Design: Two Phase 3 RCT Multicenter Single-masked Sham-controlled Groups: 351 DEX 0.7 mg 347 DEX 0.35 mg 350 Sham	3 years	BCVA improvement ≥ 15 letters 22.2% DEX 0.7 mg 18.4% DEX 0.35 mg 12.0% Sham (p≤0.018 vs DEX groups) Mean change in CRT -111.6 µm DEX 0.7 mg -107.9 µm DEX 0.35 mg -41.9 µm Sham (p<0.001 vs DEX groups)
Callanan et al, PLACID (2013)^Citation12	253 DME pretreated with laser or medical therapy	Study Design: Phase 2 RCT Multicenter Double-masked Sham-controlled Groups: 126 DEX + laser 127 Sham + laser	12 months	BCVA improvement ≥ 10 letters 27.8% DEX + laser 23.6% Sham + laser (p=0.453) Mean change in BCVA DEX + laser > Sham + laser (p<0.001) Mean change in area of vascular leakage DEX + laser > Sham + laser (p≤0.0041)
Heng et al, OZLASE (2016)^Citation13	80 DME Treatment naïve	Study Design: RCT Single-site Groups: 40 DEX + laser 40 laser	56 weeks	BCVA improvement ≥ 10 letters 18.4% DEX + laser 20.5% laser (effect estimate 1.15) Mean change in CST -113 μm DEX + laser -17 μm laser (p<0.001)
Wei et al (2021)^Citation14	284 DME no laser treatment or anti-VEGF injections in the previous 3 months	Study Design: RCT Single-site Open-label Patients: Groups: 145 DEX 0.7 mg 127 laser	12 months	Mean change in BCVA +4.3 letters DEX +1.4 letters laser (p<0.001) Mean change in CRT -209.5 μm DEX -120.3 µm laser (p<0.001) Mean change in total leakage area -8.367 mm^2 DEX -0.637 mm^2 laser (p<0.001)
DEX implant vs anti-VEGF injections
Gillies et al, BEVORDEX (2014)^Citation15	88 DME pretreated with laser	Study Design: Phase 2 RCT Single-masked Multicenter Sham-controlled Groups: 42 BEV 1.25 mg 46 DEX 0.7 mg	12 months	Mean number of injections 8.6 BEV 2.7 DEX BCVA improvement ≥ 10 letters 40% BEV 41% DEX (p=0.83) Mean change in CMT -122 µm BEV -187 µm DEX (p=0.015)
Callanan et al (2017)^Citation16	363 DME no laser treatment or anti-VEGF injections in the previous 3 months	Study Design: Phase 2 RCT Multicenter Groups: 181 DEX 0.7 mg 182 RAN 0.5 mg	12 months	Mean number of injections 2.85 DEX 8.70 RAN Mean change in BCVA +4.34 letters DEX +7.60 letters RAN (noninferiority of DEX) Mean change in CRT -173.9 µm DEX -163.5 µm RAN (p>0.05)
Sharma et al (2020)^Citation17	40 DME no anti-VEGF injections in the previous 4 months	Study Design: RCT Groups: 20 BEV 1.25 mg or RAN 0.5 mg 20 DEX 0.7 mg	6 months	Mean number of injections 4.04 BEV/RAN 1.15 DEX BCVA improvement ≥ 10 letters 50% BEV/RAN 60% DEX Mean change in BCVA (month 3) -0.31 LogMAR BEV/RAN -0.42 LogMAR DEX (p=0.27) Mean change in CFT (month 3) -177 µm BEV/RAN -227 µm DEX (p=0.02)
Ozsaygili et al (2020)^Citation18	98 DME treatment naïve	Study Design: RCT Single-site Single-masked Groups: 48 DEX 0.7 mg 50 AFL 2.0 mg	12 months	Mean number of injections 2.6 DEX 7.2 AFL BCVA improvement ≥ 10 letters 25% DEX 42% AFL (p=0.058) Mean change in BCVA +6.4 letters DEX +9.3 letters AFL (p<0.01) Mean change in CRT -318 µm DEX -209 µm AFL (p<0.001)
Comet et al, INVICTUS (2020)^Citation19	60 DME treatment naïve	Study Design: Prospective Single-site Open-label Groups: 19 RAN 0.5 mg 20 AFL 2.0 mg 21 DEX 0.7 mg	12 months	Mean number of injections 7.1 RAN 6.9 AFL 2.6 DEX BCVA improvement ≥ 15 letters 32% RAN 33% AFL 30% DEX (p>0.05) Mean change in BCVA +7.2 letters RAN +8.5 letters AFL +9.4 letters DEX (p=0.89) Mean change in CRT -99.4 μm RAN -101.7 µm AFL -162.7 µm DEX (p=0.07)
DEX implant in DME refractory to anti-VEGF
Totan et al (2016)^Citation20	30 DME refractory to BEV	Study Design: Prospective Single-site Open-label Groups: 30 DEX 0.7 mg	6 months	Mean change in BCVA +0.03 LogMAR DEX (p=0.39) Mean change in CFT -106 µm DEX (p=0.01)
Kim et al (2016)^Citation21	35 DME refractory to BEV	Study Design: Retrospective Single-site Groups: 35 DEX 0.7 mg	6 months	BCVA improvement ≥ 10 letters 26% DEX Mean change in BCVA -0.03 LogMAR DEX (p=0.652) Mean change in CFT -69.2 µm DEX (p<0.01)
Shah et al (2016)^Citation22	50 DME refractory to anti-VEGF injections	Study Design: RCT Single-site Single-masked Groups: 23 BEV 1.25 mg 27 DEX 0.7 mg	7 months	Mean number of injections 7.0 BEV 2.7 DEX BCVA improvement ≥ 10 letters 26% BEV 33% DEX (p=0.758) Mean change in BCVA +5.6 letters BEV +5.8 letters DEX (p=0.785) Mean change in CST -13 µm BEV -122 µm DEX (p=0.001)
Thomas et al (2016)^Citation23	22 DME refractory to RAN	Study Design: Retrospective Single-site Groups: 11 DEX 0.7 mg 11 RAN 0.5 mg	3 months	Mean change in BCVA -0.153 LogMAR DEX -0.125 LogMAR RAN (p=0.624) Mean change in CMT -105.8 µm DEX -47.9 µm RAN (p=0.332)
Busch et al (2018)^Citation24	110 DME refractory to AFL, RAN or BEV	Study Design: Retrospective Multicenter Groups: 72 AFL/RAN/BEV 38 DEX	12 months	Mean change in BCVA -0.4 letters AFL/RAN/BEV +6.1 letters DEX (p=0.004) Mean change in CST +18.3 µm AFL/RAN/BEV -92.8 µm DEX (p<0.001)
Koc et al (2023)^Citation25	94 DME refractory to AFL or RAN	Study Design: Retrospective Multicenter Groups: 3AFL + 3AFL 3RAN + 3RAN 3AFL + DEX 3RAN + DEX	6 months	Mean BCVA 0.49 LogMAR 3AFL + 3AFL 0.57 LogMAR 3RAN + 3RAN 0.62 LogMAR 3AFL + DEX 0.80 LogMAR 3RAN + DEX (p=0.159) Mean CMT 291.6 µm 3AFL + 3AFL 293.1 µm 3RAN + 3RAN 320.0 µm 3AFL + DEX 332.5 µm 3RAN + DEX (p=0.295)
Maturi et al, DRCR.net prot U (2018)^Citation26	129 DME refractory to anti-VEGF injections	Study Design: Phase 2 RCT Multicenter Single-masked Sham-controlled Groups: 65 DEX 0.7 mg + RAN 0.3 mg 64 Sham + RAN 0.3 mg	24 weeks	Mean change in BCVA +2.7 letters DEX + RAN +3.0 letters RAN (p=0.73) Mean change in CST -110 µm DEX + RAN -62 µm RAN (p<0.001)
Simultaneous DEX implant and anti-VEGF injections
Kaya et al (2021)^Citation27	68 DME treatment naïve or refractory to anti-VEGF	Study Design: RCT Single-site Open-label Groups: 34 DEX 0.7 mg + RAN 0.5 mg 34 RAN 0.5 mg	24 months	BCVA improvement ≥ 15 letters 65.4% DEX + RAN 26.2% RAN (p<0.0001) Mean change in BCVA +20.2 letters DEX + RAN +9.1 letters RAN (p<0.001) Mean change in CFT -394 µm DEX + RAN -275 µm RAN (p<0.05)

Abbreviations: RCT, randomized clinical trial; ME, macular edema; DME, diabetic macular edema; DEX, dexamethasone; BCVA, best-corrected visual acuity; CRT, central retinal thickness; BEV, bevacizumab; CMT, central macular thickness; CST, central subfield thickness; RAN, ranibizumab; AFL, aflibercept; CFT, central foveal thickness.

Figure 1 Preferred Reporting Items for a Systematic Review and Meta-Analyses (PRISMA) flowchart for the article selection process.

Figure 2 Risk of bias assessment for clinical studies involving patients affected by diabetic macular edema (DME) who received dexamethasone (DEX) intravitreal implant.

Notes: D1, randomization process; D2, deviations from the intended interventions; D3, missing outcome data; D4, measurement of the outcome; D5, selection of the reported result; “+”, low risk; “!”, some concerns; “–”, high risk.

Table 2 Adverse Events of Clinical Studies Involving Patients Affected by Diabetic Macular Edema Who Received Dexamethasone Intravitreal Implant

Study (First Author, RCT Name, Year)	IOP ≥ 10 mmHg Than Baseline	IOP ≥ 25 mmHg at Any Timepoint	Cataract-Related Adverse Events
RCTs supporting the use of DEX in DME
Kuppermann et al (2007)^Citation9	17% DEX 0.7 mg 12% DEX 0.35 mg 3% observation	18% DEX 0.7 mg 15% DEX 0.35 mg 0% observation	N/A
Haller et al (2010)^Citation10	15% DEX 0.7 mg 15% DEX 0.35 mg 2% observation	13.2% DEX 0.7 mg 16.4% DEX 0.35 mg 0% observation	N/A
Boyer et al, MEAD (2014)^Citation11	27.7% DEX 0.7 mg 24.8% DEX 0.35 mg 3.7% Sham	32.0% DEX 0.7 mg 27.4% DEX 0.35 mg 4.3% Sham	67.9% DEX 0.7 mg 64.1% DEX 0.35 mg 20.4% Sham
Callanan et al, PLACID (2013)^Citation12	15% DEX + laser 9% Sham + laser	16.8% DEX + laser	22% DEX + laser 9% Sham + laser
Heng et al, OZLASE (2016)^Citation13	N/A	N/A	77.8% DEX + laser 14.8% laser
Wei et al (2021)^Citation14	33.1% DEX 1.6% laser	33.8% DEX 4.7% laser	15.2% DEX 6.2% laser
DEX implant vs anti-VEGF injections
Gillies et al, BEVORDEX (2014)^Citation15	IOP ≥ 5 mmHg 19% BEV 1.25 mg 46% DEX 0.7 mg	0% BEV 1.25 mg 26% DEX 0.7 mg	4.8% BEV 1.25 mg 13% DEX 0.7 mg
Fraser-Bell et al, BEVORDEX (2016)^Citation48	IOP ≥ 5 mmHg 48% BEV 1.25 mg 74% DEX 0.7 mg	N/A	6% BEV 1.25 mg 37% DEX 0.7 mg
Callanan et al (2017)^Citation16	34.3% DEX 3.8% RAN (p<0.001)	36.5% DEX 2.2% RAN (p<0.001)	22.2% DEX 9.5% RAN (p<0.001)
Sharma et al (2020)^Citation17	N/A	0% BEV/RAN 20% DEX (p<0.001)	0% BEV/RAN 15% DEX (p<0.001)
Ozsaygili et al (2020)^Citation18	IOP ≥ 5 mmHg 16.7% DEX 0% AFL (p=0.002)	N/A	8.3% DEX 0% AFL
Comet et al, INVICTUS (2020)^Citation19	IOP increase ≥ 10 mmHg than baseline or IOP ≥ 25 mmHg at any timepoint 0% RAN 0% AFL 19% DEX		N/A
DEX implant in DME refractory to anti-VEGF
Totan et al (2016)^Citation20	N/A	IOP ≥ 21 mmHg 13.3% DEX	N/A
Kim et al (2016)^Citation21	N/A	8.6% DEX	N/A
Shah et al (2016)^Citation22	N/A	IOP ≥ 21 mmHg 0% BEV 52% DEX (p<0.001)	17% BEV 26% DEX (p=0.515)
Thomas et al (2016)^Citation23	N/A	IOP > 30 mmHg 18.1% DEX 0% RAN	N/A
Busch et al (2018)^Citation24	N/A	N/A	11.3% AFL/RAN/BEV 26.3% RAN
Maturi et al, DRCR.net prot U (2018)^Citation26	23% DEX + RAN 0% RAN	N/A	5% DEX + RAN 0% RAN (p=0.24)
Simultaneous DEX implant and anti-VEGF injections
Kaya et al (2021)^Citation27	IOP ≥ 5 mmHg 35.3% DEX + RAN 18% RAN	N/A	35.3% DEX + RAN 29.4% RAN

Abbreviations: RCT, randomized clinical trial; DME, diabetic macular edema; DEX, dexamethasone; BEV, bevacizumab; RAN, ranibizumab; AFL, aflibercept.

Figure 3 Flowchart summarizing possible determinants in patient selection for DEX implant in DME.

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