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Diabetic Macular Edema

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Last updated: April 15th, 2022

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Summary of Evidence

Treatment of Macular Edema

Observation

 

Among eyes with CI-DME and good visual acuity (6/7.5 or better), observation without treatment (unless VA worsens) may be considered.(Protocol V, 2019).{Baker CW, Glassman AR, Beaulieu WT, Antoszyk AN, Browning DJ, Chalam KV, Grover S, Jampol LM, Jhaveri CD, Melia M, Stockdale CR, Martin DF, Sun JK; DRCR Retina Network. Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity: A Randomized Clinical Trial. JAMA. 2019 May 21;321(19):1880-1894.}

 

Intravitreal Anti-VEGF injections

 

Ranibizumab vs sham

 

Ranibizumab rapidly and sustainably improved vision and reduced risk of further vision loss in patients with DME, with low rates of ocular and non-ocular harm.(RISE/RIDE, 2013). {Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, Gibson A, Sy J, Rundle AC, Hopkins JJ, Rubio RG, Ehrlich JS; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012 Apr;119(4):789-801.},{Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, Schlottmann PG, Rundle AC, Zhang J, Rubio RG, Adamis AP, Ehrlich JS, Hopkins JJ; RIDE and RISE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013 Oct;120(10):2013-22.}

 

Ranibizumab vs laser 

 

Initial ranibizumab therapy for centre-involving DME has likely better long-term vision improvement than laser or IVTA+ laser followed by deferred ranibizumab.(Protocol I, 2016). {Bressler SB, Glassman AR, Almukhtar T, Bressler NM, Ferris FL, Googe JM Jr, Gupta SK, Jampol LM, Melia M, Wells JA 3rd; Diabetic Retinopathy Clinical Research Network. Five-Year Outcomes of Ranibizumab With Prompt or Deferred Laser Versus Laser or Triamcinolone Plus Deferred Ranibizumab for Diabetic Macular Edema. Am J Ophthalmol. 2016 Apr;164:57-68.}

 

Ranibizumab vs Aflibercept vs Bevacizumab

 

At 2 years, VA outcomes were similar for eyes with baseline VA 20/32-20/40 (6/9.5 – 6/12). In those with worse VA, VA outcomes were superior in Aflibercept vs bevacizumab. Higher APTC event rates with ranibizumab over 2 years was noted. (Protocol T, 2016). {Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, Brucker AJ, Ferris FL, Hampton GR, Jhaveri C, Melia M, Beck RW; Diabetic Retinopathy Clinical Research Network. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial. Ophthalmology. 2016 Jun;123(6):1351-9.}

 

Intravitreal triamcinolone

 

At 3 years, there was no long-term benefit of IVTA over focal/grid laser. More eyes receiving 4mg IVTA were likely to require cataract surgery.(Protocol B, 2009). {Diabetic Retinopathy Clinical Research Network (DRCR.net), Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris F, Glassman AR, Hartnett E, Ip MS, Kim JE, Kollman C. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009 Mar;127(3):245-51.}

 

Dexamethasone implant

 

The DEX implant provided superior VA improvement compared to sham at 3 years.(MEAD, 2014). {Boyer DS, Yoon YH, Belfort R Jr, Bandello F, Maturi RK, Augustin AJ, Li XY, Cui H, Hashad Y, Whitcup SM; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014 Oct;121(10):1904-14.}

Evidence

1. Background

Review

2017 Tan et.al.

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2017
Review

Review of Diabetic Macular Edema: pathophsyiology, imaging, treatment, emerging therapeutic strategies.{Tan GS, Cheung N, Simó R, Cheung GC, Wong TY. Diabetic macular oedema. Lancet Diabetes Endocrinol. 2017 Feb;5(2):143-155.}

Tan et.al.
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1.1 Classification

Consensus statement

2003 Wilkinson et.al.

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2003
Consensus statement

A five-stage disease severity classification for diabetic retinopathy includes three stages of low risk, a fourth stage of severe nonproliferative retinopathy, and a fifth stage of proliferative retinopathy. Diabetic macular edema is classified as apparently present or apparently absent.{Wilkinson CP, Ferris FL 3rd, Klein RE, Lee PP, Agardh CD, Davis M, Dills D, Kampik A, Pararajasegaram R, Verdaguer JT; Global Diabetic Retinopathy Project Group. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology. 2003 Sep;110(9):1677-82.}

Wilkinson et.al.
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1.2 Principles of management

Consensus statement

2017 Schmidt-Erfurth et.al.

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2017
Consensus statement

Anti-vascular endothelial growth factor therapy has emerged as first-line therapy for diabetic macular edema (DME). Steroids have maintained a role in the management of chronically persistent DME. Laser photocoagulation is no longer recommended for the treatment of DME.{Schmidt-Erfurth U, Garcia-Arumi J, Bandello F, Berg K, Chakravarthy U, Gerendas BS, Jonas J, Larsen M, Tadayoni R, Loewenstein A. Guidelines for the Management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA). Ophthalmologica. 2017;237(4):185-222.}

Schmidt-Erfurth et.al.
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2. Observation

Clinical Trial

2019 Baker et.al. (DRCR.net Protocol V)

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2019
Clinical Trial

Among eyes with CI-DME and good visual acuity (6/7.5 or better), observation without treatment (unless VA worsens) may be considered.{Baker CW, Glassman AR, Beaulieu WT, Antoszyk AN, Browning DJ, Chalam KV, Grover S, Jampol LM, Jhaveri CD, Melia M, Stockdale CR, Martin DF, Sun JK; DRCR Retina Network. Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity: A Randomized Clinical Trial. JAMA. 2019 May 21;321(19):1880-1894.}

  • Randomized controlled trial of Aflibercept vs focal/grid laser vs observation in DME (702 patients)
  • Findings (2-years):
    • There was no significant difference in vision loss at 2 years between initial management with aflibercept or with focal/grid laser or observation and given aflibercept only if visual acuity worsened.
Outcome Aflibercept Laser Observation
Proportion of eyes with at least 5-letter VA decrease 16% 17% 19%

Baker et.al. (DRCR.net Protocol V)
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3. Anti-VEGF intravitreal injection

3.1 Ranibizumab (Lucentis)

3.1.1 Ranibizumab vs sham

Clinical Trial

2013 Nguyen et.al. (RISE and RIDE: 2 year data)

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2013
Clinical Trial

Ranibizumab rapidly and sustainably improved vision and reduced risk of further vision loss in patients with DME, with low rates of ocular and non-ocular harm.{Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, Gibson A, Sy J, Rundle AC, Hopkins JJ, Rubio RG, Ehrlich JS; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012 Apr;119(4):789-801.},{Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, Schlottmann PG, Rundle AC, Zhang J, Rubio RG, Adamis AP, Ehrlich JS, Hopkins JJ; RIDE and RISE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013 Oct;120(10):2013-22.}

  • Randomized controlled trial of Ranibizumab 0.5mg vs Ranibizumab 0.3mg vs sham intravitreal injections in DME (377/382 patients)
  • Findings (2- and 3-years):
Outcome Groups Sham RAN 0.3mg RAN 0.5mg
Gain of ≥15 letters (Proportion) at 2 years RISE 18.1% 44.8% 39.2%
RIDE 12.3% 33.6% 45.7%
Gain of ≥15 letters (Proportion) at 3 years RISE 19.2% 36.8% 40.2%
RIDE 22.0% 51.2% 41.6%

Nguyen et.al. (RISE and RIDE: 2 year data)
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Nguyen et.al. (RISE and RIDE: 3 year data)

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Nguyen et.al. (RISE and RIDE: 3 year data)
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3.1.2 Ranibizumab vs laser

Clinical Trial

2016 Bressler et.al. (DRCR.net Protocol I)

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2016
Clinical Trial

Initial ranibizumab therapy for centre-involving DME has likely better long-term vision improvement than laser or IVTA+ laser followed by deferred ranibizumab.{Bressler SB, Glassman AR, Almukhtar T, Bressler NM, Ferris FL, Googe JM Jr, Gupta SK, Jampol LM, Melia M, Wells JA 3rd; Diabetic Retinopathy Clinical Research Network. Five-Year Outcomes of Ranibizumab With Prompt or Deferred Laser Versus Laser or Triamcinolone Plus Deferred Ranibizumab for Diabetic Macular Edema. Am J Ophthalmol. 2016 Apr;164:57-68.}

  • Randomized controlled trial of prompt laser vs Ranibizumab + prompt laser vs Ranibizumab + deferred laser vs Triamcinolone + laser/very deferred ranibizumab in DME (828 patients)
  • Findings (5-years):
    • Initial ranibizumab therapy for centre-involving DME has likely better long-term vision improvement than laser alone or IVTA+laser followed by deferred ranibizumab.
Prompt laser + deferred RAN RAN + prompt laser RAN + deferred laser IVTA + laser/deferred RAN
VA letter score gain from baseline 5 8 10* 7

Bressler et.al. (DRCR.net Protocol I)
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Clinical Trial

2014 Mitchell et.al. (RESTORE: 1 year data)

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2014
Clinical Trial

Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with DME.{Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, Sutter F, Simader C, Burian G, Gerstner O, Weichselberger A; RESTORE study group. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011 Apr;118(4):615-25.} , {Schmidt-Erfurth U, Lang GE, Holz FG, Schlingemann RO, Lanzetta P, Massin P, Gerstner O, Bouazza AS, Shen H, Osborne A, Mitchell P; RESTORE Extension Study Group. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. Ophthalmology. 2014 May;121(5):1045-53.}

  • Randomized controlled trial of Ranibizumab vs Ranibizumab + laser vs laser in DME (345 patients)
  • Findings (1-year)
Outcomes RAN RAN + laser Laser
Mean BCVA letter score change at 12 months +6.1 +5.9 +0.8
Proportion with BCVA ≥ 20/40 53% 44.9% 23.6%

Mitchell et.al. (RESTORE: 1 year data)
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Schmidt-Erfurth et.al. (RESTORE: 3 year data)

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Schmidt-Erfurth et.al. (RESTORE: 3 year data)
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3.1.3 Ranibizumab vs Aflibercept vs Bevacizumab

Clinical Trial

2016 Wells et.al. (DRCR.net Protocol T)

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2016
Clinical Trial

At 2 years, VA outcomes were similar for eyes with baseline VA 20/32-20/40 (6/9.5 – 6/12). In those with worse VA, VA outcomes were superior in Aflibercept vs bevacizumab. Higher APTC event rates with ranibizumab over 2 years was noted. {Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, Brucker AJ, Ferris FL, Hampton GR, Jhaveri C, Melia M, Beck RW; Diabetic Retinopathy Clinical Research Network. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial. Ophthalmology. 2016 Jun;123(6):1351-9.}

  • Randomized controlled trial of Aflibercept Aflibercept vs Bevacizumab vs Ranibizumab in DME (660 patients)
  • Findings (2-years):
    • VA outcomes were similar among treatment groups for eyes with baseline VA 20/32-20/40
    • Among eyes with worse baseline VA, aflibercept had superior 2-year VA outcomes vs bevacizumab. Superiority of aflibercept over ranibizumab noted at 1 year was not identified at 2 years.
Outcomes Groups Aflibercept Bevacizumab Ranibizumab
VA letter score gain Overall 12.8 10.0 12.3
Worse baseline VA (20/50-20/32) 18.3 13.3 16.1
Better baseline VA (20/32-20/40) 7.8 6.8 8.6

Wells et.al. (DRCR.net Protocol T)
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3.2 Aflibercept (Eylea)

3.2.1 Aflibercept vs sham

Clinical Trial

2012 Do et.al. (DA VINCI)

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2012
Clinical Trial

VEGF Trap-Eye resulted in significant visual gain at 1 year.{Do DV, Nguyen QD, Boyer D, Schmidt-Erfurth U, Brown DM, Vitti R, Berliner AJ, Gao B, Zeitz O, Ruckert R, Schmelter T, Sandbrink R, Heier JS; da Vinci Study Group. One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology. 2012 Aug;119(8):1658-65.}

  • Randomized controlled trial of Aflibercept vs laser in DME (221 patients)
  • Findings (1-year):
Outcomes AFLI 0.5q4 AFLI 2q4 AFLI 2q8 AFLI 2PRN Laser
Mean BCVA change (letters) at 1 year +11.0 +13.1 +9.7 +12.0 -1.3
BCVA gain ≥ 15 letters (Proportion of patients) 40.9% 45.5% 23.8% 42.2% 11.4%

Do et.al. (DA VINCI)
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3.2.2 Aflibercept vs laser

Clinical Trial

2016 Brown et.al. (VISTA and VIVID: 2 year data)

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2016
Clinical Trial

IAI was superior to laser at 148 weeks, with similar efficacy in the 2q4 and 2q8 dosing groups.{Brown DM, Schmidt-Erfurth U, Do DV, Holz FG, Boyer DS, Midena E, Heier JS, Terasaki H, Kaiser PK, Marcus DM, Nguyen QD, Jaffe GJ, Slakter JS, Simader C, Soo Y, Schmelter T, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Zeitz O, Metzig C, Korobelnik JF. Intravitreal Aflibercept for Diabetic Macular Edema: 100-Week Results From the VISTA and VIVID Studies. Ophthalmology. 2015 Oct;122(10):2044-52.} , {Heier JS, Korobelnik JF, Brown DM, Schmidt-Erfurth U, Do DV, Midena E, Boyer DS, Terasaki H, Kaiser PK, Marcus DM, Nguyen QD, Jaffe GJ, Slakter JS, Simader C, Soo Y, Schmelter T, Vitti R, Berliner AJ, Zeitz O, Metzig C, Holz FG. Intravitreal Aflibercept for Diabetic Macular Edema: 148-Week Results from the VISTA and VIVID Studies. Ophthalmology. 2016 Nov;123(11):2376-2385.}

  • Randomized controlled trial of Aflibercept every 4 weeks vs Aflibercept every 8 weeks vs laser in DME (872 patients)
  • Findings (3-years):
    • Visual acuity improvements observed with both IAI regimens (over laser control) at weeks 52 and 100 were maintained at week 148.
Outcomes Group Aflibercept 2q4 Aflibercept 2q8 Laser
Mean BCVA gain VISTA +10.4 +10.5 +1.4
VIVID +10.3 +11.7 +1.6
Gain ≥ 15 letters from baseline (Proportion of patients) VISTA 42.9% 35.8% 13.6%
VIVID 41.2% 42.2% 18.9%

Brown et.al. (VISTA and VIVID: 2 year data)
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Heier et.al. (VISTA and VIVID: 3 year data)

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Heier et.al. (VISTA and VIVID: 3 year data)
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4. Steroid treatment

4.1 Intravitreal Triamcinolone

4.1.1 IVTA vs laser

Clinical Trial

2009 Beck et.al. (DRCR.net Protocol B)

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2009
Clinical Trial

At 3 years, there was no long-term benefit of IVTA over focal/grid laser. More eyes receiving 4mg IVTA were likely to require cataract surgery. {Diabetic Retinopathy Clinical Research Network (DRCR.net), Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris F, Glassman AR, Hartnett E, Ip MS, Kim JE, Kollman C. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009 Mar;127(3):245-51.}

  • Randomized controlled trial of laser vs triamcinolone in DME (306 patients)
  • Findings (3-years):
Outcomes Laser IVTA 1mg IVTA 4mg
VA change from baseline +5 0 0
Probability of cataract surgery 31% 46% 83%
IOP ≥ 10mmHg 4% 18% 33%

Beck et.al. (DRCR.net Protocol B)
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4.2 Dexamethasone implant (Ozurdex)

4.2.1 Ozurdex vs sham

Clinical Trial

2014 Boyer et.al. (MEAD)

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2014
Clinical Trial

The DEX implant provided superior VA improvement compared to sham at 3 years.{Boyer DS, Yoon YH, Belfort R Jr, Bandello F, Maturi RK, Augustin AJ, Li XY, Cui H, Hashad Y, Whitcup SM; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014 Oct;121(10):1904-14.}

  • Randomized controlled trial of Dexamethasone implant vs sham in DME (306 patients)
  • Findings (3-years):
Outcomes DEX 0.7mg DEX 0.35mg SHAM
≥15-letter improvement in BCVA 22.2% 18.4% 12.0%
Cataract formation 67.9% 64.1% 20.4%
Trabeculectomy required 0.6% 0.3% 0

Boyer et.al. (MEAD)
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