Intravitreal corticosteroids and anti-VEGF agents are effective treatments for diabetic retinopathy complications. Corticosteroids decrease vascular permeability and inflammation while anti-VEGF agents target VEGF to inhibit neovascularization. Studies show intravitreal triamcinolone, Avastin, Lucentis, Macugen, and Pegaptanib improve vision and reduce macular edema in diabetic macular edema. Avastin and Macugen also help regress neovascularization as adjunctive treatment for proliferative diabetic retinopathy. Pre-operative anti-VEGF injections enhance vitrectomy outcomes in eyes with active neovascularization or vitreous hemorrhage by reducing intraoperative bleeding. However

1. Intravitreal Injections for
Diabetic Retinopathy
Nawat Watanachai
VR Fellow
SCGH

2. What to inject into the vitreous of
diabetic eyes?
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
Corticosteroid
Anti-Vascular
endothelial growth
factors (anti-VEGF)
Avastin (Bevacizumab)
Lucentis (Ranibizumab)
Macugen(Pegaptanib)

3. In which eyes?
I.
II.
Diabetic macular edema
Adjunctive therapy
PDR with NV that not response to laser
PDR with cataract/ VH, unable to add laser
III. Eyes with active NV and/or VH, planned
for Vx

4. DR
Leakage/ occlusion of small vessels
Wide spread of ischemic retina
Imbalance between PG/IL/pro-angiogenic
factor VEGF & anti-angiogenic factor
PEDF, Angiostatin
VEGF-A + other factors  NV

5. Corticosteroids
− ↓ extravasation from leaking blood vessels (inhibit
archidonic pathway that produce IL/PG)
− ↓ proliferation of fibroblasts and granulation tissue
− ↓ breakdown of the blood-retinal barrier
− ↓ production of vascular endothelial growth factor
(VEGF)

6. AntiVEGF : Targeting VEGF
pathway

7. Anti-VEGF
antiVEGF
Structure
Target
Vitreous
(wk)
Macugen
(Pegaptanib)
RNA
aptamer
VEGF165
isoform
6
Lucentis
Fab portion All VEGF-A
(Ranibizumab)
isoforms
4-8
Avastin
(Bevacizumab)
8-12
Full-length
Ab
All VEGF-A
isoforms

8. In which eyes?
I.
Diabetic macular
edema
II.
Adjunctive therapy
PDR with NV that not
response to laser
PDR with VH, unable to
add laser
Eyes with active NV and/or
VH, planned for Vx

9. Diabetic Macula Edema
- ETDRS
- Repeated macular laser for focal/diffuse
DME may do more damage to the vision
- Diffuse DME is much less responsive to
laser than focal DME

10. I. DME: Intravitreal Triamcinolone
(IVTA)
Intravitreal triamcinolone acetonide for diabetic
macular edema: A prospective randomized study.
Jonas JB et al. J Ocul Pharmacol Ther. 2006; 22.
Unilateral 20 mg IVTA injection in bilateral DME.
33 cases
VA improvement by 3 lines: 39% in the IVTA (20mg)
eyes vs. 0% in the control eyes at 6 months.
Big dose
Effect lasts approximately 7-8 mths
IIOP ~52%

11. I.
DME : Avastin - persistent DME
- Intravitreal Avastin therapy for persistent diffuse
diabetic macular edema
- Christos Haritoglou et al, Retina 2006;26.
- 51 patients with diffuse CSME (age 23-79 yrs)
- Persistent DME after any treatment (beyond 6
mths period)
- Laser 18 eyes/
IVTA 17 eyes/
- Avastin 1.25 mg/0.05 ml
- 6 wks follow up
Vitrectomy 6 eyes

12. I. DME : Avastin - persistent DME
baseline
6 wks
12 wks
VA
(ETDRS
letters)
25.88+/14.43
31.32+/27.05+/14.33
14.83
(P=0.001) (not sig)
CRT
(Microns)
501+/-163 416+/-180 377+/-117
(P=0.001) (P=0.001)
-Intravitreal Avastin therapy for persistent diffuse diabetic
macular edema.
-Christos Haritoglou et al, Retina 2006;26.

13. I. DME : Avastin - persistent DME
- 15 eyes (29%) increased in VA of at least 3 lines
- 70% received a second injection at 12 wks
- Factors influencing treatment success
- Baseline VA +++
- Macular ischemia --- CRT +
- Age, previous treatment, area of peripheral ischemia
+/-Intravitreal Avastin therapy for persistent diffuse diabetic
macular edema.
-Christos Haritoglou et al, Retina 2006;26.

14. I. DME : Avastin - primary Rx
Primary intravitreal Avastin for DME
, Results from the Pan-American Collaborative Retina
Study Group at 6-mth follow up.
J.Arevalo et al. Ophthalmology 2007 April, 114(4).
6 centers from 6 contries
110 diffuse DME eyes/ 88 pts
Mean age 59.7+/-9.3 yrs
1.25 mg of Avastin injection
Follow up 6.31 mths (6-9)

15. I. DME : Avastin - primary Rx
VA
Baseline 6/48 or 0.87 logMAR
Final 6/24 or 0.6 logMAR (P<0.0001)
Improved >/= 2 snellen lines 43 eyes (55.1%)
Stable 32 eyes (41.1%)
Decreased >/= 2 snellen lines 3 eyes (3.8%)
Mean CRT
Baseline 387.0 +/- 182.8 microns
Final 275.7 +/- 108.3 microns (P<0.0001)
16 eyes(20.5%) needed 2nd injection
Primary intravitreal Avastin for DME.
J.Arevalo et al. Ophthalmology 2007 April, 114(4).

16. I.
I. DME : Lucentis
- VEGF is a critical stimulus for DME,
- Nguyen QD et al. Am J Ophthalmol. 2006
Dec; 142(6).
- 10 pts with chronic DME
- Lucentis 0.5 mg at 0, 1, 2 ,4 ,6 mth

17. I.
DME : Lucentis
mean VA
Mean CRT
baseline
20/80
503
7 mth
20/40
P=0.005
257
P=0.005
VA improved in all 10 pts
CRT decreased in all 10 pts
VEGF is a critical stimulus for DME,
Nguyen QD et al. Am J Ophthalmol. 2006
Dec; 142(6).

18. I. DME : Macugen
A Phase II randomized double-masked trial of
pegaptanib an anti-VEGF aptamer, for DME;
The Macugen Diabetic Retinopathy Study
Group; Ophthalmology 2006; 113:23.
Eyes with CSME involving the center of
macula corresponding leakage from FA
172 subjects, VA 20/50-20/320
Inject 0.3/1/ 3mg q 6 wks for 12-30 wks
(3-6 injections)

19. I. DME : Macugen
Result at 36 wk, 0.3 mg
Median VA 20/50 vs 20/63 (P=0.04)
Gain VA>10 letters 34% vs 10% (P=0.003)
Gain VA>15 letters 18% vs 7 % (P=0.12)
Mean decrease thickness 68 vs -4 microns
Decrease thickness>100 microns 42% vs 6% (P=0.02)
Need laser 25% VS 48% (P=0.04)
result at 82 wks (1 yr after last possible injection)
Decrease thickness 122 vs 49 microns
Required less frequency of laser treatment
1 endophthalmitis from 652 injections
A Phase II randomized double-masked trial of pegaptanib
an anti-VEGF aptamer, for DME; The Macugen Diabetic
Retinopathy Study Group; Ophthalmology 2006; 113:23

20. DME
- Focal DME with microaneurysms --> focal
laser
- Diffuse DME which do not response to grid
laser --> IVTA or antiVEGF
- DME with vitreous traction --> PPV/
combination

21. DME : diffuse type
- Predicting factors
- Younger age
- Lower degree of maculr ischemia
- Better pre-injection VA
- Shorter duration of ME
- Thicker CRT

22. In which eyes?
I.
II.
III.
Diabetic macular edema
Adjunctive therapy
PDR with NV that not response to laser
PDR with cataract/VH/etc, unable to add
laser
Eyes with active NV and/or VH, planned for Vx

23. II. Adjunctive treatment for PDR :
Avastin
-Intravitreal avastin for persistent new vessels in
DR (IBEPE Study)
-Rodrigo Jorge et al. RETINA 2006;26.
-15 eyes with actively leaking NV refractory to
PRP and BCVA worse than 20/40.
-age 60.08 +/- 7.75 yrs (49–73 yrs).
-1.5 mg of Avastin

24. persistent active NV
5½ months after PRP
1 week
6 weeks
12 weeks
II. Adjunctive
treatment for PD
R : Avastin

25. II. Adjunctive treatment
for PDR : Avastin
baseline
6 wk
1 wk
12 wk

26. II. Adjunctive treatment
for PDR : Avastin
baseline
6 wk
1 wk
12 wk

27. II. Adjunctive treatment for PDR :
Avastin
Baseline 1 wk
6wk
12wk
Mean NV
leakage
area (mm2)
27.79+/- 5.43 +/6.29
2.18
5.65 +/- 5.50+/1.76
1.24
VA
20/160
20/125
P=.05
20/125
P=.05
20/125
P=.05
IOP (mmHg) 14.93 +/- 15.33 +/- 15.20
15.26
0.77
0.84
+/- 0.78 +/-0.81
Recurrence of NV observed in 14/15 eyes at wk12

28. II. Adjunctive treatment for PDR : Macugen
Changes in retinal neovascularization after
pegaptanib (Macugen) therapy in diabetic ind
ividuals.
Macugen Diabetic Retinopathy Group.
Ophthalmology 2006;113:23–28.
Regression of ocular neovascularization
occurred in 8/13 (62%) of patients in the peg
aptanib treatment group at 36 weeks.
3/8 NV progressed at wk52 after cessation of
Macugen at wk30
0/3 in sham group

29. II. Adjunctive
treatment for PDR :
Macugen

30. In which eyes?
I.
II.
Diabetic macular edema
Adjunctive therapy
PDR with NV that not response to laser
PDR with VH, unable to add laser
III.
Eyes with active NV and/or VH,
planned for Vx

31. III. Eyes with active NV and/or
VH, planned for Vx : Avastin
Intravitreal Avastin : An Adjunctive Therapy for
Proliferative Diabetic Vitrectomy
C. Saovaprut et al,Thai J Ophthalmol 2006; 20(1)
intravitreal bevacizumab 1 mg/0.04 ml.
Vitrectomy in 1-4 weeks after injection.
Intraoperative homeostasis, postoperative bleeding
and retinal reattachment were observed.

32. CASE 1 : Avastin
VA 6/400
VA of 20/200, 12 wks after injection.
C. Saovaprut et al,Thai J Ophthalmol 2006;
20(1):20-26.

33. CASE 2 : Avastin
Preoperative intravitreal injection
of Avastin
Postoperative at 1 week
C. Saovaprut et al,Thai J Ophthalmol 2006;
20(1):20-26.

34. CASE 3 :
Avastin
C. Saovaprut et al,Thai J Ophthalmol
2006; 20(1):20-26.

35. III. Eyes with active NV and/or VH,
planned for Vx : Avastin -result
30 eyes in 28 patients
The regression of NV was noted as early as 2448 hours and completed at average 1 week.
Significantly less intraoperative bleeding,
intraocular diathermy was used only 4 times in
30 surgeries
No immediately or late postoperative bleeding
and anatomical retinal reattachment in all
patients at last follow-up. (1-10 months; mean
5.6 months).
C. Saovaprut et al,Thai J Ophthalmol 2006;
20(1):20-26.

36. In which eyes?
I.
II.
Diabetic macular edema
Adjunctive therapy
PDR with NV that not response to laser
PDR with cataract/ VH, unable to add laser
III. Eyes with active NV and/or VH, planned
for Vx

37. Adverse effects : IVTA
Infectious/ non infectious endophthalmitis
1:1000
Glaucoma, transient IIOP 25-50% of cases
Need glaucoma surgery 1-2%
RD in eyes with previously treated RB
Cataract
50-90% in 2 yrs esp PSC
Significant cataract that need surgery 15-20% in 1
yr
Reported : MH, persistent unsealed scleral
wound(30G)

38. Adverse effects : IVTA
Glaucoma/ OHT
Start ~1wk after injection
Risk factors
Younger age
Pre-op IOP > 16 mmHG
Repeated injection
Pre-op glaucoma

39. Adverse Effects : Anti-VEGF
Foreign body sensation
Subconjunctival hemorrhage
Transient IIOP/ pain/ floaters
Uveitis (esp Lucentis)
Worsening of preexisting PRH
RPE tear
Endophthalmitis
Allergic reaction
Others eg. MI, hypertension

40. Ongoing Studies
A phase 2 evaluation of anti-VEGF therapy for DME : Avastin/
US NIH (laser/ avastin/ avastin+laser)
READ2 study : avastin+laser VS Lucentis+laser for DME
Multicenter randomised clinical trial of laser treatment plus IVTA for
DME (Phase III, AUS, 2005-2008)
Macugen compared to sham injection in patients with DME involving
the center of the macula (Phase III,2005-2010)
Efficacy study of Lucentis in the treatment of DME
Laser-Lucentis-triamcinolone for PDR
Laser-Lucentis-triamcinolone for DME
RESOLVE : safety and efficacy of avastin in DME with center
involvement
Intravitreal avastin vs photocoagulation for PDR
Intravitreal avastin for treatment of NVG
Effect of macugen on surgical outcomes and VEGF levels in diavetic
patients with PDR or CSME
Study for the treatment of iris NV with Macugen (2006-2007)
Macugen to prevent worsening of macular edema following cataract
surgery in diabetic
Lucentis VS Avastin for DME/ US NIH