This document provides a review of literature on diabetic macular edema (DME). It summarizes key studies on the pathophysiology and treatment of DME, including the Early Treatment Diabetic Retinopathy Study (ETDRS), trials of intravitreal corticosteroids, anti-VEGF drugs, and combination therapies. Major studies discussed include DRCR.net, PACORES, RESOLVE, BOLT, RIDE, and RESTORE trials which evaluated laser photocoagulation, corticosteroids, ranibizumab, bevacizumab, and combination therapies for treating DME. The document concludes anti-VEGF drugs like ranibizumab and bevacizumab

1. DIABETIC MACULAR
EDEMA
REVIEW OF LITERATURE
Abubaker Ahmed
MS Ophth

2. Introduction
 DME: retinal thickening within 2DD from the
center of the macula.
 CSME : retinal thickening 500 microns from
fovea , hard exudates within 500 microns from
fovea with retinal thickening, or at least 1 DD of
thickening any part of which within 1 DD of
fovea

4. Pathophysiology
 DME is the result of breakdown of the inner
blood retinal barrier leading to incompetence
of the vessels and fluid leakage
 Retinal edema results once this fluid leakage
overwhelms the capacity of the retinal pigment
epithelial pump to remove it.

5. Pathophysiology contd
 Focal retinal ischemia due to retinal arteriolar
closure
 Macular ischemia resulting from closure of
retinal capillaries and arterioles may stimulate
VEGF which exacerbating CME.

6. Treatment of DME
 The Early Treatment Diabetic Retinopathy Study
(ETDRS) in 1985 set the guidelines for
treatment of DME : Glycemic control, optimal BP
control and macular focal/grid photocoagulation
reducing the risk of moderate vision loss by 50%

7. The Early Treatment in Diabetic Retinopathy
Study (ETDRS)
 The ETDRS was a large-scale,
multicenter, randomized clinical trial
sponsored by the National Eye Institute in
1979 designed to investigate whether
early treatment of macular edema by focal
argon laser photocoagulation could
prevent moderate visual loss

8. ETDRS
 Eyes with macular edema in the setting of mild
to moderate non proliferative diabetic
retinopathy with a visual acuity of 20/40 or
worse were divided into two treatment groups:
immediate versus delayed focal laser
photocoagulation.

9. ETDRS conclusion
 Based on three years of follow-up data, the
ETDRS concluded :
 Immediate focal photocoagulation halved the
rate of moderate visual loss.
 Treatment of center involving CSME resulted
in a 67% decrease in the rate of visual loss
 Treatment of center-sparing CSME resulted in
only an approximate 45% decrease in the rate
of visual loss.

10. Drawback
 However, as was reported by the ETDRS, only
17% of eyes with baseline vision of worse than
20/40 experienced modest visual improvement,
and a certain proportion of patients did not
respond to focal laser therapy at all

11. Other treatment modalities
 I vitre a l Co rtic o s te ro id s
ntra
 I vitre a l A
ntra nti-VEG F
 Co m bina tio n the ra p y
 Surg ic a l m a na g e m e nt (PPV)

12. I vitre a l Co rtic o s te ro id s
ntra
 Corticosteroids interfere with the regulatory
components of gene expression and inhibit the
expression of proinflammatory genes as TNF α
a nd o the r cytokines
 Inhibit the phospholipase A2 pathway, and
reduce leucocyte chemotaxis
 Corticosteroids inhibit the expression of VEGF
and VEGF gene

13. DRCR.net study 2008
 Diabetic Retinopathy Clinical Research
Network
 A multi-center, large scale, randomized clinical
trial included 840 eyes and evaluated 1mg and
4mg doses of preservative-free triamcinolone
compared with focal/grid photocoagulation for
DME

14. DRCR.net study
 At four months, the 4mg triamcinolone group
had better visual acuity but by one year there
were no significant differences.
 At 3 years, mean visual acuity was better in
the laser group than in the two triamcinolone
groups (recently published )
 Elevation of IOP and the need for cataract
surgery were higher in the 4mg triamcinolone
group.

15. I vitre a l A
ntra nti-VEG F
 VEGF has been linked to leakage of retinal
vessels and hence to the formation of retinal
edema , this was the rationale for testing anti-
VEGF drugs for the treatment of DME.
 Ranibizumab(or Lucentis) and bevacizumab
(or Avastin) are sister molecules of humanized
murine monoclonal antibodies with affinity for
binding VEGF isoforms.

16. PACORES study
 The Pan-American Collaborative Retina
Study Group
 Retrospective interventional multicenter study
evaluated the retinal thickness and visual
acuity data of 80 consecutive patients (139
eyes) receiving intravitreal Avastin of 1.25 or
2.5mg with a minimum followup of 24 months
 Arevalo JF, e t a l. Prim a ry intra vitre a l be va c iz um a b (A a s tin) fo r d ia be tic m a c ula r
v
e d e m a : results from the Pan-American Collaborative Retina Study Group at 6-month
follow-up. Ophthalmology 2007;114(4):743-750.

17. PACORES study
 Results showed that at 24 months 44.6% eyes
remained stable, 51.8% improved 2 or more
lines, and 3.6 % decreased 2 or more lines.
 Patients who received on average 5.8
injections of single or double dose Avastin
demonstrated a maintained partial resolution
of macular edema

18. RESOLVE Study
 The Sa fe ty a nd Effic a c y o f Ra nibiz um a b in
Dia be tic M c ula r Ed e m a
a
 A multicenter, randomized, and double
masked evaluated the efficacy and safety of
intravitreal ranibizumab (0.3 or 0.5mg)
compared with sham treatment in 151eyes
with DME over 12 months

19. RESOLVE Study
 Results showed a significant and continuous
improvement in BCVA and central retinal
thickness for ranibizumab versus sham.
 P. Massin, F. Bandello, J. G. Garweg et al., “Safety and efficacy of ranibizumab in
diabetic macular edema (RESOLVE study): a 12-month, randomized, controlled,
double-masked, multicenter phase II study,” Dia be te s Ca re , vo l. 3 3 , no . 1 1 , p p .
2399–2405, 2010.

20. BOLT study
The most meaningful study concerning
Bevacizumab for DME
 Compare the efficacy of anti-VEGF therapy to
focal laser photocoagulation in 80 patients
with CSME .
 A prospective, randomized phase III clinical
trial
 Michaelidis K, Kaines A, Hamilton RD, e t a l. Ap ro s p e c tive ra nd o m iz e d tria l o f
intra v itre a l bevacizumab or laser therapy in the management of diabetic macular
edema (BOLT) study) 12-month data: report 2. Ophthalmology 2010;117:1078-1086.

21. BOLT study
 Bevacizumab injections given every 6 weeks
or laser treatment performed every 4 months.
 Injected eyes received 3-9 injections, whereas
the focal laser eyes received 1-4 treatments in
the 12-month study period.

22. BOLT study
 Patients in the bevacizumab group were 5.1
times as likely to gain at least 10 letters.
 BOLT 2012 : long term effect of
Bevacizumab is maintained at 24 months
 The BOLT study suggested that intravitreal
bevacizumab therapy should be considered as
a first choice in the management of center-
involving DME.

23. RIDE study
 Double-blinded, sham-controlled randomized
studies with a followup of 36 months.
 Patients received monthly injections of 0.3 mg
ranibizumab, 0.5 mg ranibizumab, or sham.
 As twice as many patients in the ranibizumab
groups gained ≥1 5 le tte rs c o m p a re d to the
s ha m g ro up
 D. S. Boyer, J. Sy, A. C. Rundle et al., Ra nibiz um a b fo r Vis io n Lo s s d ue to Dia be tic
M c ula r Ed e m a — Re s ults o f two Pha s e IIRa nd o m iz e d tria ls , A e ric a n Dia be te s
a I m
A s o c ia tio n 7 1 st Scientific Sessions, San Diego, Calif, USA, 2011.
s

24. DRCR.net study 2011
 Ra nibiz um a b p lus Pro m p t o r De fe rre d M c ula r
a
La s e r Pho to c o a g ula tio n ve rs us Tria m c ino lo ne
p lus M c ula r La s e r Pho to c o a g ula tio n
a
 Multicenter, randomized clinical trial which
included 854 eyes of 691 patients
 M. J. Elman, N. M. Bressler, H. Qin et al., “Expanded 2-year follow-up of ranibizumab
plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular
edema,” O p htha lm o lo g y , vo l. 1 1 8 , no . 4, p p . 6 0 9 – 6 1 4, 2 0 1 1 .

25. DRCR.net study 2011
Four treatment groups:
 Prompt laser with sham injection,
 0.5 mg of ranibizumab with prompt laser
 0.5mg of ranibizumab with laser deferred for at
least 24 weeks
 4mg of triamcinolone with prompt laser.

26. DRCR.net study 2011
 At one year, the two groups treated with
ranibizumab had a significant change in mean
VA from the baseline.
 The triamcinolone and laser alone groups did
not show a significant change in VA.
 a subgroup analysis of pseudophakic eyes in
the triamcinolone group showed similar results
as for those in the ranibizumab groups.

27. RESTO RE s tud y
 A randomized, double-masked, multicenter
phase III study over 12 months
compared ranibizumab + sham laser and
ranibizumab + laser with laser + sham injection
for DM in 345 patients
 P. Mitchell, F. Bandello, U. Schmidt-Erfurth et al., “The RESTORE study:
ranibizumab monotherapy or combined with laser versus laser monotherapy for
diabetic macular edema,” O p htha lm o lo g y , v o l. 1 1 8 , no . 4, p p . 6 1 5 – 6 2 5 , 2 0 1 1 .

28. RESTO RE s tud y
 Ranibizumab or sham injections were
given monthly for three months and then
PRN; laser or sham laser was given at
baseline and then PRN after an interval of
at least three months.

29. RESTO RE s tud y
 In the ranibizumab and ranibizumab + laser
groups a rapid improvement of VA was
observed after one month which continued up to
three months and was sustained until month 12
 Likewise, the percentage of patients reaching
VA ≥ 20/40 was greater in the two ranibizumab
groups
 Ranibizumab monotherapy and combination
with laser treatment are superior to laser
treatment alone for DME.

30. Pars plana vitrectomy
 Many studies suggest that removal of the
vitreomacular traction or the vitreous itself with
vitrectomy may, in some patients be followed by
resolution of macular edema
 Patients with refractory CSME and a taut
posterior hyaloid face who have not responded
to macular laser treatment may benefit from a
vitrectomy

31. Where are we today?
 Ranibizumab monotherapy and ranibizumab in
combination with laser are more effective than
macular laser photocoagulation monotherapy.
 Bevacizumab, superiority has been shown for
combination with macular laser
photocoagulation to each of them alone.
 Combination therapy of IVTA plus macular
laser is more effective than either
monotherapy and may be comparable to anti-
VEGF plus laser in pseudophakic patients.

32.  Though intravitreal corticosteroids and anti-
VEGF drugs have different ways of action
there was no adjunctive effect found with
combination therapy.
 Further investigation of additional treatment
options is needed in order to optimize therapy.

33. Future Therapies
 VEGF Trap-Eye is a soluble VEGF receptor
fusion protein that binds all forms of VEGF-A
and related placental growth factor (PGF).
When administered as a single 4 mg
intravitreal injection in a phase 1 study, a
marked decrease in central retinal thickness
and mean macular volume was noted.

34. Future Therapies
 The phase III FAME (fluocinolone acetonide
in diabetic macular edema) trial is evaluating
the Medidur fluocinolone-based injectable
implant.
 The phase III trial of Posurdex
biodegradable implant (sustained delivery
formulation of dexamethasone) for the
treatment of diabetic macular edema is
underway.

35. Thank you