Recent advances in treatment of DME include: 1) Frequency doubled Nd:YAG and micropulse diode lasers can treat DME with less damage to the retina compared to traditional lasers. 2) Steroid implants like ILUVIEN and Ozurdex have shown benefits for DME, with ILUVIEN maintaining vision gains over 3 years and Ozurdex benefits lasting 6 months. 3) Ranibizumab injections with or without prompt laser provide mean vision improvements of 9-10 letters over 1 year for DME treatment, with sustained benefits over 2 years.

1. Recent advances in treatment of
DME
Dr VENKATESH

2. Frequency doubled Nd;YAG laser
• offers the potential of less destructive retinal effect than argon.
• In which the energy employed is the lowest capable of producing
barely visible burns at the level of RPE.
• The ‘pattern scan laser’(PASCAL) uses frequency-doubled micropulse
YAG in single shot mode.
• This greatly improves pt comfort as compared with conventional
argon laser.

3. Micropulse diode laser
• In which short duration (microseconds)burns are applied to the RPE
without significantly affecting the outer retina n choriocapillaris.

4. STEROIDS

5. ILUVIEN(alimera sciences,Alpharetta,GA)
• This is a fluocinolone acetonide intravitreal insert by alimera sciences.
• Non biodegradable device for the Rx of DME on the basis of the
publication of the FAME study results.
• This was a phase III trial,multicenter,prospective,controlled clinical
trial.
• Done for 3 yrs,the most beneficial dose is 0.2ug/day fluocinolone
acetonide.
• It had beneficial effect on visual acuity as from 3 wks of implantation
in vitreous cavity

6. • 29% of pts gaining more than 15 letters compared with 18% in control
group.

7. ozurdex
• This is a biodegradable implant that releases dexamethasone during 4
to 6 months.
• The results of a phase II clinical trial are already published and phase
III is under way.
• the response to treatment with doses of 700 µg (0.7mg) is greater
than with 350 µg, suggesting a dose response relationship.
• With doses of 700 µg,
>10 EDTRS letters in just over 30% of patients and
>15 letters in about 20% at 6 months of treatment,

8. • No differences between the treatment group (receiving 700 or 350
µg) and controls (no treatment) were observed regarding cataracts or
progression at six months.
• No cases of retinal detachment or endophthalmitis were observed in
the treatment group;
• 7.5-16.4% showed increased intraocular pressure (IOP), mostly in the
first week after intravitreal injection. All responded to medical
treatment and neither laser therapy nor surgery were required to
control the IOP [71]. About 20% of patients experienced

9. It is known that vitrectomized eyes show altered pharmacokinetics and
that clearance is much faster, thus limiting the effectiveness of many
treatments. However, with 0.7 mg of dexamethasone, therapeutic
levels of the drug were maintained during 6 months and efficacy was
acceptable in these patients (at the end of the study 21.4% had gained
at least 10 letters and 42.9% at least 5 letters). The average gain at 2
months was 6 letters and at 6 months 3 letters

10. RANIBIZUMAB N LASER
• two phase II studies (RESOLVE and READ-2) and
• two phase III studies (RESTORE and DRCR.net protocol I)
• They have been completed using ranibizumab—a total of 1313
patients with DME.

11. READ-2
• ranibizumab injections were administered at baseline and at months 1, 3, and 5,
and focal/grid laser was administered at baseline and again at month 3 only if
central subfield thickness (CST) was ≥250 μm.
• The mean change in BCVA from baseline to month 6 (primary end point) with
ranibizumab monotherapy (+7.24 letters) was superior to laser monotherapy.
• however, the BCVA change with combination therapy was not significantly
different from that of either ranibizumab or laser monotherapy at this timepoint.

12. • In total, 101 patients completed 24 months follow-up; the mean
BCVA improvement at month 6 with ranibizumab monotherapy was
sustained to month 24 and these improvements were numerically
higher than with combination therapy (+7.7 vs +6.8 letters,
respectively) .
• For the 74 patients who completed 36 months follow-up, mean BCVA
continued to improve with mean gains of +10.3 letters with
ranibizumab monotherapy and +9.5 letters with combination
therapy vs +1.4 letters for patients initially randomised to laser
monotherapy (Table 2).
• Interestingly, adding laser to ranibizumab resulted in fewer
ranibizumab injections without a major disadvantage in visual
outcome at 2 and 3 y

14. RESOLVE
• ranibizumab was administered as three consecutive monthly
ranibizumab (0.3 or 0.5 mg) injections, followed by an as-needed
regimen with predefined retreatment criteria.
• The primary efficacy outcome was the mean average change in BCVA
over 12 months, defined as the difference between BCVA at baseline
and the average of BCVA values measured at months 1–12.
• This is considered to be a more stringent regulatory end point than
mean change in BCVA as it incorporates the treatment effect over the
entire treatment period.

15. • The mean average change in BCVA with ranibizumab treatment was
superior to that of the sham control group (Table 1).
• At 12 months, ranibizumab-treated patients gained 10.3 letters in
BCVA, with a mean of 10 injections vs a loss of 1.4 letters in the sham
group (P<0.0001) (Figure 1b).
• More patients receiving ranibizumab gained ≥15 letters compared
with patients receiving sham injections (Table 1); 2.9% of the
ranibizumab group and 20.4% of the sham group lost ≥15 letters.
• Dose doubling was more frequent in the sham arm (91.8%) than in
the ranibizumab arm (68.6%), whereas a higher proportion of
patients in the sham arm received rescue laser therapy (32.7%)
compared with the ranibizumab arm (4.9%).[

17. RESTORE
• RESTORE was a 12-month, randomised, phase III study in which 345
patients with visual impairment due to DME received ranibizumab
monotherapy, and ranibizumab combined with laser or laser
monotherapy.
• Laser was administered in accordance with ETDRS guidelines.[25] The
primary end point for RESTORE was also the mean average change in
BCVA, which demonstrated the superiority of ranibizumab, either as
monotherapy or when combined with laser, compared with laser
monotherapy.

18. • Mean BCVA change at month 12 was also significantly better for
ranibizumab-treated patients than for patients receiving laser
monotherapy (+6.8 letters with ranibizumab monotherapy (P<0.0001)
and +6.4 letters with combination therapy (P=0.0004) vs +0.9 letters
with laser monotherapy.
• Similarly, more patients treated with ranibizumab experienced an
improvement of ≥10 letters than those on laser monotherapy.
• Only one patient (0.9%) receiving ranibizumab monotherapy
experienced a loss of ≥15 letters at month 12 vs four patients (3.4%)
in the combination therapy group and nine patients (8.2%) in the
laser monotherapy group.[4]

20. DRCR.net
• The DRCR.net protocol I study was an independent, randomised,
phase III trial in 854 eyes of 691 patients with centre-involved retinal
thickening due to DME.
• Patients received ranibizumab plus either prompt (within 3–10 days
of ranibizumab injection) or deferred (≥24 weeks after injection) laser,
triamcinolone plus laser or laser monotherapy.
• Ranibizumab was administered at baseline every 4 weeks to week 12.
From week 16, retreatment was guided by predefined VA and optical
coherence tomography (OCT) criteria.

21. • The study has a 5-year follow-up period; to date, data for 1-[10] and 2-
year outcomes[11] are reported. Mean BCVA change from baseline to
year 1 was significantly better with ranibizumab in combination with
either prompt or deferred laser therapy than with laser monotherapy
(Table 1).[10]
• The mean improvement of 9 letters was achieved with a median of 8
and 9 ranibizumab injections in the prompt and deferred laser
groups, respectively.
• In the first year, the ranibizumab plus prompt laser group received a
median of two laser treatments, whereas 72% of patients receiving
ranibizumab plus deferred laser did not receive laser treatment.
• BCVA improvements at year 1 were sustained during year 2, with a
median of only two and three injections in the ranibizumab plus
prompt and deferred laser groups, respectively.

22. • Subgroup analyses of data from the RESOLVE, RESTORE, and DRCR.net
trials have been carried out according to patient baseline
characteristics, including previous treatment, type of DME (focal or
diffuse), baseline central retinal thickness (CRT), or baseline BCVA.

23. • The mean average change in BCVA was consistently higher with
ranibizumab in each subgroup of RESOLVE, with similar treatment
differences between ranibizumab and sham controls.
• Similarly, the RESTORE study demonstrated the superiority of
ranibizumab (either monotherapy or adjunctive to laser) to laser
monotherapy in each subgroup (Figure 2).
• Interestingly, although the RESTORE findings indicated that patients
with VA >73 letters had lower VA gains with ranibizumab than did
patients in worse VA categories, this group with better baseline VA
also had the greatest potential to experience a mean loss of VA when
treated with laser monotherapy.

24. • Patients with CRT <300 μm also had lower VA gains with ranibizumab
than did those with thicker baseline CRT values.patients with poorer
VA (≤65 letters) or greater CST (≥400 μm) experienced a greater VA
benefit in all treatment groups than did patients with VA ≥66 letters
or CST <400 μm.[10]
•

27. Monotherapy vs Combination Therapy
• Initiating ranibizumab monotherapy is the preferred approach for
visual impairment due to DME.
• As yet, the role of adjunctive laser is unclear. In RESTORE, laser in
combination with ranibizumab did not improve outcomes compared
with ranibizumab monotherapy; thus, the principal rationale for
adjunctive laser is to reduce the number of ranibizumab injections.
• .

28. • Two-year outcomes from the READ-2 and DRCR.net studies provided
the first evidence for a reduction in the number of ranibizumab
injections when combined with laser.[10, 23]
• As VA improvements with laser occur very slowly,[23] long-term data
are required to confirm whether adding laser to ranibizumab confers
any additional benefit in terms of VA and patient quality of life, and
thus clinical judgement should prevail

29. • The REVEAL, RETAIN, RISE, and RIDE studies are also ongoing,
providing additional data for 2–3 years of treatment. Other newly
approved therapies will also need to be considered.

30. PEGAPTANIB
• The Macugen Diabetic Retinopathy Study Group (Berlin, WOC 2010)
reported that pegaptanib administered at a dose of 0.3 mg every 6 weeks
resulted in significant improvement in visual acuity, decreased central
macular thickness and reduced the need for laser treatment in patients
with DME.
• Mean improvement in visual acuity obtained with this regimen was 4.7
letters at week 36 (9 months, after 6 injections of pegaptanib), with a gain
of more than 10 letters in 37% of patients versus 20% in the control group
at week 54 (1 year, 9 injections) and a safety profile similar to that
observed in patients with AMD.
• The optimum combination of pegaptanib and focal laser has yet to be
established

31. bevacizumab
• The intravitreal Bevacizumab or Laser Therapy in the Management of
Diabetic Macular Edema (BOLT) study
• In a prospective randomized trial of intravitreal bevacizumab (IVB)
versus laser therapy for the management of diabetic macular edema,
IVB administered at a dose of 1.25 mg every 6 weeks, with a loading
dose of 3 injections and then as needed, achieved better functional
outcomes than gold standard treatment (laser therapy using ETDRS
guidelines: a minimum of 1 to a maximum of 4 modified grids) at 12
months.

32. • In the IVB group, 31% of patients gaining more than 10 letters after
one year versus 7.9% in the control group, and the safety profile of
IVB was good.
• At 12 months, after an average 9 injections of IVB, the treatment
group showed a gain of 8 ETDRS letters versus a loss of 0.5 letters in
the laser group with an average of 3 modified grids.
• IVB has beneficial effects on both visual acuity and short-term central
macular thickness in DME.

33. THANK YOU