Diabetic retinopathy is damage to the blood vessels of the retina due to diabetes. It can progress to proliferative diabetic retinopathy where new abnormal blood vessels grow on the retina or optic disc which can lead to vision loss. A clinical trial studied whether initial treatment of proliferative diabetic retinopathy with injections of the anti-VEGF drug ranibizumab followed by deferred pan-retinal photocoagulation if needed could provide visual outcomes equal to or better than prompt pan-retinal photocoagulation. At two years, vision was maintained or improved in the ranibizumab group while remaining unchanged in the laser group, suggesting anti-VEGF therapy may delay or reduce the need for laser treatment

1. DIABETIC RETINOPATHY
 DR. AJAY DUDANI

2. Diabetic Retinopathy
 Damage to the blood vessels in the retina due to diabetes.
https://www.contouravisionindia.com/single-post/What-causes-diabetic-retinopathy as visited on 13th Jan 2020
Biyani RS, Patre BM. Algorithms for red lesion detection in Diabetic Retinopathy: A review. Biomedicine &

3. Projections of DR :How big is the
problem going to be ?
https://www.nei.nih.gov/learn-about-eye-health/resources-for-health-educators/eye-health-data-and-
Between 2010 and 2050, It is
expected that the number of
people with the most common
eye diseases to double, and it will
rise from 7.7 Mn to 14.6 Mn

4. Global Burden of Diabetic
Retinopathy (DR)
35 studies = 22,896 patients 21
Among those with diabetes:
• 34.6% with any DR
• 6.95% with proliferative DR
• 6.81% with diabetic macular
edema
• 10.2% with vision-threatening DR
Among those with diabetes, increased
risk of diabetic retinopathy:
• Longer duration of diabetes
• Poorer glycemic control
• Poorer blood pressure control
• Poorer control of blood cholesterol levels
https://www.nei.nih.gov/learn-about-eye-health/resources-for-health-educators/eye-health-data-and-
DR
35%
PDR
7%
DME
7%
Vision
Threatnein
g DR
10%

5. PROTECTIVE FACTORS
• High myopia
• Choroidal degeneration
• Extensive old chorio-retinopathy

6. Diabetic Eye Disease
Key Points
k best
• Treatme
before v
nts exist but wo
ision is lost
RECOMMENDED EYE EXAMINATION SCHEDULE
Diabetes type Recommended time
of first examination
Recommended
follow-up*
Type 1 3-5 years after diagnosis Yearly
Type 2 At time of diagnosis Yearly
Prior to pregnancy
(type 1 or type 2)
Prior to conception and
early in the first trimester
No retinopathy to mild-
moderate NPDR -
every 3-12 months
rSevere NPDR or worse -
every 1-3 months
*Abnormal findings may dictate more frequent follow-up examinations

7. • Microangiopathy due to hyperglycemia
• Endothelial barrier decompensation leads to serum leakage and
retinal edema
• Later stages, VEGF
produced by ischemic
retina causes
neovascularisation
PATHOGENESIS

8. Diabetic Retinopathy
Five pathologic processes:
• Formation of micro aneurysms (outpouchings of the small
vessels)
• Excessive vascular permeability (leakage)
• Vascular occlusions (closure of blood vessels)
• Proliferation of new vessels (± hemorrhage)
• Contraction of new blood vessels: Scarring, retinal
detachment
https://www.nei.nih.gov/learn-about-eye-health/resources-for-health-educators/eye-health-data-and-

9. NON-PROLIFERATIVE DIABETIC RETINOPATHY (NPDR)
NO DR Review in 12 months
VERY MILD
Microaneurysms only
Review most patients in 12 months
MILD
Any or all of:
microaneurysms, retinal hemorrhages, exudates, cotton
wool spots
Review range 6-12 months, depending on
severity of signs, stability, systemic factors,
and patient’s personal circumstances
MODERATE
Severe retinal haemorrhages in 1-3 quadrants or mild IRMA
Significant venous beading in no more than 1 quadrant
Cotton wool spots
Review in approximately 6 months
(PDR in up to 26%, high-risk PDR in up to 8%
within a year)
SEVERE
The 4-2-1 rule-
Severe retinal haemorrhages in all 4 quadrants
Significant venous beading in ≥2 quadrants
Moderate IRMA in ≥1 quadrants
Review in 4 months
(PDR in up to 50%, high-risk PDR in up to 15%
within a year)
VERY SEVERE
≥2 of the criteria for severe
Review in 2-3 months
(High-risk PDR in up to 45% within a year)
ABBREVIATED EARLY TREATMENT DIABETIC RETINOPATHY STUDY (ETDRS) CLASSIFICATION
CATEGORY MANAGEMENT

10. CATEGORY MANAGEMENT
PROLIFERATIVE DIABETIC RETINOPATHY (PDR)
MILD-MODERATE
New vessels on the disc (NVD) < 1/3 disc area
New vessels elsewhere (NVE) < 1/2 disc area
Treatment considered according to severity of signs,
stability, systemic factors, and patient’s personal
circumstances
If not treated, review in up to 2 months
HIGH-RISK
NVD > 1/3 disc area
Any NVD with vitreous or preretinal
hemorrhage
NVE >1/2 disc area with vitreous or preretinal
hemorrhage
Laser photocoagulation
Intravitreal anti-VEGF agents
Intravitreal triamcinolone
Pars plana vitrectomy
Lipid lowering drugs
ADVANCED DIABETIC EYE DISEASE
Preretinal (retrohyaloid) and/or intragel
hemorrhage
Tractional retinal detachment
Tractional retinoschisis
Rubeosis iridis (iris neovascularisation)
Pars plana vitrectomy
PDR – formation of new vessels or fibrovascular tissue on the optic disc or inner
retina

11. OTHER CATEGORIES
• BACKGROUND DIABETIC RETINOPATHY (BDR)
It’s the earliest phase of DR.
Characterised by microaneurysms, dot and blot hemorrhages and exudates.
• DIABETIC MACULOPATHY
Refers to presence of any retinopathy at the macula.
• PRE-PROLIFERATIVE DIABETIC RETINOPATHY (PPDR)
Cotton wool spots, venous changes, IRMA and deep retinal hemorrhages.
• DIABETIC PAPILLOPATHY
It is a form of optic neuropathy seen in young type I diabetics. It is unrelated to
glycemic control or any other known feature of diabetes.

12. APPROXIMATE EQUIVALENCE OF
THE CLASSIFICATION
SYSTEMS
ETDRS NSC SDRGS AAO RCOphth
10 - None R0 - None R0 - None No apparent retinopathy None
20 - Microaneurysms only R1 - Background R1 - BDR Mild NPDR Low risk
35 - Mild NPDR Moderate NPDR
43 - Moderate NPDR R2 - Pre-
proliferative
R2 Moderate BDR High risk
47 - Moderately severe
NPDR
53 A-D - Severe NPDR R3 - Severe BDR Severe NPDR
53 E - Very severe NPDR
61 - Mild PDR
65 - Moderate PDR
R3 - Proliferative R4 - PDR PDR PDR
71, 75 - High risk PDR
81, 85 - Advanced PDR

13. MILD NPDR

14. MODERATE NPDR

17. NEW VESSELS

18. DIABETIC MACULAR OEDEMA
• Most common cause of visual impairment in diabetic retinopathy
• According to the Wisconsin Epidemiologic Study of Diabetic
Retinopathy (WESDR), the prevalence rate of macular oedema is 10 %
in the diabetic population.
• Best detected by slit-lamp biomicroscopy and stereoscopic fundus
photography.

19. Retinal thickening
within 500 µm of
centre of macula
Exudates within
500 µm of centre
of macula, if
associated with
retinal thickening
Retinal thickening one disc area (1500 µm)
or larger, any part for which is within
one disc diameter of centre of macula
CLINICALLY SIGNIFICANT MACULAR EDEMA (CSME)
As defined by ETDRS-

20. OCT
A. Diffuse edema
B. Cystoid macular edema
C. Serous retinal detachment
D. Posterior hyaloid traction

21. FLUORESCEIN ANGIOGRAPHY
- Identifies macular capillary non-perfusion.
- Identifies subtle areas of NV causing recurrent vitreous hemorrhage.

22. Diabetic Retinopathy National Institutes
of Health-supported Clinical Trials
https://www.nei.nih.gov/learn-about-eye-health/resources-for-health-educators/eye-health-data-and-

23. DIABETIC RETINOPATHY STUDY
(DRS)
ELIGIBILITY CRITERIA
1. Visual acuity ≥ 20/100 (6/36) in each eye
2. PDR in at least one eye or severe NPDR in both
3. Both eyes suitable for photocoagulation
STUDY DESIGN
One eye of each patient was assigned randomly to photocoagulation. The
other eye was assigned to follow-up without photocoagulation
CONCLUSIONS
1. Photocoagulation reduced the risk of severe visual loss by 50 % or more
2. Modest risks of decrease in visual acuity and visual field
3. Treatment benefit outweighs risks for eye with high-risk PDR

24. EARLY TREATMENT
DIABETIC RETINOPATHY
STUDY (ETDRS)
ELIGIBILITY CRITERIA
1. Visual acuity ≥ 20/40 (6/12) {20/400 (60/120) if reduction caused by macular
oedema}
2. Mild NPDR to non-high risk PDR, with or without macular oedema
3. Both eyes suitable for photocoagulation
STUDY DESIGN
1. One eye of each patient was assigned randomly to early photocoagulation and
the to deferral (careful follow-up and photocoagulation if high risk PDR
develops).
2. Patients assigned randomly to aspirin or placebo.

25. CONCLUSIONS
1. Focal photocoagulation
- reduced the risk of moderate visual loss by 50 % or more
- increased the chance of a small improvement in visual acuity
- reduced retinal thickening
2. Early scatter photocoagulation
- small reduction in risk of severe vision loss
- not indicated in mild to moderate retinopathy
- most effective in type 2 diabetes mellitus
3. Aspirin did not alter the progression of diabetic retinopathy

26. DIABETIC RETINOPATHY
VITRECTOMY STUDY
(DRVS)
ELIGIBILITY CRITERIA
1. Visual acuity ≤ 5/200 (5/60)
2. Vitreous hemorrhage consistent with visual acuity, duration 1-6 months
3. Macula attached
STUDY DESIGN
Eligible eye or eyes assigned randomly to early vitrectomy or conventional
management (vitrectomy if center of macula detaches or if vitreous hemorrhage
persists for 1 year, photocoagulation as needed and as possible)
CONCLUSIONS
Chances of recovery of VA ≥ 10/20 (3/6) increased by early vitrectomy, at least
in patients with type I diabetes, who were younger and had more severe PDR

27. GROUP NR – Very Severe PDR with Useful Vision
MAJOR ELIGIBILITY CRITERIA
1. Visual acuity ≥ 10/200 (3/60)
2. Center of macula attached
3. Extensive, active, neovascular, or fibrovascular proliferations
MAJOR DESIGN FEATURES
Same as Group H (except conventional management included vitrectomy
after a 6 months waiting period in eyes that developed severe VH)
MAJOR CONCLUSIONS
Chances of of VA ≥ 10/20 (3/6) increased by early vitrectomy, at least for eyes
with severe new vessels.
Early vitrectomy for eyes with recent severe VH and VA < 5/200 (5/60) was
beneficial, especially for patients with type I DM. Furthermore, the chances of
achieving VA of 10/20 (3/6) or better increased when early vitrectomy was
performed in eyes with severe new vessels, again especially for patients with
type I DM.

28. Treatments for Diabetic
Retinopathy
Standard therapies:
• Laser photocoagulation
• Surgical intervention (vitrectomy)
• Medical therapies delivered into
the eye (intravitreal injections*)
• Systemic medical therapies
involving blood sugar, blood
pressure, and cholesterol control
* Note : Some drugs are used as an off label indication for the
management of DR
Berco E, Rappoport D, Pollack A, Kleinmann G, Greenwald Y. Management of Diabetic Retinopathy and Other Ocular Complications in Type 1

29. Background :
Laser and supplemental therapy for
management of DR
Protocol S:
This study showed that ranibizumab injections are effective in treating proliferative
diabetic retinopathy.
At two years, vision of the ranibizumab group on average improved by half a line on
an eye chart.
Vision of the laser group remained unchanged
• Current treatment for PDR is pan-retinal photocoagulation (PRP)
 Inherently destructive
 Adverse effects on visual function
• Some eyes with PDR+DME now receive anti-VEGF as standard care for DME
• Would initial treatment of PDR with intravitreal anti-VEGF delay or prevent need for
PRP?

30. STUDY OBJECTIVE AND
TREATMENT GROUPS
Prompt
PRP
To determine if visual acuity outcomes at 2 years
in eyes with PDR (with or without concurrent
DME) that receive anti-VEGF therapy with
deferred PRP are non-inferior to those in eyes
that receive prompt PRP therapy.
0.5mg
ranibizuma
b with
deferred
PRP
(Note: Study ranibizumab may be given as needed for DME using Protocol I
retreatment as guidelines.)
Bressler NM, Beck RW, Ferris III FL. Panretinal photocoagulation for proliferative diabetic retinopathy. New England Journal of Medicine.
2011 Oct 20;365(16):1520-6.

31. Endpoints for measuring the
outcome
Primary End Point
 Is visual acuity using ranibizumab for PDR not worse than treatment with
PRP at 2 years?
 Non-inferiority margin of 5 letters
Secondary End Point
Are there potential benefits of ranibizumab on:
 Vision throughout follow-up (area under the curve)
 Peripheral vision
 Macular edema
 Incidence of vitrectomy

32. Follow-up Schedule
Baseline to
1 Year
PRP group: Visits every 16
weeks*
Ranibizumab group: Visits
every 4 weeks to assess for
PDR treatment
Both groups simultaneously
evaluated for DME treatment
1 Year to
2Years
PRP group: Visits every 16
weeks*
Ranibizumab group: Visits
every 4wk to 16wk to assess
for PDR treatment
Interval is extended if
injections for PDR and DME
deferred (“Defer and Extend”)
Bressler NM, Beck RW, Ferris III FL. Panretinal photocoagulation for proliferative diabetic retinopathy. New England Journal of Medicine.
2011 Oct 20;365(16):1520-6.
*Eyes with DME could be seen more frequently for DME
treatment as needed.

33. Ranibizu
mab
Group
N = 191
N = 160
(84%)
N = 88%
N = 22
(18, 24)
Randomization
Participants:
N = 304
Eyes: N = 394
PRP Group
N = 203
N =
168 (83%)
N =
86%
2-
Years
2-Years
Excludi
ng
Death
Baseli
ne
N =
16 (9, 22)
Median
(Quartiles) No.
Visits over 2
years
Bressler NM, Beck RW, Ferris III FL. Panretinal photocoagulation for proliferative diabetic retinopathy. New England Journal of Medicine.
2011 Oct 20;365(16):1520-6.

34. Baseline Characteristics
Ranibizu
mab
Group
(N = 191)
PRP
Group
(N = 203)
Age (yrs) – Median 52 51
Women 43% 45%
Race
White 52% 50%
Type 2 diabetes 73% 76%
Duration of Diabetes
(yrs)
18 17
Median HbA1c (%) 8.6 8.9

35. Ocular Baseline Characteristics
Ranibizu
mab
Group
(N = 189)
PRP
Group
(N = 199)
Diabetic Retinopathy Severity by Reading Center
NPDR† 10% 13%
Mild to moderate
PDR
52% 49%
High risk PDR to
advanced PDR
38% 37%
† There were 46 eyes (12%) for which NV was not identified by the reading center on the submitted color images or
quality precluded identification. In 29 of these cases (63%), subsequent review of additional images (e.g. FA) confirmed
NV, leaving 17 (4%) of 394 subjects with no photographic documentation of PDR.

36. Ocular Baseline Characteristics
Ranibizum
ab
Group
(N = 189)
PRP
Group
(N = 201)
Mean OCT CST* (µm) 262 249
< 250 µm 66% 67%
250 to 349 µm 19% 26%
≥ 350 µm 15% 7%
Presence of central-
involved DME with VA
loss**
22% 23%
*OCT values are Stratus equivalents
**Eyes with visual acuity letter score ≤ 78 (20/32 or worse) AND OCT CST ≥ machine and gender
Required ranibizumab at baseline

37. Treatment For Proliferative
Diabetic Retinopathy

38. PRP Group
Overall
(N =
203)
Completed initial full
PRP
98%
Performed in 1
Sitting
54%
Baseline PRP
Overall
(N = 203)
Eyes given additional PRP
(after completing initial full
PRP)
45%
Distribution of timing to additional PRP
From completion of initial full
PRP:
median time to additional
PRP
~7 months
Additional PRP

39. Ranibizumab Group
# of Ranibizumab Injections
Eyes With
Baseline DME
(N = 36)
Eyes Without
Baseline DME
(N = 133)
Prior to 1-year Visit (Max possible = 13)
Median 9 7
Mean 8.9 6.9
Prior to 2-year visit (Max possible= 26)
Median 14 10
Mean 13.3 10.1
Note: 97% of protocol-required injections for PDR were given
Overall
N = 191
Received PRP* before 2
years
12 (6%)
Received PRP for PDR
*1 met failure criteria, 1 with Protocol Chair approval,
1 without Chair approval, 8 during vitrectomy (e.g., via
endolaser), and 1 by non-study physician

40. Mean Change in Visual Acuity
Outlying values were truncated to 3 SD from the mean
-5
0
5
10
15
0 16 32 52 68 84 104
Mean
Visual
Acuity
Change
(Letter
Score)
Visit Week
Ranibizumab Group PRP Group
N =
N =
203
+
2.8
+ 0.2
N =
168
N =
160
2-Year Adjusted
Mean Difference:
+2.2 letters
95% Confidence
Interval: (-0.5, +5.0)
(Meets pre-specified
non-inferiority
criterion: lower
bounds of the 95%
CI of -0.5 letters was
greater than the non-
inferiority limit of -
5.0 letters)

41. -4
1
6
11
0 16 32 52 68 84 104
Mean
Visual
Acuity
Change
(Letter
Score)
Visit Week
With “Baseline DME”
Ranibizumab Group PRP Group
+
+7.
-5
0
5
10
0 16 32 52 68 84 104
Visit Week
Without “Baseline
DME”
-
0.5
+1.
8
N = 42 N = 33N =
147
N = 46 N = 37N =
155
N =
130
N =
126
*Outlying values were truncated to 3 SD from the
an Change in Visual Acuity
Stratified by Baseline DMEMe

42. Discussion
 DRCR.net Protocol S (PRP vs. Ranibizumab
for PDR):
 Treatment with 0.5-mg ranibizumab met primary non-inferiority outcome for
VA being no worse than PRP
 Summary of Ranibizumab group results vs. PRP:
 Mean change in VA from baseline to 2-years with ranibizumab no worse
than with PRP
 Superior mean visual acuity over course of 2-years (area under the curve
analysis)
 Superior mean visual field outcomes
 Decreased occurrence of vitrectomies
 Decreased development of central involved DME
 PRP rarely given for failure or futility of ranibizumab

43. Discussion
 No systemic safety concerns with ranibizumab
identified among pre-specified major safety outcomes
 Increased frequency of adverse events defined by
cardiac, endocrine, respiratory, infections/infestations,
skin and surgical conditions MedDRA systems in
ranibizumab groups could be real, due to chance, or
due to ascertainment bias (more visits in ranibizumab
group)
 Interpretation of systemic safety difficult since large
proportion of PRP group received ranibizumab per
protocol for DME

44. SYSTEMIC MANAGEMENT
• Glycemic control – Insulin, OHG
• Blood pressure control – Anti-hypertensive medications
• Cholesterol control – Statins, Fibrates
• Support renal function – ACEI, ARB
• Lifestyle modification – Smoking and alcohol cessation, exercise ,weight
control

45. DIABETES CONTROL &
COMPLICATION TRIAL (DCCT)
 STUDY GROUP
Intensive management of blood glucose (multiple daily
insulin injection) vs conventional management
 CONCLUSIONS
intensive control reduced the risk of developing retinopathy by
76% and slowed progression of retinopathy by 54%.
Intensive control reduced the risk of clinical neuropathy by
60% and albuminuria (Nephropathy) by 54%

46. UNITED KINGDOM
PROSPECTIVE DIABETES
STUDY (UKPDS)
 Patients were assigned to a conventional policy starting
with diet or to an intensive policy starting with a sulfonyl
urea or insulin. If overweight and in the intensive group,
patients were assigned to start treatment with metformin
 Patients were randomly assigned to tight control of BP
(ACE inhibitor or beta blocker) or to less tight control

47. RESULTS
 Intensive control of blood glucose level slowed progression
of retinopathy and reduced other microvascular
complications
 Intensive control of BP slowed progression of diabetic
reinopathy and reduced other microvascular &
macrovascular complications

48. PROMINENT-Eye Ancillary Study
 To assess whether treatment with pemafibrate (0.2 mg
orally BID) compared with placebo reduces the hazard rate
of diabetic retinopathy worsening in adults with type 2
diabetes and diabetic retinopathy without
neovascularization in at least one eye who are participating
in the parent PROMINENT trial.
 FIELD (Fenofibrate Intervetion and Event Lowering in
Diabetes) and The Action to Control Cardiovascular Risk in
Diabetes (ACCORD)-eye study, have demonstrated
clinically important reduction in progression of retinopathy in
patients with diabetes assigned to fibrate compared with
placebo.

49. INDICATIONS OF
TREATMENT
NVD > 1/3 disc in area Less extensive NVD
+ hemorrhage
NVE > 1/2 disc in area
+ hemorrhage

50. 1. ARGON LASER (514.5 nm)
• All eyes with CSMO should be considered for laser photocoagulation
irrespective of the level of visual acuity.
• Reduces the risk of visual loss by 50%.
• Two types- focal and grid
i. Focal treatment - Burns are applied to microaneurysms and microvascular
lesions in the centre of rings of exudates located 500-3000 µm from the
centre of the macula.

51. ii. Grid treatment – Burns are applied
to areas of diffuse retinal thickening
more than 500 µm from the centre
of the macula and 500 µm from the
temporal margin of the optic disc.
Spot size - 50-100 µm
Exposure time – 0.1-0.5sec
• 70% of eyes achieve stable visual acuity after laser photocoagulation
• 15% show improvement
• 15% subsequently deteriorate.

52. 2.QUENCY-DOUBLED Nd:YAG LASER (532 nm)
MICROROPULSE DIODE LASER (780-850 nm)
DYE LASER (570-630 nm)

53. LASER SETTINGS
• SPOT SIZE depends on the contact lens used.
With Goldmann lens spot size is set at 200-500 µm, but with a
panfundoscopic-type lens it is set at 100-300 µm because of induced
magnification.
Other lenses used are – Volk, Mainster, Rodenstock
• DURATION OF BURN - 0.05-0.1 sec
• POWER - 250-570 mW, sufficient to produce only a light intensity burn
causing stimulation of the retinal pigment epithelium. The end point is a
whitening or darkening of the microaneurysms.

54. ASSESSMENT AFTER LASER PHOTOCOAGULATION
GOOD INVOLUTION POOR INVOLUTION
• Regression of neovascularization leaving
‘ghost’ vessels or fibrous tissue
• Decrease in venous changes
• Absorption of hemorrhages
• Disc pallor
• Persistent neovascularization
• Hemorrhage

56. POST LASER

57. ANTI VEGF
 Blocks VEGF molecules, thereby decreases new vessel
formation & reduces macular edema
 BEVACIZUMAB
 RANIBIZUMAB
 AFLIBERCEPT
 PEGAPTANIB

58. BEVACIZUMAB
 Recombinant humanized monoclonal antibody
 Inhibits VEGF A & blocks angiogenesis
 Approved for use in metastatic colon cancer, certain lung
cancer, renal and ovarian cancers
 Not yet approved by FDA, off label use in ophthalmology
 Dose: 1.25 mg in 0.05 ml

59. RANIBIZUMAB
 Monoclonal antibody fragment , binds to VEGF A
 0.5 mg in 0.05 ml
 costly

60. AFLIBERCEPT
 Recombinant fusion protein
 Binds to VEGF receptors 1 and 2

61. PARS PLANA
VITRECTOMY

62. INDICATIONS OF PARS PLANA VITRECTOMY
Severe persistent vitreous hemorrhage Dense, persistent premacular hemorrhage
Progressive proliferation despite laser therapy Retinal detachment involving macula

63. BENEFITS OF PPV
Vitrectomy prevents or delays:
• Persistent intra-gel hemorrhage
• Retinal detachment
• Opaque membranes
• Rubeosis iridis
VISUAL RESULTS OF PPV
• 70 % of cases achieve visual improvement
• 10 % are made worse
• 20 % remain unchanged
POOR PROGNOSTIC FACTORS
• Age > 40 years
• Preoperative iris neovascularisation
• Cataract
• Visual acuity < 5/200 (5/60)
• Retinal detachment
• No previous photocoagulation