1. Emerging Trends In the Treatment of Diabetic Macular Edema
University of Milan
June 2007
Anthony Cavallerano, OD, FAAO
VA Boston Health Care System
New England College of Optometry
Boston, Massachusetts

2. Diagnosed Cases (Millions)
Diabetes: 20.8 Million and Climbing
14 million diagnosed million undiagnosed
Type 2 diabetes accounts for 90-95% of cases
+60% 12
+17% 8
Diagnosed Cases (Millions) 4
1980
1990
2000
Centers for Disease Control and Prevention

3. Risk Factors for Prediabetes
Age
45 years or older
Younger than 45, overweight, and have one or more of the following risk factors:
Family history of diabetes
Low HDL cholesterol and high triglycerides
Hypertension
History of gestational diabetes or gave birth to a baby weighing more than 9 pounds
Minority group background
African American
American Indian, Hispanic American/Latino
Asian American/Pacific Islander)

4. Scope of the Problem
Total: 20.8 million children and adults % of the population -- have diabetes.
10.3 million over age 60
Diagnosed: 14.6 million people
Undiagnosed: 6.2 million people
Pre-diabetes: 41 million people
1.5 million new cases of diabetes were diagnosed in people aged 20 years or older in 2005.

5. Introduction Historical Background:
Diabetic Macular Edema (DME) was unrecognized before invention of the ophthalmoscope (Helmholtz, 1851).
Jaeger in 1856 was the first to describe a “roundish or oval yellow spots and extravasations which permeate part or the whole thickness of the retina” in a patient with positive urine glucose test for Diabetes Mellitus.
That same year Von Graefe refuted any relationship of the eye findings to diabetes.

6. Introduction Historical Background (cont’d):
In 1869 Noyes established a causal relationship between the changes described by Jaeger and Diabetes Mellitus (DM).
In 1872 Nettleship confirmed this theory in his treaties on the issue (“Noyes’ glucosuric retinitis”).
In 1875 Appolinaire in Paris reported these observations and described in addition, the accumulation of lipid in the retina which he designated “glucose induced amblyopia.”
Diabetic Macular Edema (DME) was thereafter recognized as a clinical entity.

7. Diabetic Macular Edema (DME)
Definition: Diabetic macular edema
is retinal thickening caused by the accumulation of intraretinal fluid primarily in the inner and outer plexiform layers. It is believed to be a result of hyperpermeability of the retinal vasculature.
Can be present with any level of diabetic retinopathy (DR).

8. Clinically Significant Macular Edema
Retinal thickening at or within 500 µm from the center of the macula or
Hard exudates at or within 500 µm from the center of the macula if accompanied by thickening of the adjacent retina or
A zone of retinal thickening, 1 disc area or larger in size, located 1 disc diameter or less from the center of the macula

9. Factors affecting DME Incidence of DME increases with
Elevated levels of Hb A1C
Level of severity of DR
Duration of DM
Elevated diastolic blood pressure
Gender (more frequent in females)
Wisconsin Epidemiologic Study of DR
Klein R et al. Ophthalmology 1998;105:

10. US Epidemiology : 5.8 million people are known to have DM in the USA
4 to 5 million Americans have DM that has not been diagnosed
9% of diabetic population in US will have macular edema
Of these, 200,000 patients with “macular edema alone” are at risk of moderate visual loss (Aiello and Ferris, 1987).

11. Pathophysiology in Diabetic Macular edema
Collection of intraretinal fluid
Nonperfusion of capillaries
Traction on the macula
Intraretinal heme/ pre retinal heme
Macular hole formation
Combinations of above

12. Clinical Characteristics
A wide spectrum
Focal Leakage
Diffuse Leakage
Combination of diffuse and focal leakage

13. Clinical Characteristics
Focal leakage:
usually limited to well defined areas of leakage, such as microaneurysms.
F A will clearly show the source of leakage
Jalkh, A. Atlas of Fluorescein Angiography

14. Clinical Characteristics
Diffuse leakage:
widespread, poorly demarcated leakage believed to be related to the destruction of the inner blood retinal barrier.
F A will show widened intercapillary spaces, with diffusely dilated bed, and diffuse leakage.
? RPE dysfunction

15. Laser Treatment for CSME
Focal:  spots to areas of discrete leakage
Grid:  spots in areas of diffuse leakage
“Focal-Grid”: combination of the above

16. Macular edema & laser rx
ETDRS showed that in eyes with CSME, focal laser photocoagulation reduces the risk of moderate visual loss by 50% or more.
It also reported an increase in the chance of improvement on the final BCVA.

17. Macular edema & laser rx
Other studies confirmed the positive effect of laser rx (Patz et al 1973, Blankenship 1979, Olk 1985, and Lee 1991).
However, in all the studies, 15%-24% of eyes experienced moderate visual loss despite focal laser rx.
These eyes generally had diffuse diabetic macular edema (DDME) or poor macular perfusion.

18. Diabetic Retinopathy Features Reduced retinal blood flow
Closure of retinal capillaries and arterioles
Ischemia/Cotton-wool spots
Breakdown of the blood/retinal barrier with increased vascular permeability of retinal capillaries
Intraretinal microvascular abnormalities (IRMA) also found adjacent to areas of capillary closure
70% of NVE occurs in same area as IRMA
Proliferation of new vessels and fibrous tissue
Contraction of vitreous and fibrous proliferation with VH and RD

19. Current Therapies for Microvascular Complications
Intervention
Demonstrated Efficacy to Delay or Prevent
Retinopathy Nephropathy Neuropathy
Glucose Control +
BP Control
ACE Inhibitors ?+
LDL Control ?
Aspirin No
Smoking Cessation

20. Case Study EM

21. Case Studies - Patient EM
59-year-old African-American male
Type 2 DM x 11 yrs
LEE: 1.5 yr
Pt complaint “having trouble seeing”
PMHx:
Uncontrolled HTN
+ proteinuria
Last HbA1c = 11.1%
Meds: insulin, antihypertensive

22. Patient EM Cholesterol levels within normal limits
Current Albumin/Creatine level = µg/mg (Normal: µg/mg)
Triglycerides and LDL levels calculated but non- fasting

23. Case Study EM Exam Findings VA OD 20/30+ OS 20/30
Sensorimotor exam normal
No distortion with Amsler grid
Early NSC, PSC OU; early CC, vacuoles OS
IOP 14mmHg OU

24. Case Study EM
Plan
Laser treatment for macular edema within one to two weeks
Control of BP and BG

25. Case Study EM Treatment Focal laser treatment 4 month follow-up
OD at 3 weeks
OS at 7 weeks
4 month follow-up

26. Case Study EM
Notes
HTN, renal disease and dyslipidemia can affect onset and progression of retinopathy
Co-management with other health care providers
Lesions that may indicate nondiabetic etiology
Venous caliber abnormalities
Parapapillary cotton wool spots of similar onset
Flame-shaped hemorrhages
Diffuse retinal edema
White centered hemorrhages (Roth’s spots)

27. Case DG 35-year-old Caucasian male Type 1 DM 23 years
VA: OD-20/30; OS-20/40
Denies hypertension, renal disease, hypercholesterolemia/dyslipidemia

28. Patient DG Diagnosis: Plan: Moderate NPDR OU DME not CSME OD
Clinically Significant Macular Edema OS
Plan:
FA to identify treatable lesions OS
Focal laser photocoagulation OS

29. Clinical Characteristics
Focal leakage:
Well defined areas of leakage; e.g., microaneurysms
FFA will clearly show the source of leakage
Diffuse leakage:
Poorly demarcated widespread leakage
Destruction of the inner blood retinal barrier.
FFA will show widened intercapillary spaces, with diffusely dilated capillary bed, and diffuse leakage.
RPE dysfunction

30. Macular Edema & Laser Treatment
Focal:  spots to areas of discrete leakage
Focal Grid:  spots in areas of diffuse leakage
Combination of the above

31. Clinically Significant Macular Edema (CSME)
Retinal thickening at or within 500  from the center of the macula
Hard exudates at or within 500  from center of the macula with thickening of adjacent retina
An area or areas of retinal thickening at least one disc area in size, at least part of which is within one disc diameter of the center of macula

32. Role of Hypertension in DME
WESDR - diabetic patients with HTN had 3 x incidence of DME.
UKPDS__rigorous BP control with ACE-inhibitor or -blocker reduced the risk of the two-step progression of DR significantly.

33. Role of Hypertension in DR
Impairs retinal vascular autoregulation
Promotes endothelial damage in retinal vasculature
Increases expression of Vascular Endothelial Growth Factors (VEGF) and its receptors by vascular stretch of retinal endothelium

34. Role of Renal Disease in DME
Gross proteinuria associated with 95% increased risk of DME (WESDR)
Case reports of reduction of diabetic macular edema after dialysis
Type 1 patients with microalbuminuria have three-fold risk of PDR compared to those with normal levels

35. Role of Serum Lipids in DR
Elevated serum lipids are associated with increased risk of retinal hard exudates
Increased amounts of hard exudates are associated with increased risk of visual impairment
Elevated lipids, most notably triglycerides, are a risk factor for development of high-risk PDR
ETDRS Report # 18 and 22

36. Role of Protein Kinase C Activation in the Retinal Vasculature
Increases:
Basement matrix protein synthesis
Activation of leukocytes
Endothelial cell activation and proliferation
Smooth muscle cell contraction
Cytokine activation, TGF-, VEGF, endothelin
Angiogenesis
Endothelial permeability

37. Role of Vitreous in DME
Vitreomacular traction is believed to be a contributor to the multifactorial etiology of DME.
The role of the posterior hyaloid in a subset of eyes with diffuse macular edema has become increasingly recognised (Schepens et al, 1984).
Nasrallah et al observed that a posterior hyaloid separation was more common in diabetic eyes without M.E than with M.E (55% v/s 20.0%).
(Nasrallah et al, Ophthalmology vol 90: 1988)

38. Case CD 35-year-old Caucasian male Type 1 DM 10 years
VA: OD-20/25; OS-20/20
Amsler Grid: Normal OD and OS

39. Diagnosis OD Severe NPDR OD CSME OD
HE < 500 microns from center of macula
Th < 500 microns from center of macula

40. Management MA with late leakage into fovea
Lesions ring the foveal avascular zone and are < 500 microns from center and not amenable to laser photocoagulation
Novel and evolving therapies for DME

41. Diabetic Retinopathy Clinical Research Network
DRCR.net: Dedicated to multicenter clinical research of
diabetic retinopathy, macular edema & associated disorders

42. DRCR Network Overview Funding: Objective:
National Eye Institute-sponsored cooperative agreement initiated September 2002
Objective:
The development of a collaborative network to facilitate multicenter clinical research on diabetic retinopathy, diabetic macular edema and associated conditions.

43. DRCR Network Sites DRCR.net >150 sites overall >90 community
>450 total PIs
>1000 study personnel
40 States

44. DRCR CURRENTLY RECRUITING STUDIES
Randomized trial comparing intravitreal triamcinolone acetonide and laser photocoagulation for DME
Evaluation of vitrectomy for DME
Observational study of development of DME following scatter laser photocoagulation
Subclinical DME study

45. A Randomized Trial Comparing Intravitreal Triamcinolone Acetonide and Laser Photocoagulation for Diabetic Macular Edema
To determine whether intravitreal triamcinolone acetonide injections at doses of 1mg or 4mg produce greater benefit, with an acceptable safety profile, than macular laser photocoagulation in the treatment of diabetic macular edema.
To compare the efficacy and safety of the 1mg and 4mg triamcinolone acetonide doses

46. Study Design Phase 3, multicenter, randomized clinical trial
Randomization to one of three treatment groups:
Standard of care group: conventional treatment consisting of modified ETDRS photocoagulation
Intravitreal injection of 1mg of triamcinolone acetonide
Intravitreal injection of 4mg of triamcinolone acetonide
Duration of follow-up: Three years
Injection volume always = 0.05ml

47. Intraocular Formulation Comparison with Kenalog®-40
Ingredient
Allergan Form
Kenalog® -40
Triamcinolone Acetonide
2 and 8% 4%
Benzyl Alcohol -
0.99%
Polysorbate 80
0.04%
Sodium Chloride
To Isotonicity
Sodium Phosphate
0.34%
Sodium Hydroxide/ Hydrochloric Acid
to pH 7.3
to pH

48. Formulation and Packaging
Preservative & endotoxin free
Isotonic and pH Balanced
Single-unit Dosing
Allergan
Sterile, prefilled (0.05ml), single-dose, ready-to-use syringe with attached 27-gauge needle.
Shelf-stable and requires no shaking to re-suspend.
Homogeneous, white suspension, easily delivered.

49. Clinical Experience >75 active sites in >20 states
>40 sites with pending certification
First patient 7/14/04
>300 patients enrolled

50. Evaluation of Vitrectomy for Diabetic Macular Edema
To provide information on the following outcomes in eyes with DME that undergo vitrectomy: visual acuity, retinal thickening, resolution of traction (if present), surgical complications.
To identify subgroups in which there appears to be a benefit of vitrectomy and subgroups in which vitrectomy does not appear to be beneficial.

51. Subclinical Diabetic Macular Edema Study
Primary Objective: To determine the incidence of progression of subclinical diabetic macular edema (DME)
Subclinical DME—no edema involving the center of the fovea as determined by biomicroscopy but with center point thickness on OCT of at least 200 microns but less than or equal to 299 microns
Progression—increase in center point thickness of at least 50 microns to > 300 microns
Secondary Objectives:
To evaluate factors predictive of the presence of subclinical macular edema
To determine indicators of risk for progression of subclinical DME

52. STUDIES IN FOLLOW-UP PHASE
Pilot study of laser photocoagulation for diabetic macular edema
Pilot study of peribulbar triamcinolone acetonide for diabetic macular edema

53. Pilot study of laser photocoagulation for diabetic macular edema
Compare laser treatment as we now use it (called “standard method”) with a similar laser treatment that is milder in intensity, but more extensive in number (called “mild macular grid” method)

54. Pilot study of peribulbar triamcinolone acetonide for diabetic macular edema
To estimate the incidence of improvement of DME following a posterior peribulbar 40 mg triamcinolone acetonide injection compared with laser.
To estimate the incidence of improvement of DME following an anterior peribulbar 20 mg triamcinolone acetonide injection compared with laser.
To estimate the incidence of intraocular pressure elevation and other complications with each type of injection.
To provide preliminary data comparing the incidence of improvement of DME with a peribulbar triamcinolone alone versus peribulbar triamcinolone followed by laser photocoagulation.

55. UPCOMING STUDIES
A Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema: Avastin
200 patient, phase 2 randomized, multi-center clinical trial.
Provide preliminary data on the dose and dose interval related effects of intravitreally adminstered Avastin on retinal thickness and visual acuity in subjects with Diabetic Macular (DME) to aid in planning a phase 3 trial.
Provide preliminary data on the safety of intravitreally administered Avastin in subjects with DME.

56. COMPLETED STUDIES
Temporal Variation in OCT Measurements of Retinal Thickening in Diabetic Macular Edema
Determine the proportion of eyes that demonstrate a potentially meaningful change in central retinal thickening measured on OCT throughout the day.
Establish the time course of change for the eyes that experience diurnal change in central retinal thickening.
Evaluate intra-observer and inter-observer variability on OCT measurements.

57. Eye Research Determine basic mechanisms of disease
Identify potential therapeutic targets
Develop specific novel therapies
Evaluate at subcellular, cellular & organism level
Rigorous clinical trials
Opportunity to make today’s standard-of-care obsolete tomorrow