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 Anthony.cavallerano@va.gov

Diagnosed Cases (Millions) Diabetes: 20.8 Million and Climbing 14 million diagnosed + 6.8 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. 2003.

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)

Scope of the Problem Total: 20.8 million children and adults -- 7.0% 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.

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.

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.

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).

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

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;105:1801-1815

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).

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

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

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

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

Laser Treatment for CSME Focal: 50-100  spots to areas of discrete leakage Grid: 100-200  spots in areas of diffuse leakage “Focal-Grid”: combination of the above

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.

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.

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

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

Case Study EM

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

Patient EM Cholesterol levels within normal limits Current Albumin/Creatine level = 231.6 µg/mg (Normal: 0 - 20 µg/mg) Triglycerides and LDL levels calculated but non- fasting

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

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

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

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)

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

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

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

Macular Edema & Laser Treatment Focal: 50-100  spots to areas of discrete leakage Focal Grid: 100-200  spots in areas of diffuse leakage Combination of the above

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

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.

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

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

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

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

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)

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

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

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

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

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.

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

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

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

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

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 5.0 -7.5

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.

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

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.

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

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

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)

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.

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.

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.

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