Diabetic Eye Disease

I.  Overview

Diabetic retinopathy is the most common eye disease affecting people diagnosed with diabetes mellitus and a leading cause of blindness in adults.  The term “diabetic retinopathy” refers to a variety of disorders characterized by changes in the eye’s light-sensitive retina that can occur in people diagnosed with diabetes.  Diabetic eye diseases cause damage to the retina through swelling, fluid leaks, or abnormal growth of blood vessels, resulting in severe vision loss or blindness. Usually affecting both eyes, diabetic retinopathy may not be noticeable for some time, resulting in serious retinal damage before any changes in vision become noticeable.

Alimera Sciences Inc. is a privately held biopharmaceutical company that specializes in the research, development and commercialization of ophthalmic pharmaceuticals. We are currently in the process of completing two 36 month Phase 3 pivotal clinical trials with Iluvien™ for diabetic macular edema (DME). Combined enrollment of 956 patients was completed in October 2007 and a preliminary 24 month readout of the studies is planned for the end of 2009. 

As incidences of diabetes and diabetic retinopathy escalate, Alimera Sciences is in the forefront of research and development to meet the increasing need for reliable, effective treatments. Our substantial commitment of resources and extensive development experience indicates our dedication to provide effective remedies to the approximately 300,000* people diagnosed with diabetic macular edema each year.

*Source: Alimera Sciences management estimates


II. Diabetic Eye Disease ye Disease

There are two types of Diabetic Retinopathy:

Nonproliferative Retinopathy – The early stage and most common form of retinopathy, nonproliferative retinopathy, or NPDR, is a degenerative condition in which abnormal blood vessels in the retina swell and leak fluid into the macula, the part of the eye that allows us to see objects in great detail.  Build up of this fluid causes the macula to swell, resulting in blurred vision. This condition is called macular edema.  A patient with macular edema experiences blurred, distorted, or darkened vision.  NPDR typically occurs in both eyes, although the severity may differ for each eye. People with NPDR may adapt to the condition and see well enough to continue with daily activities.

Proliferative Retinopathy - The second and more severe stage of diabetic retinopathy is called proliferative retinopathy, or PDR. In this progressed stage, damaged blood vessels close, cutting off supply of blood to the retina. The body reacts by attempting to grow new blood vessels, but these tend to be abnormal and may grow in tissue that usually doesn’t contain them.  These abnormal blood vessels break and bleed into the inner parts of the eye, creating blurred vision and dark spots that obstruct vision, eventually destroying the retina and causing periods of temporary loss of vision or permanent blindness. As the condition progresses, a cycle develops wherein the eye continues to respond to a lack of blood flow by growing additional weak blood vessels which continue to hemorrhage and cause more scar tissue.  The scar tissue accumulates and begins to pull on the retina, which can ultimately cause the retina to detach from the wall of the eye, a condition called retinal detachment.  Retinal detachment results in a loss of vision but can be addressed by a retinal physician.   

Eye disorders attributable to diabetic retinopathy include diabetic macular edema, cataracts, and glaucoma.

Macular Edema - Macular edema occurs when blood vessels in the retina begin to leak into the macula, the part of the eye responsible for detailed central vision. When this occurs in a patient with diabetes, it is referred to as diabetic macular edema or DME.  These leaks cause the macula to thicken and swell, progressively distorting acute vision.  While the swelling may not lead to blindness, the effect can cause a severe loss in central vision. DME is the major cause of vision loss in people with diabetic retinopathy.  

Cataracts – A cataract is a progressive clouding in the lens of the eye that blocks light, causing blurry or distorted vision.  While cataracts can be a natural result of aging, people diagnosed with diabetes are 60% more likely to develop cataracts, usually at a younger age, and have them progress faster.  Cataract surgery is the most frequently performed surgery in the United States.

Glaucoma
Glaucoma is the result of an increase of intraocular pressure that builds in the eye, damaging the optic nerve and causing impaired vision and blindness. People with diabetes are 40% more likely to develop glaucoma than those who don’t have the disease.  Risk of glaucoma increases with age, and the longer a person has diabetes, the more likely they are to develop glaucoma.

II. Prevalence

Diabetic retinopathy is the leading cause of vision loss among working age adults in developed countries. For people with diabetes, the risk of blindness is more than 3 in 100,000 people.  The disease affects nearly half of all Americans diagnosed with diabetes, and is the leading cause of new cases of blindness among adults between the ages of 20 to 74.  Over 12,000 to 24,000 new cases of blindness occurring each year are attributed to diabetic retinopathy. 

The incidence of diabetes is rising, and will continue to do so. Here are some facts regarding diabetes.

• All diabetics with Type 1 and Type 2 diabetes are at risk of developing some form of diabetic retinopathy.
• The longer a person has diabetes, the more likely they are to develop diabetic retinopathy. 
• In the U.S., the Centers for Disease Control estimated that in 2005 23.6 million, or 7.8% of the population, are believed to have diabetes, with another 54 million in the pre-diabetic stage.
• • 23.5 million, or 10.7% of all people age 20 years or older* have diabetes, and 12.2 million, or 23.1% of all people age 60 years or older have diabetes.
• Current statistics reveal an ongoing upward trend in incidences of diabetes, from 2.5% in 1980 to 5.8% in 2007.
• Current estimates are that by 2050 12% of the population will be diagnosed with diabetes.
• At present, one out of five health care dollars is spent caring for someone with diagnosed diabetes, and one in ten health care dollars is attributed to diabetes.
• Diabetics incur medical expenses approximately 2.3 times higher than those without the disease.

*Source:  American Diabetes Association statistics:  http://www.diabetes.org/diabetes-statistics/prevalence.jsp

III. Vision Loss & Blindness

Diabetes is a disease in which the body has high levels of sugar in the blood.  Diabetes occurs when the pancreas can’t create enough of the hormone called insulin to control blood sugar levels.  In Type 1 diabetes, which occurs mainly in childhood or early adolescence, the pancreas doesn’t produce any insulin at all and daily insulin injections are required to maintain proper health. Type 2 diabetes, or non-insulin dependent diabetes, can usually be controlled by diet and exercise although Type 2 diabetics may eventually require insulin as well.

Over time, high sugar levels caused by diabetes can damage the retina, the nerve layer on the back of the eye that senses light and transmits impulses through the optic nerve to the brain. Risk factors which contribute to the onset of diabetic retinopathy include high blood pressure, pregnancy, kidney disease, high cholesterol, and smoking. Family history with diabetes and genetics can also be a factor.  Typically, the longer a person has diabetes, the more likely diabetic retinopathy can occur.

Early symptoms of diabetic retinopathy can go unnoticed because it has few or no symptoms. Early indicators include tiny hemorrhages on the back of the eye, and accumulation of fat products, or “exudates”, leaking from blood vessels in the back of the eye, which can also cause swelling and create pressure. If these minute leaks occur near the macula, they can accumulate and obstruct vision, leading to macular edema.

IV. Disease Course

As identified by the National Eye Institute, retinopathy progresses through four stages:

1. Mild Nonproliferative Retinopathy – This is the stage in which small areas of balloon-like swelling occur in tiny blood vessels in the retina.
2. Moderate Nonproliferative Retinopathy – At this stage, blood vessels that supply nutrients to the eye become closed off and blocked.
3. Severe Nonproliferative Retinopathy – More and more blood vessels cease to function, cutting off blood supply to the retina. The retina signals the body to grow new blood vessels.
4. Proliferative Retinopathy – New blood vessels appear, but they are abnormal and weak.  They grow along the clear gel that fills the eye.  When the thin, fragile walls of the blood vessels begin to leak blood, severe vision loss or blindness can occur. 

Diabetic macular edema, or DME, a complication of diabetic retinopathy, is a disease affecting the macula, the part of the retina responsible for central vision. The macula is the central portion of the retina, a small area rich in cones, the specialized nerve endings that detect color and upon which daytime vision depends.

DME occurs when the blood vessel leakage of diabetic retinopathy causes swelling in the macula. The onset of DME is painless and may go undetected by the patient until it manifests with the blurring of central vision or acute vision loss.  As DME develops, blurring occurs in the middle or just to the side of the central visual field. Visual loss from DME can progress over a period of months and make it impossible to focus clearly. DME is common in those afflicted with diabetes. The lifetime risk for diabetics to develop DME is about 10%. The condition is closely associated with the degree of diabetic retinopathy (retinal disease).

DME is classified into focal and diffuse types. Focal macular edema is caused by foci of vascular abnormalities, primarily microaneurysms, which tend to leak fluid whereas diffuse macular edema is caused by dilated retinal capillaries in the retina.

V. Treatments

Diabetic Retinopathy
Nonproliferative Retinopathy - No treatment is required for mild, moderate, and severe Nonproliferative Retinopathy, which is typically managed through control of levels of blood sugar, blood pressure, and blood cholesterol.

Proliferative Retinopathy - Treatment options for Proliferative Retinopathy include forms of laser surgery called scatter photocoagulation and focal photocoagulation. In photocoagulation, tiny burns are placed on the retina with a special laser. These burns seal the blood vessels and stop them from growing and leaking. In scatter photocoagulation, abnormal blood vessels are shrunk by a retina specialist who appliesapplying as many as 2,000 laser burns in a polka dot pattern in areas of the retina away from the macula. While some loss of side vision may occur, scatter photocoagulation can save the rest of a person’s sight. However, it is only effective before bleeding or detachment has progressed very far. In focal photocoagulation, specific leaking blood vessels in a small area of the retina, usually near the macula, are addressed. The retina specialist identifies individual blood vessels for treatment and makes a limited number of laser burns to seal them.

Diabetic Macular Edema
Two types of laser treatment for DME are focal and grid. Focal laser treatment is used to treat focal diabetic macular edema; the aim is to close leaking microaneurysms. Grid laser treatment is used to treat diffuse DME and is applied to areas of retinal thickening in which there is diffuse leakage; the aim is to produce a retinal burn of mild to moderate intensity.

The patient is rechecked several months after treatment and, if the DME is not responding to treatment, the laser treatment is repeated. The goal of treatment is to maintain current visual acuity and reduce the chances of progressive visual loss. Even with successful treatment, visual acuity often does not improve.

If bleeding in the inner eye is severe, blood is removed from the center of the eye in a surgical procedure called a vitrectomy.  A small instrument is placed through an incision to remove the clouded vitreous gel and replace it with a salt solution. While this procedure does not cure the disease, it is repeatable should DME reoccur.

Glaucoma
Treatment for glaucoma may be medication or surgery, dependent on the type of glaucoma being treated.  Medication which reduces pressure in the eye is usually applied using eye drops.  When medication is not sufficient, laser surgery is used to lower the pressure in the eye and prevent damage to the optic nerve.

Cataracts
The effects of mild cataracts can be reduced by wearing sunglasses with glare control lenses.  When cataracts progress to the point that they impair everyday activities, surgery can be very successful in restoring vision. A relatively simple procedure, the clouded lens is removed from the eye and replace with a clear plastic lens. 

VI. Experimental Research

Iluvien™, an innovative new product developed by Alimera Sciences, may soon revolutionize treatment for diabetic macular edema (DME).  This new procedure uses a tiny intravitreal insert to deliver a low dose of corticosteroid fluocinolone acetonide directly into the retina for slow release
for up to three years. Patients would receive during an in-office procedure that takes minutes
and is administered through a self-healing wound, eliminating sutures. is currently in
Phase III clinical trials and not approved by any regulatory agencies.
To learn more, click here