Diabetic retinopathy is the most prevalent microvascular complication affecting diabetics and is the leading cause of blindness in working-age adults in the United States.
Currently, 17 million Americans have diabetes mellitus, and the past decade has witnessed a 39% increase in prevalence in the adult population, said Anthony A. Cavallerano, OD, FAAO, clinical coordinator of the Joslin Vision Network in Boston. More startling is the fact that there was a 70% upsurge in young adults in the 30- to 39-year-old age group, he said.
At this time, treatment options for diabetic retinopathy and macular edema include two forms of laser surgery: panretinal photocoagulation for proliferative diabetic retinopathy and focal photocoagulation for macular edema. However, a number of alternatives are being investigated for preventing and treating diabetic macular edema, according to Dr. Cavallerano.
Recent research has indicated that there is a great deal of hope for treating diabetic macular edema patients through the Envision TD (Bausch & Lomb, Rochester, N.Y.) ophthalmic implant.
Preventive measures such as nutritional supplements and aspirin intake are also being investigated, Dr. Cavallerano said. Most of these trials are directed toward improving retinal blood flow, he said, which is markedly reduced following prolonged hyperglycemia.
The Envision implant
Among the most noteworthy new approaches to diabetic macular edema treatment is Bausch & Lombs Envision TD, which is a small implant containing the steroid fluocinolone acetonide.
Usually treated with laser surgery: Clinically significant macular edema and proliferative diabetic retinopathy.
The steroid is implanted into the back of the eye to enable the delivery of consistent and sustained levels of fluocinolone directly to the affected area of the eye for up to 3 years.
Results of a recent phase 3, randomized, masked, clinical trial studying Envision found that patients with the implant showed a reduction in macular edema, as well as improved or stabilized visual acuity.
This positive news certainly underscores our confidence in the Envision technology and marks a significant step on the road to commercialization of this product, said Margaret Graham, director of corporate communications for Bausch & Lomb. The clinical trials data, along with the results of a second pivotal study now underway, will be part of our application to the Food and Drug Administration in 2003 to gain approval to market this product in the United States.
In the multicenter trial, 80 patients were randomized to receive standard of care (macular grid laser or observation) or either a 0.5-mg or 2-mg treatment. The 2-mg dose was discontinued early in the diabetic macular edema trial because data from other studies did not suggest a therapeutic advantage for the 2-mg over the 0.5-mg dose.
The primary endpoint for this trial was change in macular edema at 6 months compared to baseline, as assessed by retinal thickening. Patients receiving the 0.5-mg implant showed statistically significant improvement in macular edema compared to those receiving standard of care. Further, patients receiving the 0.5-mg implant experienced a greater improvement in severity of their diabetic retinopathy compared to those treated with standard of care. More than 80% of these patients also had improved or stable visual acuity, compared to 50% treated with standard of care.
The data show that treatment with the implant reduces the severity of the disease, improves or stabilizes patients vision and has a good safety profile, Ms. Graham said. The trial met its endpoints achieved what it set out to prove. While this is good news, we still have a long way to go before this product is approved, she said.
Vitamin E, aspirin, PKC
According to Dr. Cavallerano, there are several emerging alternatives in the treatment and prevention of diabetic retinopathy.
It is known that vitamin E has an effect on retinal hemodynamics and, therefore, is being studied in patients with diabetes, he said. The exact amount of vitamin E that might be beneficial is still unknown, but a number of ongoing clinical trials will help identify the proper dosage.
Another preventive regimen evaluated as part of the Early Treatment Diabetic Retinopathy Study (ETDRS) was the daily intake of aspirin, Dr. Cavallerano said. It was determined through ETDRS that aspirin treatment (650 mg per day) did not alter the progression of diabetic retinopathy, he said. Nor did it increase the risk of vitreous hemorrhage.
Dr. Cavallerano added, however, that the fact that the dosage was not modified or investigated during the ETDRS has prompted renewed interest in this approach. There is now renewed interest in determining if aspirin, by improving blood flow, may help maintain the inner blood retinal barrier, he said.
Another possible approach to managing diabetic macular edema is the use of oral dosage forms of protein kinase-C (PKC) inhibitors, Dr. Cavallerano said.
Studies have shown that activating PKC increases endothelin-1, a substance that reduces blood flow through its vasoconstrictive effect, he said. Oral dosage forms of PKC inhibitors are being investigated as a means to help maintain the retinal vascular integrity and thus prevent or reduce diabetic macular edema.
Progression of the disease
The first stage of diabetic retinopathy is called nonproliferative or background retinopathy. At the onset of this stage, abnormal blood vessels leak fluid, blood cells, proteins and fats into the surrounding retinal tissue.
Small blood vessels on the surface of the retina may hemorrhage, causing swelling. The hemorrhages increase as the disease worsens. Nonproliferative diabetic retinopathy often has no symptoms and may not pose a threat to vision at this stage.
Proliferative diabetic retinopathy is the result of severe vascular compromise and is visible as neovascularization of the disc, the iris and elsewhere in the retina.
At this stage, the vessels may break and bleed into the vitreous, thus blocking vision. Proliferative scar tissue may also form near the retina, detaching it from the back of the eye. Proliferative retinopathy can lead to impaired vision and blindness.
Diabetic macular edema
Diabetic macular edema is retinal thickening caused by the accumulation of intraretinal fluid, resulting from reduced retinal blood flow and hyperpermeability of the retinal vasculature.
The edema is clinically significant if the thickening involves or threatens the center of the macula. According to Dr. Cavallerano, 400,000 diabetic people have macular edema, half of whom are at risk for moderate vision loss.
Diabetic macular edema can occur as a result of focal or diffuse leakage from retinal vessels or through a combination of both effects, he said. The risk factors for development and progression of diabetic macular edema include elevated glycosylated hemoglobin A1C levels, duration of diabetes, elevated diastolic blood pressure and level of diabetic retinopathy.
Patients with proliferative diabetic retinopathy are treated with panretinal photocoagulation, which causes regression of the neovascular tissues. As a result, the risk of severe vision loss is substantially reduced.
This treatment is an in-office or outpatient procedure done with or without an anesthetic injection adjacent to the eye. The laser treatment usually takes less than 30 to 40 minutes per session.
A complete laser treatment, however, may require up to three or four sessions, with a total of 1,000 to 2,000 laser applications.
In some patients with proliferative diabetic retinopathy, the vitreous hemorrhage prevents the doctors ability to perform the laser treatment. If the vitreous hemorrhage fails to clear within a few weeks or months, a vitrectomy surgery may be performed to mechanically clear the hemorrhage. Laser photocoagulation is then applied, either at the time of the vitrectomy or shortly thereafter.
Focal and grid laser treatments
In treating diabetic macular edema, both focal and grid laser surgeries are commonly used. Focal treatment is possible when there are a small number of leakage areas that can be targeted for treatment. The fluorescein angiogram is often used as a guide for this procedure.
The ETDRS elucidated that in eyes with clinically significant macular edema, focal argon laser photocoagulation reduces retinal thickening, Dr. Cavallerano said. This reduces the risk of moderate visual loss by 50%.
When the leakage is diffuse in nature, a grid pattern of laser may be used instead. Laser spots are applied in a grid pattern over the swollen area of retina.
In focal photocoagulation, laser therapy seals the leakage sites of macular blood vessels, slowing the swelling that causes impaired vision. This procedure serves to prevent vision loss and may result in a modest improvement in vision.
For Your Information:
- Anthony A. Cavallerano, OD, FAAO, is clinical coordinator of the Joslin Vision Network at the Joslin Diabetes Center and a member of the Editorial Board of Primary Care Optometry News. He can be reached at 1 Joslin Place, Boston, MA 02215; (617) 732-2588; fax: (617) 732-2545. Dr. Cavallerano has no direct financial interest in the products mentioned, nor is he a paid consultant for any companies mentioned.
- Margaret Graham is director of corporate communications for Bausch & Lomb. She can be reached at 1905 World Headquarters, One Bausch & Lomb Place, Rochester, NY 14604; (585) 338-5469 fax: (585) 338-0317.