Drugs and Laser Treatments for Diabetic Retinopathy

Drugs and Laser Treatments for Diabetic Retinopathy

Using Drugs and Lasers to Expand Treatment Options for Diabetic Retinopathy

Joel A. Pearlman, MD, PhD

Steroids and anti-VEGF drugs offer a useful adjunct to laser treatment for diabetic retinopathy.

According to a 2004 study, an estimated 10.2 million US adults age 40 and older have diabetes. Of these, 40.3% have some form of retinopathy, and vision is threatened in 8.2%.1 As this population is both large and rapidly growing, eyecare clinicians and researchers are being driven to explore various therapeutic options—including both drugs and lasers—in an effort to minimize vision loss due to this condition. In particular, clinicians have recently begun using anti-VEGF drugs to treat some patients with diabetic retinopathy.

Etiology and Presentation

Poor glycemic control is the most important risk factor for the development of retinopathy among diabetics, but hypertension, smoking, and the type of diabetes also influence patients’ risk of retinal involvement, with almost all type 1 diabetics eventually developing some type of retinopathy. In addition, clinical experience suggests that there are additional risk factors that have yet to be identified, as some patients with only moderately controlled diabetes do not develop significant retinopathy, even after many years, while others develop severe retinopathy despite maintaining good glycemic control and having no other risk factors.

The main problem underlying many of diabetes’ deleterious effects is vasculopathy, which causes both retinopathy and systemic problems such as renal failure. While the mechanism that causes this damage is still being investigated, high blood glucose levels are thought to damage the cells in the small blood vessels that are responsible for vascular integrity. When these cells cannot function normally, blood vessels start leaking, resulting in edema (Figure 1). In more severe cases, this process can also cause vasoocclusion and ischemia, leading to hemorrhage and retinal detachment.

On a molecular level, research has shown that vascular endothelial growth factor (VEGF) mediates much of the dysfunction seen in diabetic retinopathy. Specifically, VEGF increases the permeability of blood vessels and is necessary for the growth of abnormal blood vessels. Supporting this protein’s significance in the disease process, the level of VEGF in the eyes of diabetic patients increases with the severity of their disease.

Diabetic retinopathy is usually asymptomatic in its early stages. As it progresses, macular edema can develop and cause blurry vision. In more severe cases, patients may suffer intraocular bleeding and further vision loss due to retinal traction and nerve cell death from compromised perfusion. After a number of years, even asymptomatic patients develop small intraretinal hemorrhages and cotton wool spots in areas of the superficial retina with compromised blood flow.

Treatment Options

Because good diabetes management can significantly reduce the risk of retinopathy, all diabetic individuals need to be well educated about their condition. Primary care physicians can help to optimize blood glucose and hypertension control as well as counsel patients about the necessity of regular eye (and foot) exams. Stressing the importance of prevention is particularly important in asymptomatic patients, as this group may not appreciate the potential severity of their condition. Unfortunately, by the time patients do develop symptoms, their retinopathy is often advanced and the success of treatment may be limited.

While not all patients with diabetic retinopathy require treatment, laser therapy and/or medication is indicated when there is clinically significant macular edema, significant areas of ischemia, growth of abnormal blood vessels, or vitreous hemorrhage and traction. The treatment regimen needs to be individually tailored to the patient, taking into account the severity of disease, location of edema, concurrent illnesses, and overall compliance.

Historically, laser therapy was the only treatment available for diabetic retinopathy. Even with the development of anti-VEGF drugs and other agents, lasers still play a large role in managing this condition. Specifically, focal or grid laser is indicated for patients with macular edema, and panretinal photocoagulation is used to treat proliferative disease.

Drugs for Diabetic Retinopathy

While laser therapy can help to stabilize vision in patients with diabetic retinopathy, researchers and clinicians have continued to search for other treatments that might improve visual outcomes. Given what we know about how VEGF causes edema and neovascularization, drugs that reduce the activity of this protein promise to offer effective adjunctive treatment for diabetic retinopathy. Like lasers, drugs are not a panacea, but they do offer a potential way to improve on laser treatment alone.

Because medical therapy can offer a rapid treatment response, an intravitreal injection may be a good first step for patients in whom the goal is to reduce edema and neovascularization quickly, after which laser treatment can be performed to obtain a more long-term effect. For example, I would probably consider pharmacological therapy as an initial treatment for patients with complex retinopathy, vitreous hemorrhage, or neovascular glaucoma, to quiet their disease and allow for more controlled, less aggressive laser therapy.

I also consider using medications to treat patients with diffuse macular edema and good perfusion. If patients have diffuse edema with poor macular perfusion, I am likely to be less aggressive with this treatment, since ischemic damage in these cases reduces the likelihood of achieving a reasonable visual effect.

I will occasionally use anti-VEGF drugs prior to vitrectomy. Because anti-VEGF drugs can induce temporary regression of neovascularization, preoperative use of these drugs reduces the amount of bleeding during surgery and makes the procedure easier to perform. Surgeons should use caution when using anti-VEGF drugs in this manner, however, as contraction of the abnormal blood vessels can sometimes result in progressive detachment if surgery is not performed promptly.

Today’s Drug Options

No intraocular drugs are currently FDA-approved for the treatment of diabetic retinopathy, but both anti-VEGF drugs and steroids are used off label. In some cases, medications are used along with laser treatment, in the expectation that using both treatments together can improve visual outcomes and/or allow gentler laser treatments to achieve the same effect.
Based on their use in macular degeneration, several anti-VEGF drugs are currently being used for diabetic retinopathy, including pegaptanib (Macugen®; Eyetech, Inc.), ranibizumab (Lucentis®; Genentech), and bevacizumab (Avastin®; Genentech). By blocking the action of some or all isoforms of the VEGF protein, these drugs help to reduce edema and neovascularization. Another anti-VEGF drug, VEGF-Trap, is not yet commercially available but is currently undergoing clinical trials and may soon become part of clinicians’ drug armamentarium.

While anti-VEGF drugs are often effective, they do not work in all patients, so steroids are also used to treat diabetic retinopathy. Like anti-VEGF agents, steroids such as triamcinolone are very effective in reducing edema, but they have a more pronounced side-effect profile that includes elevated intraocular pressure (IOP) and cataract formation. Some IOP elevations are mild and transient and do not require treatment. However, these IOP spikes can also be fairly dramatic, with pressures above 40 mmHg. Clinicians should keep a close watch on patients who have received a steroid injection, as elevated pressures may require management with either medications or surgery, sometimes months after the injection.

THE BOTTOM LINE

A valuable adjunct to lasers, medical therapy holds promise for improving treatment of diabetic retinopathy. By quickly reducing edema and neovascularization, steroids or anti-VEGF drugs can help stabilize diabetic retinopathy. When used perioperatively, anti-VEGF drugs can reduce the amount of bleeding that occurs during surgery. Because the use of medications for the treatment of diabetic retinopathy is still relatively new, there remains debate about how best to use these agents. Data from numerous ongoing clinical trials should soon be available to help guide clinical practice.

Joel A. Pearlman, MD, PhD, is a retina specialist with Vitreoretinal Medical Group, Inc., in Sacramento, CA. Refractive Eyecare managing editor Kay Downer assisted in the preparation of this manuscript.

References

1. Kempen JH, et al; Eye Diseases Prevalence Research Group. The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol. 2004 Apr;122(4):552-63.