Diabetic Retinopathy: An Update on Treatment

Diagnosis 

Patient 1 has clinically significant macular edema and mild nonproliferative retinopathy. Focal macular laser photocoagulation is required to prevent further vision loss. Patient 2 has high-risk proliferative diabetic retinopathy and a small tractional retinal detachment. She is at high risk for severe vision loss and will require aggressive intervention with panretinal photocoagulation and possible vitrectomy.

Diabetes mellitus is estimated to affect 23.6 million individuals in the US,1 and most patients with type I or type II diabetes have evidence of retinopathy after 20 years.2, 3 Diabetic retinopathy is the primary cause of blindness in adults aged 20-74 years in the US, causing an estimated 12,000 to 24,000 new cases of blindness annually.1

The major risk factors for diabetic retinopathy are hyperglycemia and increased duration of diabetes. Other risk factors include hypertension, hyperlipidemia, pregnancy, and microalbuminuria.3, 4 All of these risk factors contribute to retinal metabolic changes and microvascular injury that result in diabetic retinopathy.

Nonproliferative diabetic retinopathy is an early stage in disease progression. Loss of retinal capillary pericytes and endothelial cells has been demonstrated early in diabetes5 and underlies the clinical signs of nonproliferative diabetic retinopathy, which include intraretinal dot-blot hemorrhages, microaneurysms, and venous beading. Microvascular injury with infarction of small areas of the nerve fiber layer leads to puffy white patches on the retina called cotton-wool spots (Table).

Table. Funduscopic Findings in Diabetic Retinopathy

	Nonproliferative Diabetic Retinopathy	Microaneurysms; venous beading; intraretinal hemorrhages; cotton-wool spots
	Proliferative diabetic retinopathy	Abnormal new vessels of the retina, optic disc, or iris; vitreous hemorrhage
	Diabetic macular edema	Retinal thickening; yellow exudates

Proliferative diabetic retinopathy is a later and more severe stage of the disease characterized by neovascularization. Sustained retinal ischemia causes release of vascular endothelial growth factor and insulin-like growth factor, which induce growth of new vessels on the optic disk, iris, retinal surface, and into the vitreous. The abnormal vessels are fragile and may hemorrhage into the vitreous or form fibrous bands, causing tractional retinal detachment. Neovascularization of the iris may occlude aqueous outflow, resulting in neovascular glaucoma.

Clinically significant macular edema is the most common cause of moderate vision loss (≤20/40 vision) in all types of diabetic retinopathy. As microvascular damage weakens the blood-retinal barrier, plasma leaks from vessels into the retina; when this fluid is resorbed, lipid and lipoprotein elements are retained in the retina and are visible as yellow exudates.

The majority of severe vision loss (≤20/200 vision) in diabetic retinopathy is the result of complications from proliferative diabetic retinopathy—vitreous hemorrhage, retinal detachment, and neovascular glaucoma. Most patients with diabetic retinopathy are asymptomatic until very late stages of the disease. Symptoms, when present, may include decreased visual acuity and contrast sensitivity, new onset floaters, or dark curtain.

Management 

Current treatment strategies for diabetic retinopathy are thought to be 90% effective in preventing severe vision loss.6 Given the asymptomatic nature of diabetic retinopathy until its latest stages and the effectiveness of early intervention,7 referral for regular screening by an ophthalmologist is essential. The American Academy of Ophthalmology recommends type I diabetics be examined 3-5 years after diagnosis and yearly thereafter; type II diabetics should be examined at the time of diagnosis and yearly thereafter.6

Primary prevention of diabetic retinopathy involves strict glycemic and blood pressure control. The Diabetes Control and Complications Trial8 and the United Kingdom Prospective Diabetes Study9 showed that intensive glycemic control substantially reduces the incidence and progression of diabetic retinopathy in type I and II diabetes. Blood pressure control also significantly reduces the incidence and progression of diabetic retinopathy, although the specific antihypertensive agent utilized does not appear to be significant.10, 11

Established secondary interventions for diabetic retinopathy include pan-retinal photocoagulation, focal laser photocoagulation, and surgical vitrectomy. Pan-retinal photocoagulation applies hundreds of laser burns to the peripheral retina, reducing the amount of ischemic retina that drives angiogenesis. Pan-retinal photocoagulation has been the cornerstone of treatment for severe retinopathy since the Diabetic Retinopathy Study, which showed that it reduces the risk of severe vision loss by 50% in patients with severe diabetic retinopathy.12

Focal laser photocoagulation is indicated for patients with clinically significant macular edema; it targets microaneurysms near the macula, reducing the plasma leakage responsible for intraretinal swelling. The Early Treatment Diabetic Retinopathy Study showed that focal laser photocoagulation reduces the risk of moderate vision loss by 50%-70% in patients with macular edema.7

Vitrectomy involves surgical removal of the vitreous, blood, and fibrovascular retinal tissue. It is recommended for severe proliferative diabetic retinopathy when it is unresponsive to pan-retinal photocoagulation, associated with severe vitreous hemorrhage, or associated with traction on the macula. The Diabetic Vitrectomy Study first demonstrated the ability of early vitrectomy to preserve or restore vision in patients with severe proliferative diabetic retinopathy;13 since this study, many advances have been made in vitreoretinal surgery.

Vascular endothelial growth factor is produced by multiple retinal cell types in response to ischemia. It is a potent promoter of vascular permeability and neovascularization, making it the primary target for emerging treatment for diabetic retinopathy. Intravitreal injection of vascular endothelial growth factor into healthy primate eyes induces changes similar to proliferative diabetic retinopathy.14 The concentration of vascular endothelial growth factor is increased by a factor of 20 in the vitreous of patients with proliferative diabetic retinopathy, and levels subsequently fall after pan-retinal photocoagulation.15

Currently, 4 intravitreal inhibitors of vascular endothelial growth factor provide promising possibilities for targeted nonsurgical treatment of diabetic retinopathy. Pegaptanib (Macugen, OSI/Eyetech, Melville, NY) and bevacizumab (Avastin, Genentech, Inc., South San Francisco, CA) have been demonstrated to reduce neovascularization and improve diabetic macular edema, respectively.16, 17, 18 Ranibizumab (Lucentis, Genentech, Inc.) and VEGF Trap-Eye (Regeneron Pharmaceuticals, Inc., Tarrytown, NY) are currently being evaluated for treatment of macular edema.

All of the vascular endothelial growth factor antagonists appear to require repeated intravitreal injections to sustain benefits, increasing the likelihood of local complications including uveitis, cataract, retinal detachment, and endophthalmitis. Theoretical concerns about occlusion of native retinal vessels, hypertension, stroke, myocardial infarction, and thrombosis have not been demonstrated in large studies of these agents.

The central role of vascular endothelial growth factor in severe, vision-threatening diabetic retinopathy warrants further investigation to determine if inhibitors of this protein will become part of routine care of diabetic retinopathy.

Intravitreal triamcinolone acetonide also has received significant attention for the treatment of diabetic macular edema. While triamcinolone does reduce macular thickness in the short term,19 its 3-year visual benefit was found to be inferior to standard focal macular laser, with higher rates of glaucoma and cataract.20

Conclusion 

As the leading cause of new-onset blindness in the working-age population in the US, diabetic retinopathy causes a profound burden of psychologic, functional, and economic morbidity. Diabetic retinopathy progresses predictably from the early nonproliferative stage to the later proliferative stage. It is largely asymptomatic until its latest stages, emphasizing the importance of early referral by primary care providers for regular screening examinations. Application of focal macular laser and panretinal photocoagulation at appropriate disease stages reduces the risk of further vision loss. Ongoing research will determine the utility of inhibitors of vascular endothelial growth factor as an additional tool in the management of diabetic retinopathy.