Systemic Control
Glycemic control delays development and progression of diabetic retinopathy.

The United Kingdom Prospective Diabetes Study looked at Type 2 diabetes, comparing tight control with oral agents or insulin vs. conventional treatment. The study showed that intensive therapy reduced the risk of developing diabetic retinopathy by 21 percent. Intensive therapy reduced the risk of progression of retinopathy by 34 percent.

The Diabetes Control and Complications Trial studied Type 1 diabetes, comparing tight control with intensive insulin vs. conventional treatment. Intensive therapy reduced the risk of developing diabetic retinopathy by 76 percent. Intensive therapy reduced the risk of progression of existing retinopathy by 54 percent. Together, these studies make a strong case in support of tight glycemic control in patients with diabetes.

For antihyperglycemic and antihypertensive management to be effective, diabetic retinopathy/macular edema (DR/ME) must be detected early in order to prevent serious complications. Maintaining strict systemic glucose and blood pressure control has been proven difficult for many diabetic patients. Even with optimal systemic glucose and blood pressure control in a normal clinical setting, vascular complications are regarded as an inevitable outcome of diabetes.

A substantial number of patients will still develop progressive retinopathy and will require either laser photocoagulation or vitrectomy.

Surgical Therapy
Current laser or surgical treatments are only applicable for late stages of retinopathy, including proliferative diabetic retinopathy or sight-threatening ME. The Diabetic Retinopathy Study and Early Treatment Diabetic Retinopathy Study showed that photocoagulation can reduce the risk of severe visual loss by approximately 50 percent.

The mechanism by which laser photocoagulation achieves this effect in patients with ME is quite interesting. In brief, laser photocoagulation leads to decreased oxygen requirements by the retina due to photoreceptor destruction. Laser therapy also increases transfer of oxygen from the choroid to the retina through the laser scar. This increased oxygen concentration and decreased consumption leads to autoregulatory constriction of the retinal arterioles, decreased pressure within retinal capillaries and, according to Starling’s law, decreased retinal vascular leakage. In addition, laser photocoagulation destroys ischemic retina, leading to decreased production of the vascular endothelial growth factor, which is a permeability factor that facilitates leakage through diabetic vessels.

Pharmacologic Therapies
Due to the limitations of current treatments, new pharmacologic therapies are being developed to target the underlying biochemical causes and complications of diabetes.

Vascular endothelial growth factor is perhaps the best-described mediator of ocular angiogenesis, as there have been numerous preclinical studies demonstrating its role in retinal neovascularization. Protein kinase-C-ß is a key regulatory isoenzyme involved in signal transduction downstream from the VEGF receptor. PKC-ß is chronically activated by high glucose concentrations, probably due to an increase in the de novo synthesis of its physiological activator, diacylglycerol. PKC-ß activation is thought to contribute to diabetes-associated abnormalities in blood flow, vascular permeability, basement membrane synthesis, extracellular matrix synthesis, endothelial cell function, vasomotor function, and vascular growth factor signaling. LY333531, a PKC-ß selective inhibitor,  is currently in clinical trials to assess whether it can delay or stop the progression of DR and ME at the preproliferative stage. PKC412, which can inhibit multiple PKC isoforms, is also in clinical trials for the treatment of ischemic retinopathy.

Proliferative diabetic retinopathy is a focus of intensive pharmacologic research. (Joseph Arroyo Photo)

Aldose reductase is an enzyme that converts glucose to sorbitol. It is the first enzyme in the polyol pathway, a series of enzymatic reactions in the synthesis of fructose. Normally, aldose reductase has a low affinity for glucose and little glucose substrate enters the polyol pathway. During hyperglycemia, however, cellular levels of glucose increase, particularly in tissues such as the retina where glucose entry is independent of insulin. The excess glucose is largely metabolized by aldose reductase, and this increased flux of glucose through the polyol pathway is associated with diabetic abnormalities. Animal models have been used to show the use of aldose reductase inhibitors to block the flux of glucose through the polyol pathway prevents diabetic abnormalities. However, in clinical trials, aldose reductase inhibitors have not shown consistent beneficial results to date.

Growth hormone is thought to exacerbate diabetic retinopathy, as diabetic dwarves who lack growth hormone generally do not exhibit retinal complications. In addition, pituitary removal was formerly used as a treatment for severe, refractory proliferative diabetic retinopathy. IGF-1 is a mediator of the growth hormone effect, and somatostatin, a serum peptide, represents a natural antagonist to IGF-1. Octreotide, a somatostatin analogue, is used to combat excessive growth hormone production in acromegaly and is currently in Phase III trial, in a long-acting subcutaneous form, for proliferative diabetic retinopathy.

Angiostatic steroids are also being considered for the treatment of DR/ME. Steroid compounds have long been known to possess angiostatic properties and several small clinical and preclinical studies have demonstrated efficacy in inhibiting retinal and choroidal neovascularization. A multicenter randomized prospective trial of a sustained antiangiogenic steroid (fluocinolone) delivery device, similar to a ganciclovir implant, is currently recruiting patients. There have also been several preliminary reports of intravitreal injection of triamcinolone acetonide leading to improvement in visual acuity and retinal thickness in patients with DR/ME.

Diabetic retinopathy and macular edema are among the most common causes of severe visual loss in the United States. Laser photocoagulation, which represents the only treatment modality well-studied in large, randomized, controlled, prospective clinical trials, shows limited efficacy. New pharmacologic modalities now being evaluated show promise, but must undergo rigorous prospective randomized clinical trial prior to widespread acceptance. Clinicians who treat patients with diabetic retinopathy can look forward to many new therapies for this devastating disorder.

Dr. Ciulla is in the Department of Ophthalmology at Indiana University School of Medicine. Contact him at (317) 274-3821, fax (317) 274-1288, or e-mail tciulla@iupui.edu. 

Suggested Reading

1. Fabbro D, Ruetz S, Bodis S, et al. PKC412--a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des. 2000;15:17-28.

2. Jonas JB, Sofker A. Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema. Am J Ophthalmol 2001;132:425-7.

3. Raskin P, Arauz-Pacheco C. The treatment of diabetic retinopathy: a view for the internist. Ann Intern Med 1992;117:226-33.

4. Stefansson E. The therapeutic effects of retinal laser treatment and vitrectomy. A theory based on oxygen and vascular physiology. Acta Ophthalmol Scand 2001, 79:435-40

5. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-86.

6. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Brit Med Journal. 1998;317:703-13.Hormone Therapy for Dry Eye