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Management of Diabetic Retinopathy in the 21st Century

Paul Chous, M.A., O.D. and Type 1 diabetic since 1968 brings us an update on the Management of Diabetic Retinopathy in the 21st Century

Management of Diabetic Retinopathy in the 21st Century

Paul Chous, M.A., O.D.
Doctor of Optometry
Type 1 diabetic since 1968

For most patients with diabetic retinopathy, the treatment of choice is improved metabolic control. This is to say that improving blood glucose levels (with an HbA1c goal as close to normal as possible, but less than 6.5%), blood pressure levels (with a goal of less than 130/80), and blood lipid levels (with a goal of LDL cholesterol less than 100, HDL cholesterol more than 50 and triglycerides less than 150) greatly reduces the risk of diabetic retinopathy getting worse.  In fact, improved metabolic control is recommended for every patient having diabetes, both those with and without retinopathy, because it reduces the risk of virtually all diabetes complications.

However, when diabetic retinopathy progresses to a level that threatens vision, more aggressive therapy is recommended. In fact, laser photocoagulation is the “gold standard” treatment for the most serious stages of diabetic retinopathy – proliferative diabetic retinopathy retinopathy (PDR) and clinically significant diabetic macular edema (CSME) – as laser has been shown to reduce the risk of both moderate and severe permanent vision loss by 50-75%,.

Laser therapy for treatment of diabetic retinopathy is not without its drawbacks, though, because it is destructive by design; some retinal tissue is intentionally sacrificed in order to preserve the function of other, more visually important areas of retina. As a result, patients very often experience a loss of peripheral vision, abnormal blind spots (scotoma), and reduced ability to see at night or in dimly lit environments (nyctalopia). Moreover, pan-retinal laser photocoagulation for treatment PDR results in a loss of best corrected vision in up to 11% of treated patients. Furthermore, sometimes laser treatment simply doesn’t work to stop progression of retinopathy and prevent substantial vision loss.  It is for all these reasons that scientists have been trying to develop drug therapies to replace or at least minimize the need for laser treatment.

In fact, a whole host of novel pharmaceutical and neutriceutical agents have been developed and, sometimes, tested for treating retinopathy. Unfortunately, most of these therapies have either not worked, caused serious medical side effects, and/or have not been tested in large, rigorously designed clinical trials. This is beginning to change, however, as vision scientists have uncovered the biochemical processes that lead to the development and progression of diabetic retinopathy.
One type of drug designed to interrupt the chemical signals causing growth of abnormal retinal blood vessels (as happens in proliferative diabetic retinopathy and several other serious eye diseases like retinal venous occlusion, neovascular age related macular degeneration and ocular histoplasmosis) are the VEGF inhibitors. VEGF is an acronym for vascular endothelial growth factor, an inflammatory cytokine, one isoform of which is released by damaged blood vessels in the eye when they are exposed to high blood glucose levels for an extended period of time. Pegaptanib (MacugenTM), ranibizumab (LucentisTM), and bevacizumab (AvastinTM) are three VEGF inhibitors that are being tested for treating both PDR and CSME. Macugen and Avastin have both been shown to improve visual acuity and reduce retinal thickening due to diabetic macular edema, whereas Avastin and Lucentis have been shown to cause regression of neovascularization due to PDR.  Avastin is far less costly than the other agents and is currently FDA-approved for treatment of colorectal cancer, but is now being frequently used off-label by a growing number of retinal specialists.

Octreotide (SandostatinTM) is another drug that may prove beneficial in the treatment of proliferative retinopathy; it is currently used to treat certain endocrine tumors because it suppresses blood vessel growth that promotes their development. In the eye, octreotide inhibits the vasoproliferative activity of growth hormone and may prove particularly helpful in treatment of PDR associated with the onset of puberty.

Protein kinase C (PKC) is a family of proteins implicated in the development of diabetic macular edema, and PKC inhibitors may help forestall this disease, the most common cause of significant vision loss from diabetes. Ruboxistaurin (ArxxantTM) is the first such drug shown to prevent vision loss from macular edema in patients with moderate to severe non-proliferative diabetic retinopathy; however, it’s ultimate FDA approval remains in question. 

As for currently available nutriceuticals, benfotiamine is a non-prescription, fat-soluble form of Vitamin B1 (thiamine) that has been shown to block production of PKC and other biochemical modulators of diabetes complications; it totally prevented diabetic retinopathy in laboratory animals and is currently in human trials. Genestein, a soy isoflavone that blocks downstream VEGF receptors by inhibiting tyrosine kinase, has been shown to ameliorate retinal vascular permeability in diabetic animals and is currently available in an OTC eye supplement called Ocuvite DF.

The insulin sensitizing agents, rosiglitazone (AvandiaTM) and pioglitazone (ActosTM) have been implicated in the rare development of diabetic macular edema, especially in patients who experience peripheral fluid edema and weight gain. Perhaps ironically, recent evidence presented at the Association for Research in Vision and Ophthalmology meeting indicates that patients treated with AvandiaTM were much less likely to develop serious diabetic retinopathy and no more likely to develop macular edema than were other patients with similar HbA1c values, blood pressure and duration of diabetes; it is thought that drugs like AvandiaTM and ActosTM may block downstream action of VEGF.

There is also some evidence that cholesterol-lowering “statin” drugs and certain high blood pressure medicines (ACE inhibitors and ARBs) may lower the risk of diabetic retinopathy above and beyond their lipid-lowering and hypotensive effects, respectively.  Finally, corticosteroids are now widely used in combating retinopathy, often in combination with laser treatment, as they have been shown to improve or stabilize vision in certain circumstances (primarily severe macular edema).
Although new drugs for diabetic retinopathy hold great promise, it must be remembered that excellent metabolic control and timely laser treatment are still the current “gold standards” for managing this serious eye disease, and for good reason: they prevent blindness in the overwhelming majority of patients. However, treatment and prevention of diabetic retinopathy in the 21st Century will almost certainly involve a combination of therapies that battle the disease via distinct and complementary mechanisms. The Diabetic Retinopathy Clinical Research Network (www.DRCR.net) represents a collaborative network of vision researchers designed to better implement multicenter clinical research initiatives focused on retinal disorders associated with diabetes. Hopefully, this strategy will bring new and more effective treatment modalities to patients in the near future.

Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985 Dec;103(12):1796-806.

  Diabetic Retinopathy Study Research Group:  Photocoagulation treatment of proliferative diabetic retinopathy: the second report of Diabetic Retinopathy Study findings.  Ophthalmology 1978; 85:82-106.

Adamis AP, Altaweel M, Bressler NM, Cunningham ET Jr, Davis MD, Goldbaum M, Gonzales C, Guyer DR, Barrett K, Patel M; Macugen Diabetic Retinopathy Study Group. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology. 2006 Jan;113(1):23-8.

Avery RL. Regression of retinal and iris neovascularization after intravitreal bevacizumab (Avastin) treatment. Retina. 2006 Mar;26(3):352-4.

Grant MB, Caballero S Jr. The potential role of octreotide in the treatment of diabetic retinopathy. Treat Endocrinol. 2005;4(4):199-20

The PKC-DRS Study Group. The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase C beta Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter randomized clinical trial. Diabetes. 2005 Jul;54(7):2188-97.

Hammes H, Brownlee M et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents diabetic retinopathy. Nature: Medicine 2003; 9: 294-9.

Nakajima M, Cooney M.  Normalization of retinal vascular permeability in experimental diabetes with genestein.  Inves Oph Vis Science 2001; 42(9): 2210-14.

Ryan EH Jr, Han DP, Ramsay RC, Cantrill HL, Bennett SR, Dev S, Williams DF. Diabetic macular edema associated with glitazone use. Retina. 2006 May/June;26(5):562-570.

Rosiglitazone May Delay Progression to Proliferative Diabetic Retinopathy. Abstract 2333, Association for Research in Vision and Ophthalmology annual meeting, Fort Lauderdale, FL, May 2, 2006.

Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985 Dec;103(12):1796-806.

  Diabetic Retinopathy Study Research Group:  Photocoagulation treatment of proliferative diabetic retinopathy: the second report of Diabetic Retinopathy Study findings.  Ophthalmology 1978; 85:82-106.

Adamis AP, Altaweel M, Bressler NM, Cunningham ET Jr, Davis MD, Goldbaum M, Gonzales C, Guyer DR, Barrett K, Patel M; Macugen Diabetic Retinopathy Study Group. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology. 2006 Jan;113(1):23-8.

Avery RL. Regression of retinal and iris neovascularization after intravitreal bevacizumab (Avastin) treatment. Retina. 2006 Mar;26(3):352-4.

Grant MB, Caballero S Jr. The potential role of octreotide in the treatment of diabetic retinopathy. Treat Endocrinol. 2005;4(4):199-20

The PKC-DRS Study Group. The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase C beta Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter randomized clinical trial. Diabetes. 2005 Jul;54(7):2188-97.
Hammes H, Brownlee M et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents diabetic retinopathy. Nature: Medicine 2003; 9: 294-9.

Nakajima M, Cooney M.  Normalization of retinal vascular permeability in experimental diabetes with genestein.  Inves Oph Vis Science 2001; 42(9): 2210-14.

Ryan EH Jr, Han DP, Ramsay RC, Cantrill HL, Bennett SR, Dev S, Williams DF. Diabetic macular edema associated with glitazone use. Retina. 2006 May/June;26(5):562-570.

Rosiglitazone May Delay Progression to Proliferative Diabetic Retinopathy. Abstract 2333, Association for Research in Vision and Ophthalmology annual meeting, Fort Lauderdale, FL, May 2, 2006.