American Journal of Health-System Pharmacy

Ryan, Gina, J.

doi: 10.2146/ajhp070332pmid: 17720889

Purpose. The goal of treatment of diabetic retinopathy, limitations of laser photocoagulation, endpoints used in clinical studies of diabetic retinopathy treatments, and the mechanism of action, efficacy, and safety of several new and emerging therapies targeting the biochemical pathways that link chronic hyperglycemia with microvascular damage in patients with diabetic retinopathy are discussed. Summary. Improving or preserving vision is the primary goal of treatment for diabetic retinopathy. Limitations of laser photocoagulation include a lack of efficacy in some cases, discomfort from the procedure, the need for repeated treatment, and a risk of retinal damage and scarring. Visual acuity, quality of life, and macular thickness are used as endpoints in clinical studies of diabetic retinopathy treatments. Microvascular damage in patients with chronic hyperglycemia is mediated by interrelated pathways involving aldose reductase, advanced glycation end products, protein kinase C (PKC), and vascular endothelial growth factor (VEGF). Oral aldose reductase inhibitors have been studied with some success only in patients with diabetic peripheral neuropathy. The oral PKC inhibitor midostaurin and oral selective PKC β inhibitor ruboxistaurin appear promising for improving or maintaining visual acuity, with gastrointestinal complaints the most commonly reported adverse effects. Intra-vitreal injection of corticosteroids or VEGF inhibitors is associated with short-lived improvement in or maintenance of visual acuity, a need for repeated injection, and a risk of local adverse effects. Conclusion. A variety of promising new therapies for diabetic retinopathy targeting the biochemical pathways that cause microvascular damage are under investigation. Additional clinical research is needed to determine the role of these new therapies in treating diabetic retinopathy. Aldose reductase inhibitors, Antibodies, Diabetic retinopathy, Enzyme inhibitors, Lasers, Midostaurin, Quality of life, Ruboxistaurin, Steroids, cortico-, Toxicity The primary goal of treatment for diabetic retinopathy is to improve or preserve vision by reducing neovascularization (i.e., the growth of fragile new blood vessels), macular edema, and vascular leaking and preventing retinal detachment. The macula is the densest area of photoreceptors in the retina and plays a vital role in vision. Leakage of capillaries can result in edema and vision loss. Retinal detachment can lead to blindness. Laser photocoagulation surgery is the primary mode of treatment of patients with diabetic retinopathy who are at high risk of vision loss, but it is not always effective for improving vision.1 In many cases, retinal damage and vision loss have already occurred, and laser therapy merely maintains vision (i.e., avoids further vision loss). Multiple trips to the ophthalmologist for repeated laser treatments often are required, and the procedure is uncomfortable. Moreover, photocoagulation is ablative, destroying retinal tissue. Scars from laser therapy may enlarge over time.2 The shortcomings of laser photocoagulation surgery provided the impetus for development of pharmacologic therapies for diabetic retinopathy. The endpoints used in clinical studies of various therapies for diabetic retinopathy include visual acuity, quality of life (QOL), and macular thickness. The National Eye Institute, National Institutes of Health Early Treatment Diabetic Retinopathy Research Study (ETDRS) chart (available at http://www.nei.nih.gov/photo/charts/index.asp, Ref EC02) is used to measure visual acuity. There are five letters on each line of the chart, and an improvement in acuity by two or three lines (i.e., 10–15 letters) or more is considered clinically significant. Blindness has a tremendous adverse impact on QOL. Lesser degrees of vision impairment also can lower QOL (e.g., by prompting revocation of a driver’s license).3 Macular thickness is sometimes used as a surrogate measure for visual acuity, although reductions in macular thickness are not always accompanied by improvements in visual acuity if permanent damage is present. Optical coherence tomography, a noninvasive method, is used to measure macular thickness. The number of patients enrolled in a study and the number of eyes evaluated are both considerations in evaluating the results of clinical studies of diabetic retinopathy treatments. In some studies, endpoints in both eyes are assessed by the investigators. In other studies, the study endpoints are assessed in only one eye. If results are reported for only one eye per patient, it usually is the worst of the two eyes. The interrelated biochemical pathways that are thought to contribute to diabetic retinopathy in patients with chronic hyperglycemia—the aldose reductase pathway, advanced glycation end product pathway, and protein kinase C (PKC) pathway—are targets for new drug therapies.4,5 These new therapies—aldose reductase inhibitors, PKC inhibitors, and vascular endothelial growth factor (VEGF) inhibitors—reduce microvascular damage from hyperglycemia.5,–7 VEGF is a growth factor involved in intracellular signaling pathways that lead to the vascular endothelial cell proliferation, migration, and proteolysis associated with angiogenesis.6 The activity of drug therapies for diabetic retinopathy may be primarily systemic or localized (i.e., given by intravitreal injection). Systemic drug therapies that have been developed and studied for diabetic retinopathy or macular edema include aldose reductase inhibitors, the PKC inhibitor midostaurin, and the selective PKC βinhibitor ruboxistaurin. Aldose reductase inhibitors Aldose reductase is the rate-limiting enzyme in the conversion of glucose to sorbitol, an energy-dependent process that uses nicotinamide adenine dinucleotide phosphate (NADPH).5,6 Excessive amounts of glucose activate this enzyme, which increases sorbitol formation, depletes NADPH, and can cause oxidative stress and inflammation. Sorbitol is converted to fructose. Nonenzymatic glycation of fructose results in high levels of advanced glycation end products, which activate PKC and cause cell damage and dysfunction. Increased free oxygen radical formation, which also causes vascular damage, occurs. Depletion of NADPH reduces nitric oxide formation, which can alter blood flow.6 Inhibition of aldose reductase decreases the conversion of glucose to sorbitol and the formation of advanced glycation end products and free oxygen radicals.5 It also inhibits the activation of PKC. Several aldose reductase inhibitors have been developed and studied over the past two decades. Their usefulness has been limited by minimal efficacy or toxicity (liver or kidney damage).8,–10 Epalrestat, fidarestat, and ranirestat are the most recently studied aldose reductase inhibitors.11,–13 These agents have been studied for the treatment of diabetic peripheral neuropathy. In a three-year, open-label study of 594 patients with diabetic peripheral neuropathy, epalrestat 150 mg/day orally was well tolerated and significantly more effective than placebo in preventing deterioration of median motor nerve conduction velocity, the primary endpoint (p < 0.001).11 No studies of these aldose reductase inhibitors in patients with diabetic retinopathy have been performed to date, but there are hopes that a member of this class of drugs will prove useful for both diabetic peripheral neuropathy and retinopathy. PKC inhibitors Activation of PKC increases vascular permeability, endothelial hyperplasia, and neovascularization, leading to microvascular damage.6,7 Inhibiting PKC activation may prevent these effects. Midostaurin. Midostaurin (formerly known as PKC412) is an oral PKC inhibitor. It also inhibits VEGF receptor and has been used investigationally in patients with leukemia (VEGF appears to promote cancer cell survival).14,–16 The efficacy and safety of oral midostaurin 50 mg/day, 100 mg/day, and 150 mg/day were evaluated in a three-month, randomized, double-blind, placebo-controlled, parallel-group study of 141 eyes in 141 adults with nonproliferative diabetic retinopathy (NPDR), mild proliferative diabetic retinopathy (PDR), or clinically significant diabetic macular edema.17 The patients had a best corrected visual acuity of 20/80. There was a statistically significant improvement from baseline in visual acuity over the three-month study period in the group that received midostaurin 100 mg per day (p = 0.007). However, the greatest improvement was only 4.36 letters on the ETDRS chart (in the 100-mg/day group), and this amount is not considered clinically significant (a 10- to 15-letter improvement is required for clinical significance). After discontinuation of the active drug, the improvements in visual acuity observed in the midostaurin groups were gradually lost (i.e., visual acuity returned to baseline levels). The most common adverse effects from midostaurin were dose-related nausea, diarrhea, and vomiting.17 The frequency of nausea, the most common treatment-related adverse effect, was 38%, 21%, 6%, and 3% in the midostaurin 150 mg/day, 100 mg/day, 50 mg/day, and placebo groups, respectively. Adverse effects were mild or moderate in severity and transient in most cases. Fourteen patients (9.9%) receiving midostaurin, including 8 (22%) patients in the 150-mg/day group, withdrew from the study because of adverse effects.17 Vomiting was the most common reason for study withdrawal. Liver enzyme elevations (plasma concentrations of alanine aminotransferase, aspartate aminotransferase, or both more than three times the upper limit of the normal range) were reported in one patient (3%) in the midostaurin 50-mg/day group, one patient (3%) in the midostaurin 100-mg/day group, and three patients (8%) in the midostaurin 150-mg/day group.17 These elevations resolved after discontinuation of the drug. Ruboxistaurin. There are several PKC isoforms, but PKC βis the one thought to be the primary isoform activated by hyperglycemia in retinal and other blood vessels associated with the microvascular and macro-vascular complications of diabetes.6,7 Ruboxistaurin is an oral selective PKC β inhibitor that is not yet approved by the Food and Drug Administration (FDA). The efficacy and safety of ruboxistaurin 32 mg/day as a single daily dose were evaluated in a 36-month, randomized, double-blind, placebo-controlled, parallel-group study of 685 patients (1183 eyes) with moderate to severe NPDR.18 A best corrected visual acuity of 20/125 and no history of panretinal photocoagulation in at least one eye were among the eligibility criteria. Moderate visual loss was the primary end point and was defined as a loss of visual acuity of 15 letters or more for six months. In an intent-to-treat analysis, ruboxistaurin treatment resulted in a significant 40% reduction in the occurrence of sustained moderate visual loss, from 9.1% in placebo-treated patients to 5.5% in ruboxistaurin-treated patients (p = 0.034).18 The cumulative probability of sustained moderate visual loss did not begin to differ markedly between the two groups until after 18 months of treatment. In both treatment groups, most patients (88%) experienced no change from baseline in visual acuity (defined as a loss or gain in visual acuity of 14 or fewer letters) over the course of the study. There was no significant difference in the rate of withdrawal from the study between the ruboxistaurin group (4.6%) and the placebo group (2.6%).18 Treatment-emergent diabetic nephropathy was reported in significantly more ruboxistaurin-treated patients (2%) than placebo-treated patients (0%, p = 0.015), but there were no significant differences between the two groups in the change from baseline in estimated glomerular filtration rate or other adverse effects indicative of renal or diabetes-related complications. In a previous 36-month dose-finding study, the most common adverse effect from ruboxistaurin 32 mg/day was diarrhea.19 It affected 35 (15%) of 235 patients receiving this dosage. The findings of ruboxistaurin and midostaurin studies probably reflect the difficulty in treating diabetic retinopathy. Avoiding loss of visual acuity may be considered a favorable outcome, even if improvement in visual acuity is not observed. Additional clinical studies of ruboxistaurin are planned.20,21 Intravitreal therapies Medications may be given by intravitreal injection directly into the sclera to produce localized effects. Usually, the eye is cleaned and then anesthetized with a topical anesthetic before subconjunctival injection of a local anesthetic. Intravitreal injection is painful despite the use of topical and local anesthetics (the process of administering the local anesthetic often is uncomfortable). This route of administration is associated with complications. Often there is a red spot on the sclera at the injection site. Patients may see floaters in the field of vision for several days after the injection. Endophthalmitis (i.e., inflammation of the vitreous body, usually due to infection) and retinal detachment are rare but serious complications of intravitreal injection. Drugs that have been administered by intravitreal injection include corticosteroids and VEGF inhibitors. Corticosteroids are the best studied group of drugs given by intravitreal injection for the treatment of diabetic retinopathy. Corticosteroids. The anti-inflammatory activity of cortico-steroids inhibits angiogenesis and neovascularization by preventing basement membrane dissolution (a process that is necessary for angiogenesis), endothelial cell migration, and expression of growth factors (e.g., VEGF, transforming growth factor-β).22,–25 The safety and efficacy of intravitreal injection of triamcinolone acetonide were explored in a two-year, randomized, double-blind study of 69 eyes in 43 patients with diabetic macular edema and impaired vision (20/30 or worse) that persisted or recurred after laser treatment.26 Patients were randomly assigned to receive triamcinolone acetonide 4 mg/0.1 mL by intravitreal injection or saline by subconjunctival injection as a placebo every six months as needed for up to two years. The average number of triamcinolone acetonide injections given during the two-year study was 2.6.26 In the 60 eyes in 35 patients that were available for evaluation after two years, the mean change from baseline in visual acuity was a gain of 3.1 letters in the triamcinolone acetonide group and a loss of 2.9 letters in the placebo group, a difference that is significant (p = 0.01). Compared with placebo-treated patients, the percentage of triamcinolone-treated patients with a 15-letter or more gain in visual acuity was higher (12% versus 3% with placebo) and a 15-letter or more loss in visual acuity was lower (3% versus 11% with placebo). However, a majority of patients in both groups (26% treated with triamcinolone acetonide and 37% treated with placebo) had no change in visual acuity (i.e., a gain or loss of less than five letters). There was a significantly greater reduction in macular thickness in the triamcinolone acetonide group (125 μm) compared with the placebo group (71 μm, p = 0.009). In the 34 eyes treated with triamcinolone acetonide in the two-year study, an increase in intraocular pressure of 5 mm Hg or more was observed in 23 (68%) eyes and glaucoma medication was required in 15 (44%) eyes.26 By contrast, an increase in intraocular pressure of 5 mm Hg or more occurred in 3 (10%) of 30 placebo-treated eyes (p < 0.0001), with a need for glaucoma medication in 1 (3%) placebo-treated eye (p = 0.0002). In 28 triamcinolone acetonide- treated eyes with cataracts, cataract progression occurred in 12 (43%) eyes and cataract surgery was performed in 15 (54%) eyes. By contrast, in 21 placebo-treated eyes with cataracts, cataract progression occurred in 3 (14%) eyes (p = 0.03) and cataract surgery was performed in none (0%, p < 0.0001). The differences between active treatment and placebo in these adverse effects were significant. In another study of 23 eyes with clinically significant diabetic macular edema, including 12 eyes that were refractory to laser treatment and 11 eyes that had not been treated with laser therapy, a single 4-mg intravitreal dose of triamcinolone acetonide significantly reduced retinal thickness in both groups of eyes (p < 0.001).27 The effect was maximal seven days after the injection and persisted until three months after the injection, but retinal thickness returned toward baseline values within six months after the injection. Visual acuity also improved significantly from baseline in both groups of eyes (p < 0.001), with an effect that was maximal two weeks after injection, persisted for three months, and diminished within six months. The findings of these studies demonstrate that macular edema is difficult to treat, avoiding vision loss is sometimes all that can be achieved with triamcinolone acetonide, and repeated injections are needed because the benefits are short-lived. The need for repeated corticosteroid injections raises concerns about the long-term effects of exposure to the drug. Clinical research is under way to explore the use of other corti-costeroids (e.g., dexamethasone, fluocinolone acetonide) by intravitreal injection for the treatment of diabetic retinopathy. Anecortave acetate is a steroid derivative that is in Phase I clinical trials for age-related macular degeneration. VEGF Inhibitors. Bevacizumab, pegaptanib, and ranibizumab are VEGF inhibitors; they bind to VEGF, preventing it from binding to its receptor. None of these agents currently is approved by FDA for the treatment of NPDR, PDR, or diabetic macular edema. Bevacizumab is approved by FDA for the treatment of metastatic colorectal and non-squamous non-small cell lung cancer.28 Pegaptanib and ranibizumab are approved by FDA for the treatment of neovascular (wet) age-related macular degeneration, a condition with a pathogenesis similar to that involved in diabetic retinopathy.29,30 Bevacizumab. Intravitreal injection of bevacizumab (6.2 μg– 1.25 mg) was evaluated in 45 eyes of 32 patients with retinal or iris neovascularization due to diabetes mellitus (i.e., PDR).31 All 44 eyes with neovascularization demonstrated by fluorescein angiography had complete or at least partial reduction in leakage of the neovascularization within one week after the injection. In two cases, a subtle decrease in leakage of retinal or iris neovascularization in the fellow uninjected eye was noted, suggesting that therapeutic systemic levels might have been achieved after intravitreal injection. No major ocular or systemic adverse events were reported. The safety and efficacy of intra-vitreal bevacizumab were evaluated in a prospective, nonrandomized, open-label study of 15 patients with diabetes with actively leaking new vessels that were refractory to laser treatment and best-corrected ETDRS visual acuity worse than 20/40.32 Patients were followed for 12 weeks after the administration of single 1.5-mg doses. Significant decreases from baseline in the mean area of actively leaking new vessels were observed 1 week and 12 weeks after the injection (p < 0.05), with no leakage detected 6 weeks after the injection. Significant improvements from baseline in best-corrected ETDRS visual acuity also were observed after 1 week, 6 weeks, and 12 weeks (p < 0.05). No major adverse effects were reported. However, subconjunctival hemorrhage and foreign body sensation were reported in 26.6% and 6.6% of subjects, respectively. These adverse effects resolved within one week of treatment. In a prospective case series, 51 consecutive patients (51 eyes) with diffuse diabetic macular edema and NPDR or PDR received intravitreal bevacizumab 1.25 mg and were followed for at least six weeks.33 Follow-up visits were made two weeks after the injection and then at four-week intervals. Repeat injections were performed for patients with a limited response (i.e., no reduction in retinal thickness or no improvement in visual acuity) to the first injection or recurrent edema associated with reduced visual acuity. All 51 patients had received prior treatment, such as focal laser therapy (35%), full-scatter panretinal laser therapy (37%), vitrectomy (12%), or intravitreal injection of triamcinolone (33%). Sixteen (70%) of 23 patients who were followed for 12 weeks received at least two injections. A significant increase from baseline in the mean visual acuity was observed after 6 weeks (p = 0.001), although some regression occurred by 12 weeks. An increase in visual acuity of at least three lines was observed in 15 (29%) of 51 eyes after 6 weeks and 6 (26%) of the 23 eyes that were followed for 12 weeks. The mean retinal thickness decreased significantly from baseline after 2 weeks (p = 0.002), 6 weeks (p = 0.001), and 12 weeks (p = 0.001). Two patients with vitreous hemorrhage due to PDR so extensive that it precluded panretinal photocoagulation were treated with at least one 1.25-mg intravitreal injection of bevacizumab.34 Improvement in visual acuity began within the first week after injection in both patients. After one month of follow-up, one patient had two lines of improvement in visual acuity and the other patient had five lines of improvement (i.e., improvement was clinically significant in both patients). Regression of retinal neovascularization was observed in both patients after one month of follow-up. One patient received a repeat injection at the one-month follow-up visit because of slight leakage from neovascularization on the nerve. The other patient received a repeat injection after three months of follow-up because the retinal neovascularization showed early signs of reperfusion. The vitreous hemorrhage in both patients showed partial resolution after one week of follow-up and nearly complete regression after one month. No adverse events were observed in either patient. These studies suggest that intravitreal bevacizumab may provide benefit to patients with diabetic retinopathy. Additional research is needed to determine whether intravitreal administration causes systemic effects, because increases in blood pressure necessitating adjustment in antihypertensive drug therapy were associated with systemic therapy in patients with neovascular age-related macular degeneration.35 Pegaptanib. The efficacy and safety of pegaptanib in treating diabetic macular edema were evaluated in a Phase II randomized, double-blind, placebo-controlled dose-finding study.36 A total of 172 patients with type 1 or type 2 diabetes, no prior photocoagulation therapy, best-corrected visual acuity between 20/50 and 20/320 in the study eye, and diabetic macular edema involving the center of the macula were enrolled. Pegaptanib 0.3 mg, 1 mg, or 3 mg or placebo was given by intravitreal injection at the time of study entry, week 6, and week 12, followed by additional injections, focal photocoagulation, or both as needed for another 18 weeks. An average of 4.5–5 injections were given to each patient, and injections were given on average once every 7 to 8 months over the 36-month study period.35 In 16 patients with neovascularization, 8 (50%) patients had regression of the neovascularization. However, the neovascularization progressed in these patients after pegaptanib was discontinued. The average change from baseline in visual acuity after 36 weeks was a reduction of 0.4 letters in the placebo group and 1.1 letters in the pegaptanib 3-mg group and an increase of 4.7 letters in both the pegaptanib 1-mg and 3-mg groups.36 The differences between the 0.3-mg and 1-mg groups and placebo were statistically significant (p = 0.04 and 0.05, respectively). Significantly larger percentages of patients receiving pegaptanib 0.3 mg gained 10 or more letters (approximately two lines) and 15 or more letters (approximately 3 lines) in visual acuity over the 36-week study period than patients treated with placebo (34% versus 10% for a gain of ≥ 10 letters, p = 0.003, and 18% versus 7% for a gain of ≥ 15 letters, p = 0.12). The percentage of patients in the pegaptanib 0.3-mg, 1-mg, and 3-mg groups and the placebo group with no loss in visual acuity (i.e., a ≥ 0 increase from baseline in letters) was 73%, 72%, 60%, and 51%, respectively. The difference between pegaptanib 0.3 mg and placebo was significant (p = 0.023). These findings suggest that although pegaptanib improves visual acuity in some patients with diabetic macular edema, it merely prevents loss of visual acuity in many patients (i.e., the condition is difficult to treat). More pegaptanib-treated patients than placebo-treated patients experienced eye pain (31% versus 17%, p = 0.029), punctate keratitis (inflammation of pinpoint areas in the outer layer of the cornea) (18% versus 17%), cataracts (13% versus 10%), eye discharge (11% versus 10%), and vitreous floaters (22% versus 7%, p = 0.009).36 The small difference in frequency of punctate keratitis between patients receiving pegaptanib and patients receiving placebo suggests that the condition probably is related to the intravitreal injection process, not necessarily the drug. Ranibizumab. The safety and efficacy of intravitreal injection of ranibizumab 0.5 mg were evaluated in 10 patients with chronic diabetic macular edema.37 Injections were given at baseline, one month, two months, four months, and six months (i.e., a total of five injections were given). The primary outcome was change in thickness of the fovea at the center of the macula over the seven-month study period. The mean foveal thickness decreased by 85% (p = 0.005). The mean visual acuity improved by 12.3 letters (p = 0.005), an amount that is statistically and clinically significant. The injections were well tolerated, with no ocular or systemic adverse events. Additional research is needed to evaluate the safety and efficacy of ranibizumab and other VEGF inhibitors in patients with diabetic retinopathy. Several studies of ranibizumab are under way.38,–41 Future research In patients with diabetic retinopathy, preserving vision appears more feasible than improving vision when drug therapy targets only one of the interrelated biochemical pathways involved in microvascular damage. A multipronged approach with more than one drug targeting more than one pathway may be needed to improve vision. Research is needed to identify the optimal strategy for preventing the microvascular damage associated with vision loss in patients with diabetic retinopathy. Conclusion The primary goal of treatment for diabetic retinopathy is to improve or preserve vision. The biochemical pathways by which hyperglycemia causes microvascular damage are the target for recently developed drug therapies. The results of research using systemic therapy with aldose reductase inhibitors or PKC inhibitors and intravitreal corticosteroids or VEGF inhibitors are promising. Footnotes Based on the proceedings of a symposium held December 5, 2006, during the ASHP Midyear Clinical Meeting and Exhibition in Anaheim, CA, and supported by an educational grant from Eli Lilly and Company. Dr. Ryan received an honorarium for her participation in the symposium and for the preparation of this article. Dr. Ryan was recommended as faculty by the commercial supporter of this educational activity. Dr.Ryan reports that she has no affiliations with or financial interest in a commercial organization that poses a conflict of interest with this article. References 1 American Academy of Ophthalmology. Diabetic retinopathy preferred practice pattern. 2003 . http://www.aao.org/education/library/ppp/upload/Diabetic_Retinopathy.pdf (accessed 2007 Feb 22). 2 Maeshima K, Utsugi-Sutoh N, Otani T et al. Progressive enlargement of scattered photocoagulation scars in diabetic retinopathy. Retina . 2004 ; 24 : 507 –11. Crossref Search ADS PubMed 3 Cuilla TA, Amador AG, Zinman B. 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A phase II randomized double-masked trial of pegaptanib, an antivascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology . 2005 ; 112 : 1747 –57. Crossref Search ADS PubMed 37 Nguyen QD, Tatlipinar S, Shah SM et al. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol . 2006 ; 142 : 961 –9. Crossref Search ADS PubMed 38 Efficacy study of Lucentis in the treatment of diabetic macular edema. http://www.clinicaltrials.gov/ct/show/NCT00387582?order=4. (accessed 2007 Mar 5). 39 Study comparing two doses of ranibizumab in the treatment of clinically significant diabetic macular edema. http://www.clinicaltrials.gov/ct/show/NCT00440609?order=7. (accessed 2007 Mar 5). 40 RESOLVE: safety and efficacy of ranibizumab in diabetic macular edema withcenter involvement. http://www.clinicaltrials.gov/ct/show/NCT00284050?order=13 (accessed 2007 Mar 5). 41 The READ-2 (ranibizumab for edema of the macula in diabetes) study. http://www.clinicaltrials.gov/ct/show/NCT00407381?order=14. (accessed 2007 Mar 5). Copyright © 2007. American Society of Health-System Pharmacists, Inc. All rights reserved.

Morello, Candis, M.

doi: 10.2146/ajhp070330pmid: 17720892

Purpose. The morbidity and mortality from and economic impact of diabetes mellitus in the United States, pathogenesis of microvascular diabetic complications, contribution of poor long-term glycemic control to risk for diabetic retinopathy and other microvascular complications, prevalence of diabetic retinopathy, methods for measuring visual acuity, and manifestations of disease progression and etiology of blindness in patients with diabetic retinopathy are discussed. Summary. Diabetic retinopathy and other microvascular and macrovascular complications of diabetes cause considerable morbidity and mortality and have a large economic impact in the United States. Patients with poor long-term glycemic control are more vulnerable to diabetic retinopathy than to other microvascular complications of diabetes. Diabetic retinopathy is the third leading cause of all cases of blindness in the United States and the leading cause of new cases in adults. Retinopathy is already present at the time of diagnosis in 20% of patients with type 2 diabetes. Retinopathy and other micro-vascular complications are attributed to chronic hyperglycemia, vascular damage and leakage, edema, capillary basement membrane thickening, neovascularization, hemorrhage, and ischemia. Measurements of visual acuity loss are expressed in terms of the distance at which a person with normal vision can see what the test subject can see from 20 feet away. Diabetic retinopathy begins as nonproliferative abnormalities and progresses to proliferative diabetic retinopathy. Macular edema can develop at any time in the progression of diabetic retinopathy. Macular ischemia, retinal and vitreous hemorrhage, and retinal detachment are the primary causes of blindness in patients with diabetic retinopathy. Conclusion. Diabetic retinopathy is a costly and progressive condition associated with chronic hyperglycemia. It is potentially vision-threatening. Diabetic retinopathy, Economics, Epidemiology, Mortality Diabetes mellitus is a major cause of morbidity and mortality in the United States. In 2002, diabetes was the sixth leading cause of death as listed on U.S. death certificates.1 The risk for death among Americans with diabetes is about twice that for people the same age without diabetes.1 About two thirds of deaths in people with diabetes are attributed to macrovascular complications, which usually manifest as heart disease or stroke.1 Heart disease death rates and the risk for stroke in adults with diabetes are two to four times higher than in people without diabetes.1 Microvascular complications affecting the nervous system, kidneys, and eyes also are common. Roughly 60–70% of patients with diabetes develop nerve damage, which can lead to ulcer formation and the need for amputation.1 Diabetes accounts for more than 60% of nontraumatic lower-extremity amputations in the United States.1 The disease is the leading cause of kidney failure and new cases of blindness in adults.1 In 2002, direct medical expenses and indirect costs associated with diabetes in the United States amounted to $132 billion.2 This figure includes nearly $40 billion in indirect costs attributable to restricted activity, lost workdays, permanent disability, and premature mortality. Direct medical expenses included $23 billion for diabetes care and $25 billion for management of diabetes complications, with $422 million for ophthalmic complications. The direct medical expenses for people with diabetes were about 2.4 times higher than those for people without diabetes. Pathogenesis The microvascular complications of diabetes are the result of chronic hyperglycemia, which causes vascular damage, increased vascular permeability, vascular leakage, and edema.3 Vascular tone is decreased by hyperglycemia, resulting in increased blood pressure. Extracellular matrix accumulation also occurs, causing basement membrane thickening, which can lead to occlusion and ischemia. Compensatory growth of abnormal new blood vessels (i.e., neovascularization) that are fragile and prone to hemorrhage also occurs. These pathophysiologic changes manifest as diabetic neuropathy, diabetic nephropathy, and diabetic retinopathy. The symptoms of diabetic neuropathy (tingling, pain, numbness, or impaired sensation in the feet) are the result of diminished blood flow to the nerves. Diabetic nephropathy is characterized by changes in glomerular filtration rate, expansion of extracellular matrix in the mesangial area (i.e., in the central part of the glomerulus), glomerular capillary crowding, and overt renal occlusion, leading to kidney failure. Diabetic retinopathy is characterized by reduced retinal capillary blood flow, retinal and vitreous hemorrhage, reduced visual acuity, and, ultimately, blindness. Analysis of data from the Diabetes Control and Complications Trial, a landmark study of the impact of intensive treatment on long-term complications in 1441 patients with type 1 diabetes, showed that the relative risk of microvascular complications increases progressively with increases in A1C beyond 6%, with no threshold for developing complications.4,5 As A1C increases, the risk for retinopathy increases more rapidly than the risk for other microvascular complications (i.e., patients with type 1 disease and poor long-term glycemic control are particularly vulnerable to retinopathy). Studies in patients with type 2 diabetes have shown that using intensive treatment to control A1C delays the onset of and reduces the progression of microvascular complications.6 Diabetic retinopathy In 2002, diabetic retinopathy was the third leading cause of blindness among all cases of blindness in the United States.7 The percentage of cases of blindness attributed to age-related macular degeneration, glaucoma, and diabetic retinopathy was 50%, 18%, and 17%, respectively. Diabetic retinopathy begins as mild, nonproliferative abnormalities and progresses to moderate and severe nonproliferative diabetic retinopathy (NPDR) and then proliferative diabetic retinopathy (PDR).8 Macular edema can develop at any time in the progression of diabetic retinopathy.9 Diabetic retinopathy may begin to develop years before a clinical diagnosis of diabetes is made. One in five patients with type 2 disease has retinopathy at the time of diagnosis.8 More than 60% of patients with type 2 diabetes and almost all patients with type 1 diabetes develop retinopathy during the first 20 years of the disease.8 Approximately 40% of adults 40 years of age and older with diabetes have retinopathy, and the condition is vision-threatening in 20% of these patients.10 Vision-threatening diabetic retinopathy is defined as severe NPDR, PDR, macular edema, or more than one of these. Persons 50 years of age or older with diabetes have twice the risk of vision impairment as people the same age without diabetes.11 The primary area of the eye affected by diabetic retinopathy is the retina, which lines the inner surface of the eyeball (Figure 11). Light enters the eye through the pupil and passes through the lens and vitreous gel until it reaches the retina, which contains photoreceptors that convert light into nerve signals that are transmitted via the optic nerve to the brain. The macula at the center of the retina contains the highest concentration of photoreceptors. The fovea at the center of the macula processes the details needed for reading and driving a motor vehicle. Damage to the macula is vision-threatening. Figure 1. Open in new tabDownload slide Schematic diagram of eyeball cross-section. Available at http://www.nei.nih.gov/photo/charts/index.asp. From National Eye Institute, National Institutes of Health. Figure 1. Open in new tabDownload slide Schematic diagram of eyeball cross-section. Available at http://www.nei.nih.gov/photo/charts/index.asp. From National Eye Institute, National Institutes of Health. Measuring visual acuity The Early Treatment Diabetic Retinopathy Research Study (ETDRS) acuity scale and chart (Figure 22) are the worldwide standard for testing visual acuity and are used in clinical trials. They were developed to improve on inadequacies associated with the older Snellen and Sloan acuity tests, which had inconsistencies in the type and spacing of letters (Figure 3 3). The ETDRS visual acuity chart has the same number of letters (five) and a similar level of difficulty in the types of letters in each row, with equal illumination of the letters within a row and in different rows. The scale also has equal spacing of letters within a row and equal spacing of rows on a logarithmic scale (i.e., 0.1 log unit separation between rows). Figure 3. Open in new tabDownload slide Snellen visual acuity chart. Available at http://www.nei.nih.gov/photo/charts/index.asp. From National Eye Institute, National Institutes of Health. This chart was used with the Snellen visual acuity test, which has been superseded by the newer Early Treatment Diabetic Retinopathy Research Study visual acuity test. The newer test uses a chart (Figure 22) with equal illumination and spacing of letters in rows and equal spacing of rows on a logarithmic scale. Figure 3. Open in new tabDownload slide Snellen visual acuity chart. Available at http://www.nei.nih.gov/photo/charts/index.asp. From National Eye Institute, National Institutes of Health. This chart was used with the Snellen visual acuity test, which has been superseded by the newer Early Treatment Diabetic Retinopathy Research Study visual acuity test. The newer test uses a chart (Figure 22) with equal illumination and spacing of letters in rows and equal spacing of rows on a logarithmic scale. Figure 2. Open in new tabDownload slide Early Treatment Diabetic Retinopathy Research Study visual acuity chart. Available at http://www.nei.nih.gov/photo/charts/index.asp. From National Eye Institute, National Institutes of Health. The 20/20 line (i.e., row) can be read by persons with normal vision from a distance of 20 feet. Measurements of visual acuity loss are expressed in terms of the distance at which a person with normal vision can see what the test subject can see from 20 feet away. For example, 20/40 visual acuity means that the test subject can see from 20 feet away what persons with normal vision can see from 40 feet away. Figure 2. Open in new tabDownload slide Early Treatment Diabetic Retinopathy Research Study visual acuity chart. Available at http://www.nei.nih.gov/photo/charts/index.asp. From National Eye Institute, National Institutes of Health. The 20/20 line (i.e., row) can be read by persons with normal vision from a distance of 20 feet. Measurements of visual acuity loss are expressed in terms of the distance at which a person with normal vision can see what the test subject can see from 20 feet away. For example, 20/40 visual acuity means that the test subject can see from 20 feet away what persons with normal vision can see from 40 feet away. The 20/20 line (i.e., row) on the ETDRS visual acuity chart can be read by persons with normal vision from a distance of 20 feet. Measurements of visual acuity loss are expressed in terms of the distance at which a person with normal vision can see what the test subject can see from 20 feet away. For example, 20/40 visual acuity means that the test subject can see from 20 feet away what persons with normal vision can see from 40 feet away. Moderate vision loss reflects a three-line or 15-letter vision loss (e.g., a change from 20/20 to 20/40 vision), which can impair reading and the ability to drive a motor vehicle.12 Further deterioration to 20/80 vision (i.e., the ability to see 20 feet from the ETDRS visual acuity chart what a person with normal vision can see from 80 feet away) results in difficulty reading objects at a distance, including road signs. Many states prohibit persons with such vision loss from driving a motor vehicle (i.e., their driver’s license is revoked). More than visual acuity is affected in patients with diabetic retinopathy; poor night vision, problems with distinguishing colors, and reduced vision field may also occur. Legal blindness is defined as 20/200 vision, which is associated with difficulty walking as well as reading and driving. Severe vision loss is defined as <5/200 on two consecutive visits at four-month intervals with an inability to read any letters on the ETDRS visual acuity chart.12 In research, the ETDRS acuity scale is used to categorize the severity of NPDR (Table 11). A numerical value is assigned to reflect the severity as indicated by the presence and number of microaneurysms (i.e., focal dilations of retinal capillaries), hard exudates, hemorrhages, and other bleeding abnormalities found in one or more of the four quadrants evaluated during a dilated ophthalmoscopic examination. Hard exudates comprise extracellular lipids and proteins (e.g., fibrinogen), and they form after abnormal retinal capillaries leak and fluid resorption occurs. Cotton-wool spots (formerly referred to as soft exudates) are accumulations of cytoplasmic debris in the retina. Venous beading (sac-like bulges in the vessel wall) is indicative of extensive retinal ischemia. Table 1. Early Treatment Diabetic Retinopathy Research Study Acuity Scale13 Level Severity Definition aNPDR = nonproliferative diabetic retinopathy. bIRMA = intraretinal microvascular abnormalities. 10 No retinopathy Diabetic retinopathy absent 20 Very mild NPDRa Microaneurysms only 35 Mild NPDR Microaneurysms with hard exudates, cotton-wool spots, or mild retinal hemorrhages 43 Moderate NPDR Microaneurysms plus mild IRMAb or moderate retinal hemorrhages 47 Moderate NPDR More extensive IRMA, severe retinal hemorrhages OR venous beading in one quadrant 53 Severe NPDR Severe retinal hemorrhages in four quadrants OR venous beading in at least two quadrants OR moderately severe IRMA in at least one quadrant Level Severity Definition aNPDR = nonproliferative diabetic retinopathy. bIRMA = intraretinal microvascular abnormalities. 10 No retinopathy Diabetic retinopathy absent 20 Very mild NPDRa Microaneurysms only 35 Mild NPDR Microaneurysms with hard exudates, cotton-wool spots, or mild retinal hemorrhages 43 Moderate NPDR Microaneurysms plus mild IRMAb or moderate retinal hemorrhages 47 Moderate NPDR More extensive IRMA, severe retinal hemorrhages OR venous beading in one quadrant 53 Severe NPDR Severe retinal hemorrhages in four quadrants OR venous beading in at least two quadrants OR moderately severe IRMA in at least one quadrant Open in new tab Table 1. Early Treatment Diabetic Retinopathy Research Study Acuity Scale13 Level Severity Definition aNPDR = nonproliferative diabetic retinopathy. bIRMA = intraretinal microvascular abnormalities. 10 No retinopathy Diabetic retinopathy absent 20 Very mild NPDRa Microaneurysms only 35 Mild NPDR Microaneurysms with hard exudates, cotton-wool spots, or mild retinal hemorrhages 43 Moderate NPDR Microaneurysms plus mild IRMAb or moderate retinal hemorrhages 47 Moderate NPDR More extensive IRMA, severe retinal hemorrhages OR venous beading in one quadrant 53 Severe NPDR Severe retinal hemorrhages in four quadrants OR venous beading in at least two quadrants OR moderately severe IRMA in at least one quadrant Level Severity Definition aNPDR = nonproliferative diabetic retinopathy. bIRMA = intraretinal microvascular abnormalities. 10 No retinopathy Diabetic retinopathy absent 20 Very mild NPDRa Microaneurysms only 35 Mild NPDR Microaneurysms with hard exudates, cotton-wool spots, or mild retinal hemorrhages 43 Moderate NPDR Microaneurysms plus mild IRMAb or moderate retinal hemorrhages 47 Moderate NPDR More extensive IRMA, severe retinal hemorrhages OR venous beading in one quadrant 53 Severe NPDR Severe retinal hemorrhages in four quadrants OR venous beading in at least two quadrants OR moderately severe IRMA in at least one quadrant Open in new tab Progression and manifestations NPDR initially is mild, with only microaneurysms, but it progresses to moderate and then severe NPDR. Severe NPDR is defined as more than 20 intraretinal hemorrhages in each of four quadrants, definite venous beading in at least two quadrants, or prominent intraretinal microvascular abnormalities in at least one quadrant with no signs of PDR.12 NPDR may be asymptomatic, which underscores the need for screening and early detection. It also may be accompanied by blurred vision, a symptom associated with hyperglycemia. Floaters (i.e., black, peppery spots in the vision), loss of central or peripheral vision, and flashes of light also are among the signs and symptoms of NPDR. Altered color vision and blue/yellow color blindness (i.e., loss of blue and yellow colors, leaving primarily green and red colors) is an early symptom of diabetic retinopathy. Neovascularization is the hallmark of PDR. PDR is more common in patients with type 1 diabetes than in patients with type 2 diabetes.14 Signs and symptoms of PDR include blurred vision, floaters, loss of central or peripheral vision, and flashes of light, but the onset typically is more sudden, and blurring of vision often is more severe than in NPDR. Flame-shaped intraretinal hemorrhages are commonly found during ophthalmoscopic examination because the new blood vessels are fragile. Diabetic macular edema is characterized by intraretinal fluid accumulation in the macula and retinal thickening, which manifest as slow degradation in and blurring of vision and distorted images. The image distortion is particularly problematic when retinal thickening occurs near the fovea, which affects the central area of the field of vision.15 The incidence of macular edema is higher in patients with type 2 diabetes who use insulin than in patients with type 1 diabetes and is lowest in patients with type 2 diabetes who do not use insulin.14 Causes of blindness There are three primary mechanisms by which diabetic retinopathy causes blindness: macular ischemia, retinal and vitreous hemorrhage, and retinal detachment.16 Macular ischemia leads to hypoxia and death of light-sensitive cells (i.e., photoreceptors), a process that is slow. The prognosis is good if the situation is detected early and treated promptly, but the prognosis is poor if ischemia is the result of vascular occlusion. Retinal and vitreous hemorrhage can cause pooling of blood in the back of the eye that obscures vision. The condition may occur suddenly and resolve spontaneously, but without treatment it can lead to permanent vision loss. Detachment of the retina from the inside of the eyeball can occur suddenly. It constitutes an ophthalmic emergency because permanent vision loss can occur if it is not treated immediately. Conclusion Diabetic retinopathy is a common and costly complication of diabetes. The condition is progressive and potentially devastating because it can lead to blindness. Footnotes Based on the proceedings of a symposium held December 5, 2006, during the ASHP Midyear Clinical Meeting and Exhibition in Anaheim, CA, and supported by an educational grant from Eli Lilly and Company. Dr. Morello received an honorarium for her participation in the symposium and for the preparation of this article. Dr. Morello was recommended as faculty by the commercial supporter of this educational activity. Dr.Morello reports that she has no affiliations with or financial interest in a commercial organization that poses a conflict of interest with this article. References 1 Centers for Disease Control and Prevention. National Diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, 2005. Atlanta, GA: US Dept of Health and Human Services, Centers for Disease Control and Prevention; 2005. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf (accessed 2007 Feb 24). 2 Hogan P, Dall T, Nikolov P, American Diabetes Association. Economic costs of diabetes in the US in 2002. Diabetes Care . 2003 ; 26 : 917 –32. Crossref Search ADS PubMed 3 Sheetz MJ, King GL. Molecular understanding of hyperglycemia’s adverse effects for diabetic complications. JAMA . 2002 ; 288 : 2579 –88. Crossref Search ADS PubMed 4 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. Crossref Search ADS PubMed 5 Skyler JS. Diabetic complications. The importance of glucose control. Metab Clin North Am . 1996 ; 25 : 243 –54. Crossref Search ADS 6 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998 ; 352 : 837 –53. Crossref Search ADS PubMed 7 Resnikoff S, Pascolini D, Etya’ale D et al. Global data on visual impairment in the year 2002. Bull World Health Organ . 2004 ; 82 : 844 –51. PubMed 8 American Diabetes Association. Retinopathy in diabetes. Diabetes Care . 2006 ; 27 (suppl 1): S84 –7. 9 American Optometric Association. Opto-metric clinical practice guideline: care of the patient with diabetes mellitus. 2002. www.aoa.org/documents/CPG-3.pdf (accessed 2007 Feb 22). 10 Kempen JH, O’Colmain BJ, Leske MC et al. The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol . 2004 ; 122 : 552 –63. Crossref Search ADS PubMed 11 Centers for Disease Control and Prevention. Prevalence of visual impairment and selected eye diseases among persons aged ≥50 years with and without diabetes—United States, 2002. MMWR Morb Mortal Wkly Rep . 2004 ; 53 : 1069 –71. PubMed 12 American Academy of Ophthalmology. Diabetic retinopathy preferred practice pattern. 2003. http://www.aao.org/education/library/ppp/upload/Diabetic_Retinopathy.pdf (accessed 2007 Feb 22). 13 The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial. Arch Ophthalmol . 1995 ; 113 : 36 –51. Crossref Search ADS PubMed 14 Frank RN. Diabetic retinopathy. N Engl J Med . 2004 ; 350 : 48 –58. Crossref Search ADS PubMed 15 Cuilla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies. Diabetes Care . 2003 ; 26 : 2653 –64. Crossref Search ADS PubMed 16 Rosenblatt BJ, Benson WE. Diabetic retinopathy. In: Yanoff M, Duker JS, eds. Ophthalmology, 2nd ed. St. Louis, MO: Mosby; 2004 :877–86. Copyright © 2007. American Society of Health-System Pharmacists, Inc. All rights reserved.

doi: 10.1093/ajhp/64.suppl_12.S22pmid: N/A

Learning objectives After studying these articles, the reader should be able to: Describe the prevalence, etiology, pathogenesis, natural history, and clinical manifestations of retinopathy in patients with diabetes mellitus. Identify the anatomical structure in the eye that plays a critical role in processing visual details needed for reading and driving a motor vehicle, and explain the method for measuring visual acuity, how to interpret visual acuity measurements, and what changes in visual acuity measurements constitute a clinically significant improvement from diabetic retinopathy therapies. Specify the frequency of screening for diabetic retinopathy recommended by the American Diabetes Association (ADA), name a modifiable risk factor for diabetic retinopathy that can be targeted to reduce the risk for and progression of retinopathy, and explain the role of antidiabetic, antihypertensive, lipid-lowering, and aspirin therapy in patients with or at risk for diabetic retinopathy. Discuss the uses, advantages, and disadvantages of currently available laser photocoagulation and intra-ocular surgical techniques in patients with diabetic retinopathy. Identify an endpoint used in clinical studies of various therapies for diabetic retinopathy. Name drug therapies that target a biochemical pathway involved in diabetic retinopathy and explain their mechanism of action, efficacy, and safety in preventing microvascular damage and loss of visual acuity. Self-assessment questions For each question there is only one best answer. Which of the following is the percentage of patients with type 2 diabetes mellitus who have diabetic retinopathy at the time of diagnosis? 5%. 20%. 40%. 80%. Which of the following anatomic structures in the eye processes the visual details needed for reading and driving a motor vehicle? Ciliary body. Optic disk. Fovea. Retina. Which of the following visual acuity measurements is considered legally blind? 20/20. 20/40. 20/80. 20/200. Which of the following changes in visual acuity is considered a clinically significant improvement? 10–15 lines or more. 10–15 letters or more. 4 or 5 lines or more. 2 or 3 letters or more. The sequence for progression of diabetic retinopathy is best described as: Nonproliferative diabetic retinopathy (NPDR) followed by proliferative diabetic retinopathy (PDR) and then macular edema. PDR followed by NPDR and then macular edema. NPDR followed by PDR, with macular edema at any time in the progression of the disease. PDR followed by NPDR, with macular edema at any time in the progression of the disease. The clinical manifestations of NPDR and PDR differ because: The onset typically is more sudden and blurring of vision often is more severe in PDR than NPDR. The onset typically is more gradual and blurring of vision often is more severe in PDR than NPDR. The onset typically is more sudden and blurring of vision often is less severe in PDR than NPDR. The onset typically is more gradual and blurring of vision often is less severe in PDR than NPDR. Which of the following pathophysiologic findings is the hallmark of PDR? Edema. Hard exudates. Microaneurysms. Neovascularization. The three primary causes of blindness in patients with diabetic retinopathy are: Macular ischemia, retinal and vitreous hemorrhage, and retinal detachment. Retinal capillary basement membrane thickening, macular edema, and neovascularization. Macular edema, retinal and vitreous hemorrhage, and neovascularization. Macular edema, hard exudate formation, and neovascularization. Which of the following is the frequency of screening for diabetic retinopathy recommended by the ADA? Monthly. Quarterly. Semi-annually. Annually. For which of the following modifiable risk factors for diabetic retinopathy has control been shown to reduce the risk for and prevention of retinopathy? Elevated A1C only. Elevated blood pressure only. Elevated A1C and blood pressure. Elevated A1C and blood pressure and dyslipidemia. Which of the following statements about the role of aspirin therapy in patients with or at risk for diabetic retinopathy is correct? Aspirin should not be used because it increases the risk for vitreous hemorrhage. Aspirin should not be used because it lacks cardiovascular benefits in patients with diabetes. Aspirin should be used because it prevents retinopathy. Aspirin should be used because of its cardiovascular benefits. Which of the following is a laser technique used for patients with PDR? Focal photocoagulation. Grid photocoagulation. Panretinal (scatter) photocoagulation. Vitrectomy. Which of the following is an advantage of laser photocoagulation treatments for diabetic retinopathy? Substantial reduction in risk of visual loss. Lack of invasiveness and discomfort. Lack of need for repeated treatment. Lack of scar tissue formation. Which of the following is sometimes used as a surrogate measure for visual acuity in clinical trials of treatments for diabetic retinopathy? Number of cotton-wool spots. Number of hard exudates. Macular thickness. Venous tortuosity. Which of the following key elements of the biochemical pathways linking chronic hyperglycemia with retinal microvascular damage is targeted by epalrestat? Aldose reductase. Advanced glycation end products. Protein kinase C. Free oxygen radicals. Which of the following are the most common adverse effects from midostaurin? Increased intraocular pressure and cataracts. Gastrointestinal effects (nausea, diarrhea, and vomiting). Endophthalmitis and punctate keratitis. Elevations in liver enzymes (alanine aminotransferase or aspartate aminotransferase). Which of the following is a potential advantage of ruboxistaurin over midostaurin? Its lack of selectivity for any PKC isoform. Its selectivity for PKC β. Its oral route of administration. The need for a topical and local anesthetic before administration. Which of the following statements about the efficacy of intravitreal corticosteroids in the treatment of diabetic retinopathy is correct? They often cause loss of visual acuity. They often prevent loss in visual acuity but do not improve visual acuity. They often improve visual acuity to a clinically significant extent but not to a statistically significant extent. They often improve visual acuity to a clinically and statistically significant extent. Which of the following is a VEGF inhibitor that has been used investigationally to treat diabetic retinopathy? Bevacizumab. Epalrestat. Midostaurin. Ruboxistaurin. Which of the following are VEGF inhibitors that are approved by FDA for the treatment of neovascular (wet) age-related macular degeneration, a condition with a pathogenesis similar to that involved in diabetic retinopathy? Bevacizumab and ranibizumab. Fidarestat and ranirestat. Midostaurin and ruboxistaurin. Pegaptanib and ranibizumab. AJHP continuing education AJHP CE Process Continuing education (CE) credit for this AJHP supplement is free for both members and nonmembers. Successful completion of a CE test is required to obtain CE credit. The CE test can only be taken online through ASHP’s CE Testing Center. After successful completion (score of 70% or better), you will be able to immediately print your own CE statement for your records. You will have two opportunities to pass the CE test, and you may stop and return to the test at any time before submitting your final answers. ASHP will keep a record of the credits you have earned from this and other CE activities, and you will be able to view your entire transcript through the CE Testing Center. Instructions for the CE Testing Center Go to http://ce.ashp.org and select “Enter CE Testing Center.” ASHP members and registered customers: Type in either your 8-digit ASHP ID or your user name, and password Click on “Register for Tests.” Follow instructions to select the desired supplement or, an easy way to search, click on “Edit”; select “Find on this Page”; type in a word or phrase in the title. Nonmemebers: Click on the “Become a Registered User” link at the bottom of the page. Fill out the information requested and create your password. Go back to http://ce.ashp.org and select “Enter CE Testing Center.” You will automatically be logged into the center. To view the complete list of available AJHP CE articles and supplements go to www.ashp.org, click on “Continuing Education” on the left menu, and then click on “AJHP CE Publications” under “Self-Study Programs.” While many of these are free to nonmembers, some are not. To have access to all the CE AJHP has to offer for free, consider becoming a member of ASHP. To find out more about the benefits of being an ASHP member, go to www.ashp.org and click on “Member Center” on the left menu. Supplement: New pharmacologic approaches to treating diabetic retinopathy: An opportunity for pharmacist involvement in patient care ACPE #: 204-000-07-009-H01P CE credit: 1.5 hours (0.15 CEUs) Expiration date: September 1, 2010 The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Questions? Call ASHP Processing Center: 866-279-0681 (toll free) +1-301-664-8700 (international callers) Copyright © 2007. American Society of Health-System Pharmacists, Inc. All rights reserved.

Bloomgarden, Zachary, T.

doi: 10.2146/ajhp070331pmid: 17720893

Purpose. The anatomy of the eye and the pathogenesis, clinical features, and prevalence of vision impairment from diabetic retinopathy are described. Screening and risk factors for and treatment of diabetic retinopathy also are addressed. Summary. The macula and fovea play a critical role in vision. Several interrelated biochemical pathways involving aldose reductase, advanced glycation end products, and protein kinase C link chronic hyperglycemia with retinal capillary endothelial cell damage and dysfunction in patients with diabetic retinopathy. Vision loss and blindness from diabetic retinopathy usually are the result of vascular leakage or ischemia. Screening for retinopathy should be performed within three to five years after the onset of type 1 diabetes and shortly after the diagnosis of type 2 disease, with annual follow-up examinations in both types of diabetes. In patients with diabetic retinopathy, severe vision impairment is less common and less readily corrected than mild vision impairment, and vision impairment is more common and less readily corrected in elderly patients with diabetes than in younger diabetics. Modifiable risk factors for diabetic retinopathy include A1C level, hypertension, cigarette smoking, and dyslipidemia. Tight control of blood glucose concentrations and blood pressure can reduce the risk for and progression of diabetic retinopathy. Aspirin therapy and smoking cessation also are recommended. Dyslipidemia in patients with diabetes is associated with retinopathy progression and vision loss. Treatment of dyslipidemia provides cardiovascular benefits in patients with diabetes, but whether it provides vision benefits remains to be determined. Laser photocoagulation therapy reduces the risk of vision loss in patients with diabetic macular edema, severe nonproliferative diabetic retinopathy, or proliferative diabetic retinopathy. Intraocular surgery may be used for patients with vitreous hemorrhage and retinal detachment of the macula. Conclusion. Therapeutic approaches used for patients with or at risk for diabetic retinopathy include drug therapy to reduce modifiable risk factors, laser photocoagulation, and intraocular surgery. Screening plays an important role in early detection and intervention to prevent the progression of diabetic retinopathy. Aspirin, Diabetic retinopathy, Diagnosis, Geriatrics, Hyperlipidemia, Lasers, Platelet aggregation inhibitors, Smoking, Surgery The pupil is surrounded by the circular iris, a muscular tissue that gives the eye its color and regulates the amount of light that enters by dilating and constricting to change the size of the pupil. The cornea is a transparent membrane that covers the pupil and iris. It connects with the sclera, the outer layer of the eyeball that forms the white part of the eye. The lens is suspended behind the pupil by ligaments attached to the ciliary body, forming an anterior chamber that contains aqueous humor and a posterior chamber that contains vitreous gel. Light that enters the pupil is focused by the lens in the retina. The shape of the lens is altered by the ciliary body to allow focusing of light from sources at different distances. The retina lines the posterior three quarters of the inner surface of the eyeball and contains rods and cones with a mean surface area of approximately 1000 mm.2 The eyeball measures 22 mm from the anterior to posterior pole (i.e., on a straight line from the center of the pupil to the back of the eyeball). The ora serrata is the junction between the retina and the ciliary body. The distance from ora serrata to ora serrata is 32 mm (i.e., roughly across the eyeball from top to bottom or side to side). Thus, the eyeball has an elliptical shape with the shortest dimension from front to back of the eyeball. The portion of the human eye that is critical to vision is miniscule. The optic nerve contains fibers leading from the rods and cones in the retina to the brain. The optic portion in the retina where the optic nerve exits occupies less than 4 mm.2 The adjacent macula is a depressed area 3 mm in diameter at the center of the retina that contains the fovea, a rod-free area with thin, densely packed cones. The macula and fovea are critical to vision. Pathogenesis of diabetic retinopathy Hyperglycemia causes several biochemical abnormalities that are thought to contribute to diabetic retinopathy by causing damage to and dysfunction of retinal capillary endothelial cells. Increased intracellular glucose concentrations activate aldose reductase, an enzyme that converts glucose to sorbitol.1 The reduction of glucose to sorbitol is an energy-dependent process, and excessive enzyme activity results in oxidative stress, which causes cellular dysfunction and damage. Glucose attaches nonenzymatically to proteins, resulting in the formation of advanced glycation end products that can cause cellular dysfunction and damage.1 Activation of protein kinase C (PKC), which plays a role in intracellular signaling, can alter gene expression and protein function, resulting in cell damage and dysfunction. The aldose reductase pathway, advanced glycation end product pathway, and PKC pathway are interrelated. All of these pathways are thought to contribute to retinal vascular endothelial cellular dysfunction and damage, to abnormal cell growth and survival, increased vascular permeability, altered blood flow, ischemia, abnormal angiogenesis, and to the basement matrix thickening associated with diabetic retinopathy.1 These pathways are targets for therapies for diabetic retinopathy. Vision loss and blindness from diabetic retinopathy usually are the result of vascular leakage or ischemia. Vascular leakage involves hemorrhage or the formation of hard exudates containing extracellular lipids and proteins after leakage and resorption of fluid occur.2 It manifests as nonproliferative diabetic retinopathy (NPDR). Vision loss is substantial when the macula is affected, resulting in the condition referred to as “clinically significant macular edema.” Ischemia from vascular damage and disruption in local perfusion results in angiogenesis and neovascularization, which manifest as proliferative diabetic retinopathy (PDR).2 The new blood vessels formed are fragile and prone to hemorrhage, which can impair vision, ultimately causing blindness. Vascular endothelial growth factor and fibroblast growth factor are among several angiogenic factors involved in intracellular signaling pathways that lead to the vascular endothelial cell proliferation, migration, and proteolysis associated with angiogenesis.1 These angiogenic factors also are targets for new therapies for diabetic retinopathy. Clinical features Clinical features of NPDR include microaneurysms (focal dilations of retinal capillaries), intraretinal hemorrhages, cotton-wool spots (accumulations of cytoplasmic debris in the retina), hard exudates, venous tortuosity or beading (sac-like bulges in the vessel wall), and intraretinal microvascular abnormalities.3 Clinically significant macular edema (defined in terms of the size and location near the center of the macula of retinal thickening or hard exudates) is common in patients with NPDR, although it can develop at any stage of diabetic retinopathy.2,4 It is associated with increased retinal capillary permeability, leakage, and intraretinal fluid accumulation. PDR may be accompanied by areas of retinal and vitreous hemorrhage, which obscure vision, and retinal detachment, which can cause scarring and permanent blindness. Screening Patients with diabetes fear blindness more than any other complication of the disease.5,6 The American Diabetes Association (ADA) recommends screening for retinopathy with an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within three to five years after the onset of type 1 diabetes and shortly after the diagnosis of type 2 diabetes.7 Subsequent examinations should be performed annually for patients both with type 1 and with type 2 disease. Less frequent examinations, at intervals of two to three years, may be considered for patients with normal results, while more frequent examinations are needed if retinopathy is progressing. In women with diabetes who are pregnant or planning a pregnancy, a comprehensive eye examination should be performed during the first trimester, with close follow-up throughout the pregnancy and for one year after delivery. Eye examinations are not required for women with gestational diabetes mellitus because they are not at increased risk for diabetic retinopathy.7 Characteristics of 2308 adults with diabetes who were recruited through a multimedia campaign for the Diabetic Retinopathy Awareness Program, a prospective study of the impact of an educational intervention, provide insight into adherence to diabetes vision care guidelines.9 Two thirds of the recruits were adherent to guidelines. However, among the other 813 adults, more than one year had elapsed since the most recent eye examination in 557 (69%) patients, and the eye examination was performed without dilation in the other 256 (31%) patients. These findings suggest that there are substantial numbers of Americans with diabetes who are not adequately screened for retinopathy. Several nonmodifiable and modifiable risk factors are associated with diabetic retinopathy (Table 11). Diabetic persons with these characteristics should be more closely screened. Albuminuria is, to a certain degree, a marker of capillary leakage and may respond to blood pressure treatment, particularly with angiotensin-directed agents. Table 1. Risk Factors for Diabetic Retinopathy3,10,11 Nonmodifiable risk factors Duration of diabetes Age (in patients with type 2 disease) Level of retinopathy Albuminuria Pregnancy Modifiable risk factors A1C level (i.e., degree of long-term hyperglycemia) Hypertension Dyslipidemia Cigarette smoking Nonmodifiable risk factors Duration of diabetes Age (in patients with type 2 disease) Level of retinopathy Albuminuria Pregnancy Modifiable risk factors A1C level (i.e., degree of long-term hyperglycemia) Hypertension Dyslipidemia Cigarette smoking Open in new tab Table 1. Risk Factors for Diabetic Retinopathy3,10,11 Nonmodifiable risk factors Duration of diabetes Age (in patients with type 2 disease) Level of retinopathy Albuminuria Pregnancy Modifiable risk factors A1C level (i.e., degree of long-term hyperglycemia) Hypertension Dyslipidemia Cigarette smoking Nonmodifiable risk factors Duration of diabetes Age (in patients with type 2 disease) Level of retinopathy Albuminuria Pregnancy Modifiable risk factors A1C level (i.e., degree of long-term hyperglycemia) Hypertension Dyslipidemia Cigarette smoking Open in new tab Prevalence of diabetic retinopathy The ADA criteria for the diagnosis of diabetes (a two-hour plasma glucose concentration of 200 mg/dL or higher during an oral glucose tolerance test or a fasting plasma glucose concentration of 126 mg/dL or higher) and the goal A1C of 7% for the diabetes population are based on data from three large population studies using the presence of retinopathy as a marker for diabetes.12,–14 These data include unpublished National Health and Nutrition Examination Survey (NHANES) III data and data from a study of Pima Indians and another study conducted in Egypt. The prevalence of vision impairment among adults with diabetes was assessed using data from NHANES, a large epidemiologic study.8 Measurements of visual acuity loss were expressed in terms of the distance at which a person with normal vision can see what the test subject could see from 20 feet away. For example, a test subject who could see from 20 feet away what persons with normal vision can see from 40 feet away had 20/40 visual acuity. Subjects with 20/40 or better visual acuity were considered normal, and those with visual acuity worse than 20/40 were considered impaired. In 1237 NHANES participants with diabetes, 11% had vision impairment; the impairment was correctable with eyeglasses or contact lenses in about two thirds of these subjects. The NHANES vision impairment data were stratified by severity, with mild impairment defined as visual acuity worse than 20/40 but better than 20/200, and severe impairment defined as 20/200 visual acuity or worse.8 The prevalence of mild impairment was 9.7% before vision correction and 2.9% after correction. The prevalence of severe impairment was 1.4% before correction and 1.0% after correction. Thus, severe vision impairment is less common than mild vision impairment, but it also is less correctable. When the NHANES data were stratified by age, the prevalence of vision impairment was 8.0% without correction and 0.9% after correction among persons 20–64 years of age.8 However, in subjects 65 years of age or older, the prevalence of vision impairment was 15.8% without correction and 8.5% after correction. Thus, vision impairment is more common and less readily corrected in elderly patients with diabetes than in younger diabetics. In the Australian Diabetes, Obesity, and Lifestyle Study of 2177 adults 25 or more years of age with type 2 diabetes, the prevalence of diabetic retinopathy increased with the duration of diabetes and increases in A1C.15 The prevalence of retinopathy was similar in patients with a duration of diabetes of less than four years regardless of their A1C. However, among patients whose duration of diabetes was four to eight years and more than eight years, there was a marked increase in prevalence of retinopathy in those with an A1C greater than 7.5%. Half of patients with an A1C greater than 7.5% who had diabetes for more than eight years had retinopathy. Similar relationships were observed between the prevalence of retinopathy, duration of diabetes, and systolic blood pressure; the prevalence of retinopathy increased as the duration of diabetes increased, and also as the systolic blood pressure increased from less than 132 mm Hg to 132–148 mm Hg and greater than 148 mm Hg. Glycemic control The impact of glycemic control on the risk for diabetic retinopathy and other diabetes complications has been demonstrated in several landmark epidemiologic and interventional studies.16,–19 A reduction in the risk of complications by roughly one third is associated with each 1% reduction in A1C. In the Diabetes Control and Complications Trial (DCCT), 1441 patients with type 1 diabetes were randomly assigned to receive intensive therapy with an external insulin pump or three or more daily insulin injections based on frequent blood glucose monitoring or with conventional therapy with insulin injections for up to nine years.16 The mean duration of follow-up was 6.5 years, and median A1C values were approximately 7% in the intensive therapy group and 9% in the conventional therapy group throughout the study. In a subset of 726 patients without retinopathy at baseline, intensive therapy reduced the risk for retinopathy by 76% compared with conventional therapy. In the other 715 patients, who had mild retinopathy at baseline, intensive therapy slowed the progression of retinopathy by 54% and reduced the development of PDR or severe NPDR by 47%. In all 1441 diabetic patients, intensive therapy reduced the risk of albuminuria, an early sign of diabetic nephropathy, by 54% and and reduced the risk of clinical neuropathy by 60%. When the DCCT results were stratified by the mean A1C value during the study, the risk of retinopathy progression over time decreased as the A1C value decreased.20 There was no apparent threshold A1C value below which the risk of retinopathy progression was eliminated.20 After the DCCT ended in 1993, 1208 participants were enrolled and followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, an observational study.21 Patients in the conventional therapy group were encouraged to use intensive therapy, and patients in both groups were followed by physicians in their own communities. The median A1C levels in the intensive therapy group and the conventional therapy group were 7.2% and 9.1%, respectively, at the end of the DCCT and 7.9% and 8.2%, respectively, at the end of the EDIC study. At the end of the DCCT, approximately 3% of patients in the intensive therapy group and 7% of patients in the conventional therapy group required photocoagulation (a laser treatment needed when retinopathy progresses); thus, the use of intensive therapy was associated with a significant 56% reduction (p = 0.004) in the likelihood that photocoagulation would be needed. At the end of the EDIC study, photocoagulation was required by about 4% of patients in the intensive therapy group and 13% of patients in the conventional group, again showing a significant reduction (p = 0.007) in the need for photocoagulation after the use of intensive therapy. The results of the EDIC study demonstrate that the initial period of intensive therapy reduced the risk of retinopathy progression on a long-term basis despite gradual loss of rigorous A1C control. UK Prospective Diabetes Study In the United Kingdom Prospective Diabetes Study (UKPDS), 3867 adults with type 2 diabetes were randomly assigned to intensive treatment with a sulfonylurea or insulin to maintain a fasting plasma glucose <108 mg/dL or conventional treatment (diet and a goal fasting plasma glucose <270 mg/dL).17,22 At study initiation, 36% of patients had retinopathy. The median A1C over a 10-year follow-up period was 7.0% in the intensive treatment group and 7.9% in the conventional treatment group, a difference that is significant (p < 0.0001). Intensive therapy was associated with a 12% reduction in any diabetes-related endpoint (i.e., sudden death, death from hypoglycemia or hyperglycemia, fatal or nonfatal myocardial infarction [MI], angina, heart failure, stroke, renal failure, amputation of at least one digit, vitreous hemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction) compared with conventional therapy. There was a complication-free interval of 14.0 years in the intensive therapy group and 12.7 years in the conventional therapy group. Intensive treatment also produced a 25% reduction in microvascular endpoints (p = 0.0099), a 24% reduction in cataract extractions compared with conventional treatment (p = 0.046), and 16% reduction in risk of MI ofborderline clinical significance (p = 0.052). The risk of progression of retinopathy was not significantly different between the two treatment groups during the first three years of the study. However, compared with conventional therapy, intensive therapy significantly reduced the risk of progression after 6 years, 9 years, and 12 years by 17% (p = 0.017), 17% (p = 0.012), and 21% (p = 0.015), respectively. After 12 years had elapsed, retinopathy had progressed in 49% of patients in the conventional therapy group but in only 39% of patients in the intensive therapy group. The requirement for retinal photocoagulation was reduced from 11.0 events per 1000 patient-years in the conventional therapy group to 7.9 events per 1000 patient-years in the intensive therapy group, representing a 28% reduction (p = 0.0031). In the intensive therapy group, the need for photocoagulation was similar regardless of whether glyburide, chlorpropamide, or insulin was used. However, chlorpropamide was less effective in preventing retinopathy progression than glyburide and insulin after 12 years. Two UKPDS substudies compared the impact on microvascular endpoints of using metformin for intensive therapy instead of or in addition to a sulfonylurea or insulin.23 In one substudy of 1704 overweight patients who were followed for a median of 10.7 years, the absolute risk of microvascular complications with metformin (6.7 events per 1000 patient-years) was slightly lower than with other intensive therapies (7.7 events per 1000 patient-years) as well as lower than with conventional therapy (9.2 events per 1000 patient-years). In the other substudy, 537 overweight and non-overweight patients were followed for a median of 6.6 years after random assignment to add or not add metformin to sulfonylurea therapy; the absolute risk of microvascular disease in the metformin plus sulfonylurea group (10.1 events per 1000 patient-years) was again somewhat lower than that in the sulfonylurea alone group at 12.1 events per 1000 patient-years. Blood pressure control As a substudy of the UKPDS, the impact of tight control of blood pressure (an average of 144/82 mm Hg) versus less tight control of blood pressure (154/87 mm Hg on average) on any diabetes-related endpoint and on microvascular outcomes was studied after a median follow up of 8.4 years in 1148 patients with type 2 diabetes and hypertension.24 Tight blood pressure control was associated with a 24% reduction in any diabetes-related endpoint and a 37% reduction in microvascular endpoints (retinopathy requiring photocoagulation, vitreous hemorrhage, and fatal or nonfatal renal failure), compared with less tight control. Most of the reduction in microvascular endpoints was attributed to a reduced need for retinal photocoagulation. There was no significant difference in the percentage of patients with any diabetes-related endpoint between those treated with an angiotensin-converting-enzyme (ACE) inhibitor and those treated with a beta blocker.25 After nine years of follow up, there was a 34% reduction in retinopathy progression and a 47% reduction in loss of visual acuity in the group with tight blood pressure control compared with the group with less tight control.24,25 The difference between tight and less tight blood pressure control in the percentage of patients with retinopathy progression was not significant after 1.5 years, but it was significant after 4.5 years (p = 0.019) and 7.5 years (p = 0.0038). After 7.5 years, retinopathy progression had occurred in 34% of patients with tight blood pressure control and 51% of patients with less tight control. The difference between the tight blood pressure control group and the less tight blood pressure control group in the percentage of patients with loss of visual acuity was not significant after 1.5 years or 4.5 years, but it was significant after 7.5 years (10% in the tight blood pressure control group and 19% in the less tight blood pressure control group, p = 0.0036).24 Some clinicians have suggested, on the basis of the UKPDS results, that tight blood pressure control has a greater impact on retinopathy progression than tight glycemic control.17,24,25 However, two or three antihypertensive agents were used simultaneously to achieve tight blood pressure control in most UKPDS patients, an approach that might be considered more aggressive than the monotherapy approach used to control blood glucose in UKPDS.24 Ideally, aggressive treatment with multiple agents should be used to achieve tight control of both blood glucose and blood pressure in patients with diabetes. The impact of the ACE inhibitor lisinopril on retinopathy progression was evaluated in a two-year randomized, double-blind, placebo-controlled study of 324 normotensive adults with type 1 diabetes.26 About two thirds of the patients had retinopathy at the beginning of the study. Lisinopril significantly reduced the risk of retinopathy progression, by 50% compared with placebo (p = 0.02). Efforts to replicate these results in other clinical studies have not, however, been successful. Roles of aspirin, smoking, and lipids According to the ADA, optimal glycemic control can substantially reduce the risk for and progression of diabetic retinopathy, and optimal blood pressure control can reduce the risk for and progression of diabetic retinopathy.7 Aspirin provides cardiovascular benefits to patients with diabetes, but concerns have been raised about the potential for an increased risk of vitreous hemorrhage from aspirin use in patients with diabetic retinopathy.7 Although prevention of diabetic retinopathy was not observed in patients with mild-to-severe NPDR or early PDR who received aspirin 650 mg/day in the Early Treatment of Diabetic Retinopathy Study (ETDRS), a clinical study of 2244 eyes that were followed for at least four years, aspirin did not increase the risk of vitreous hemorrhage.27,28 Therefore, aspirin therapy is recommended for patients with or at risk for diabetic retinopathy unless they have contraindications, such as allergy or increased risk of bleeding.7 The ADA recommends abstinence from cigarette smoking or smoking cessation for patients with diabetes.7 Smoking increases the risk of macrovascular and microvascular complications, including diabetic retinopathy.11 In the ETDRS, retinal hard exudates were twice as common at baseline in enrollees with elevated total or low-density lipoprotein (LDL) cholesterol concentrations as in patients with normal levels.10,29 Patients with elevated baseline total cholesterol levels (≥240 mg/dL) also developed hard exudates 50% more rapidly than patients with lower levels (<200 mg/dL). High baseline total cholesterol levels increased the risk of developing moderate vision loss over a five-year period by 50%. Whether lowering total or LDL cholesterol levels reduces the risk for or progression of retinopathy in patients with diabetes has not been demonstrated although such as approach clearly provides cardiovascular benefits to patients with diabetes and therefore should be encouraged.7 Surgery and photocoagulation Laser photocoagulation is the primary mode of treatment for diabetic retinopathy. A variety of types of laser treatments are used. Focal and grid photocoagulation may be used to treat macular edema.30 Focal photocoagulation involves the pinpointed application of light, creating miniscule burns, which occlude leaking microaneurysms.30 Grid photocoagulation involves the application of burns in a grid or pattern to areas of edema caused by diffuse leakage or nonperfusion. Panretinal (scatter) photocoagulation is used to treat PDR. It involves a scatter pattern on the peripheral fundus (the back of the eyeball). Panretinal photocoagulation indirectly promotes regression of neovascularization by reducing ischemia and the elaboration of growth factors (e.g., vascular endothelial growth factor).31 In the ETDRS, laser photocoagulation was associated with a 50% reduction in the risk of moderate visual loss after three years in patients with clinically significant macular edema (or less severe diabetic retinopathy involving the center of the macula).3,32 The incidence of moderate visual loss was 33% without the surgical procedure and 14% with the procedure. The surgery also increased the likelihood of moderate visual gain and reduced retinal thickening. In 3463 patients with PDR participating in the Diabetic Retinopathy Study, panretinal photocoagulation reduced the risk of severe visual loss after five years by 50%.3,33 The incidence of severe visual loss was about 30% without the procedure and about 15% with the procedure. Laser photocoagulation surgery is not always effective for improving vision, especially if retinal damage and vision loss already have occurred.3 The approach destroys retinal tissue, and scars may enlarge over time.34 Other disadvantages of laser therapy include the need for repeated treatments and occasional discomfort associated with the procedure. The ADA recommendations for the treatment of retinopathy acknowledge the role of laser therapy in reducing the risk of vision loss in patients with high-risk characteristics: macular edema, severe NPDR, or PDR.7 The ADA recommends that patients with such characteristics be referred to an ophthalmologist who is knowledgeable and experienced in the management and treatment of diabetic retinopathy.7 Patients with advanced PDR can develop vitreous hemorrhage and retinal detachment of the macula. Such patients may undergo vitrectomy, an intraocular surgical procedure performed under local anesthesia with sedation. This procedure improves vision in most patients, and it may reverse severe vision loss.3,35 Conclusion Screening for diabetic retinopathy plays an important role in early detection and intervention to prevent the progression of diabetic retinopathy. Addressing modifiable risk factors for diabetic retinopathy can reduce the risk for and progression of this complication. Footnotes Based on the proceedings of a symposium held December 5, 2006, during the ASHP Midyear Clinical Meeting and Exhibition in Anaheim, CA, and supported by an educational grant from Eli Lilly and Company. Dr. Bloomgarden received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Bloomgarden was recommended as faculty by the commercial supporter of this educational activity. Dr. Bloomgarden reports that he has no affiliations with or financial interest in a commercial organization that poses a conflict of interest with this article. References 1 Sheetz MJ, King GL. Molecular understanding of hyperglycemia’s adverse effects for diabetic complications. JAMA . 2002 ; 288 : 2579 –88. Crossref Search ADS PubMed 2 Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies. Diabetes Care . 2003 ; 26 : 2653 –64. Crossref Search ADS PubMed 3 American Academy of Ophthalmology. Diabetic retinopathy preferred practice pattern. 2003 . http://www.aao.org/education/library/ppp/upload/Diabetic_Retinopathy.pdf (accessed 2007 Feb 22). 4 Kinyoun J, Barton F, Fisher M et al. Detection of diabetic macular edema. Ophthalmoscopy versus photography—Early Treatment Diabetic Retinopathy Study Report Number 5. The ETDRS Research Group. Ophthalmology . 1989 ; 96 : 746 –50. Crossref Search ADS PubMed 5 Loewe R, Freeman J. Interpreting diabetes mellitus: differences between patient and provider models of disease and their implications for clinical practice. Cult Med Psychiatry . 2000 ; 24 : 379 –401. Crossref Search ADS PubMed 6 Meltzer D, Egleston B. How patients with diabetes perceive their risk for major complications. Eff Clin Pract . 2000 ; 3 : 7 –15. PubMed 7 American Diabetes Association. Standards of medical care in diabetes—2007. Diabetes Care . 2007 ; 30 (suppl 1): S4 –41. Crossref Search ADS PubMed 8 Centers for Disease Control and Prevention. Correctable visual impairment among persons with diabetes—United States, 1999–2004. MMWR Morb Mortal Wkly Rep . 2006 ; 55 : 1169 –72. PubMed 9 Schoenfeld ER, Greene JM, Wu SY et al. Patterns of adherence to diabetes vision care guidelines: baseline findings from the Diabetic Retinopathy Awareness Program. Ophthalmology . 2001 ; 108 : 563 –71. Crossref Search ADS PubMed 10 Chew EY, Klein ML, Ferris FL 3rd et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Arch Ophthalmol . 1996 ; 114 : 1079 –84. Crossref Search ADS PubMed 11 Chaturvedi N, Stephenson JM, Fuller JH. The relationship between smoking and microvascular complications in the EURODIAB IDDM Complications Study. Diabetes Care . 1995 ; 18 : 785 –92. Crossref Search ADS PubMed 12 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care . 2007 ; 30 (suppl 1): S42 –7. Crossref Search ADS PubMed 13 McCance DR, Hanson RL, Charles MA et al. Comparison of tests for glycated haemoglobin and fasting and two hour plasma glucose concentrations as diagnostic methods for diabetes. Br Med J . 1994 ; 308 : 1323 –8. Crossref Search ADS 14 Engelgau MM, Thompson TJ, Herman WH et al. Comparison of fasting and 2-hour glucose and HbA1c levels for diagnosing diabetes. Diagnostic criteria and performance revisited. Diabetes Care . 1997 ; 20 : 785 –91. Crossref Search ADS PubMed 15 Tapp RJ, Shaw JE, Harper CA et al. The prevalence of and factors associated with diabetic retinopathy in the Australian population. Diabetes Care . 2003 ; 26 : 1731 –7. Crossref Search ADS PubMed 16 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. Crossref Search ADS PubMed 17 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998 ; 352 : 837 –53. Crossref Search ADS PubMed 18 Ohkubo Y, Kishikawa H, Araki E et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin- dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract . 1995 ; 28 : 103 –17. Crossref Search ADS PubMed 19 Klein R, Klein BE, Moss SE et al. Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy. Arch Intern Med . 1994 ; 154 : 2169 –78. Crossref Search ADS PubMed 20 The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes . 1995 ; 44 : 968 –83. Crossref Search ADS PubMed 21 The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med . 2000 ; 342 : 381 –9. Crossref Search ADS PubMed 22 UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance. Diabetologia . 1991 ; 34 : 877 –90. Crossref Search ADS PubMed 23 UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet . 1998 ; 352 : 854 –65. Crossref Search ADS PubMed 24 UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J . 1998 ; 317 : 703 –13. Crossref Search ADS 25 Matthews DR, Stratton IM, Aldington SJ et al. Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69. Arch Ophthalmol . 2004 ; 122 : 1631 –40. Crossref Search ADS PubMed 26 Chaturvedi N, Sjolie AK, Stephenson JM et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet . 1998 ; 351 : 28 –31. Crossref Search ADS PubMed 27 Early Treatment Diabetic Retinopathy Study Research Group. Effects of aspirin treatment on diabetic retinopathy. ETDRS report number 8. Ophthalmology . 1991 ; 98 (5 suppl): 757 –65. Crossref Search ADS PubMed 28 American Diabetes Association. Retinopathy in diabetes. Diabetes Care . 2006 ; 27 (suppl 1): S84 –7. 29 Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol . 1985 ; 103 : 1796 –806. Crossref Search ADS PubMed 30 Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Ophthalmology . 1991 ; 98 (5 suppl): 766 –85. Crossref Search ADS PubMed 31 Lip PL, Belgore F, Blann AD et al. Plasma VEGF and soluble VEGF receptor FLT-1 in proliferative retinopathy: Relationship to endothelial dysfunction and laser treatment. Invest Ophthalmol Vis Sci . 2000 ; 41 : 2115 –9. PubMed 32 Early Treatment Diabetic Retinopathy Study Research Group. Focal photo- coagulation treatment of diabetic macular edema. Relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report no. 19. Arch Ophthalmol . 1995 ; 113 : 1144 –5. Crossref Search ADS PubMed 33 Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings. Ophthalmology . 1978 ; 85 : 82 –106. Crossref Search ADS PubMed 34 Maeshima K, Utsugi-Sutoh N, Otani T et al. Progressive enlargement of scattered photocoagulation scars in diabetic retinopathy. Retina . 2004 ; 24 : 507 –11. Crossref Search ADS PubMed 35 Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Four-year results of a randomized trial: Diabetic Retinopathy Vitrectomy Study Report 5. Arch Ophthalmol . 1990 ; 108 : 958 –64. Crossref Search ADS PubMed Copyright © 2007. American Society of Health-System Pharmacists, Inc. All rights reserved.

Ryan, Gina, J.

doi: 10.2146/ajhp070329pmid: N/A

In the United States, 20.8 million people, or 7% of the population, have diabetes mellitus, including 6.2 million people in whom the disease has not been diagnosed.1 Most people (90%–95%) with diabetes have type 2 disease.1 Another 41 million Americans have prediabetes (impaired fasting glucose, impaired glucose tolerance, or both), which increases the risk of type 2 diabetes.1 Diabetes is a growing public health problem in this country.2,3 Its prevalence increased by 33% between 1990 and 1998 and by 8% between 2000 and 2001. The disease is the leading cause of new cases of blindness in adults; it is responsible for 12,000 to 24,000 new cases of blindness each year.1 Approximately 4.1 million American adults 40 years of age or older have diabetic retinopathy, which can lead to blindness.4 The number with diabetic retinopathy is projected to increase, given the aging of the U.S. population and the increasing prevalence of diabetes.5 Pharmacists have long been aware of the need to control blood glucose concentrations to prevent retinopathy and other microvascular and macrovascular complications of diabetes.6 However, the treatment of diabetic retinopathy has not been within the scope of most pharmacists’ practice because drug therapy has played a relatively small role. New pharmacologic therapies provide an opportunity for pharmacists to become involved in the treatment of diabetic retinopathy and to have a positive impact on patients with this complication. The first article in this supplement provides an overview of the etiology and natural history of diabetic retinopathy, with a discussion of the prevalence of diabetic retinopathy, manifestations of disease progression, and etiology of blindness. It also explains methods for measuring visual acuity. In the second article, the pathogenesis, clinical features, and prevalence of vision impairment from diabetic retinopathy are described. Also discussed are diabetic retinopathy screening, risk factors, and treatment. The third article focuses on endpoints used in clinical studies of diabetic retinopathy therapies and the mechanism of action, efficacy, and safety of several new and emerging drugs targeting the biochemical pathways that link chronic hyperglycemia with microvascular damage. Footnotes Based on the proceedings of a symposium held December 5, 2006, during the ASHP Midyear Clinical Meeting and Exhibition in Anaheim, CA, and supported by an educational grant from Eli Lilly and Company. Dr. Ryan received an honorarium for her participation in the symposium and for the preparation of this article. Dr. Ryan was recommended as faculty by the commercial supporter of this educational activity. Dr. Ryan reports that she has no affiliations with or financial interest in a commercial organization that poses a conflict of interest with this article. References 1 Centers for Disease Control and Prevention. National Diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, 2005. Atlanta, GA: US Dept of Health and Human Services, Centers for Disease Control and Prevention; 2005. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf (accessed 2007 Feb 24). 2 Mokdad AH, Ford ES, Bowman BA et al. Diabetes trends in the U.S.: 1990–1998. Diabetes Care . 2000 ; 23 : 1278 –83. Crossref Search ADS PubMed 3 Mokdad AH, Ford ES, Bowman BA et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA . 2003 ; 289 : 76 –9. PubMed 4 Kempen JH, O’Colmain BJ, Leske MC et al. The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol . 2004 ; 122 : 552 –63. Crossref Search ADS PubMed 5 Narayan KM, Boyle JP, Geiss LS et al. Impact of recent increase in incidence on future diabetes burden: U.S., 2005–2050. Diabetes Care . 2006 ; 29 : 2114 –6. Crossref Search ADS PubMed 6 American Diabetes Association. Standards of medical care in diabetes—2007. Diabetes Care . 2007 ; 30 (suppl 1): S4 –41. Crossref Search ADS PubMed Copyright © 2007. American Society of Health-System Pharmacists, Inc. All rights reserved.