Diabetic Retinopathy and Diabetic Macular Edema Pathophysiology, Screening, and Novel Therapies

Reviews/Commentaries/Position Statements REVIEW ARTICLE

Diabetic Retinopathy and Diabetic Macular Edema Pathophysiology, screening, and novel therapies

1 THOMAS A. CIULLA, MD emia. These blood vessels grow in an at- 2 ARMANDO G. AMADOR, MD tempt to supply oxygenated blood to the 3 BERNARD ZINMAN, MDCM, FRCP(C), FACP hypoxic retina. At any time during the progression of DR, patients with diabetes can also develop DME, which involves retinal thickening in the macular area. DME occurs after breakdown of the Diabetic retinopathy (DR) and diabetic macular edema (DME) are leading causes of blindness in blood-retinal barrier because of leakage of the working-age population of most developed countries. The increasing number of individuals dilated hyperpermeable capillaries and mi- with diabetes worldwide suggests that DR and DME will continue to be major contributors to croaneurysms. The current management vision loss and associated functional impairment for years to come. Early detection of retinopathy in individuals with diabetes is critical in preventing visual loss, but current methods of strategy for DR/DME requires early detec- screening fail to identify a sizable number of high-risk patients. The control of diabetes- tion and optimal glycemic control to slow associated metabolic abnormalities (i.e., hyperglycemia, hyperlipidemia, and hypertension) is the progression of disease. Adherence to also important in preserving visual function because these conditions have been identified as risk these recommendations is hampered by factors for both the development and progression of DR/DME. The currently available interven- the fact that the condition is generally tions for DR/DME, laser photocoagulation and vitrectomy, only target advanced stages of disease. asymptomatic at early stages. Current Several biochemical mechanisms, including protein kinase C–␤ activation, increased vascular treatments for DR/DME, such as laser endothelial growth factor production, oxidative stress, and accumulation of intracellular sorbitol photocoagulation, only target advanced and advanced glycosylation end products, may contribute to the vascular disruptions that stages of disease. Several pharmacological characterize DR/DME. The inhibition of these pathways holds the promise of intervention for DR therapies are being developed to treat at earlier non–sight-threatening stages. To implement new therapies effectively, more individuals will need to be screened for DR/DME at earlier stages—a process requiring both improved early stages of DR/DME, but will require a technology and interdisciplinary cooperation among physicians caring for patients with renewed emphasis on early detection. diabetes. This review will focus on the current understanding of the epidemiology and Diabetes Care 26:2653–2664, 2003 pathophysiology of DR/DME, the updated clinical diagnostic grading system, CURRENT EPIDEMIOLOGY, NEW PATHOPHYSIOLOGY screening and management, and the ra- INSIGHTS, UPDATED DIAGNOSTIC STAGING SYSTEM, tionale behind the potential for pharma- RECENT SCREENING TECHNOLOGIES, AND TREATMENT — cological treatments. Diabetic retinopathy (DR) and diabetic macular edema (DME) are common microvascular complications in patients with diabetes and may have a sudden and debilitating impact on visual acuity (VA), eventually leading to blindness. Advanced stages of DR Epidemiology are characterized by the growth of abnormal retinal blood vessels secondary to isch- Type 2 diabetes has reached epidemic ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● proportions, fueled by an aging popula- From the 1Midwest Eye Institute, Indianapolis, Indiana; the 2Lilly Research Laboratories, Indianapolis, tion and the rapid increase in obesity (1). Indiana; and the 3Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, University of Toronto, DR is a major cause of vision loss in pa- Toronto, Canada. Address correspondence and reprint requests to Bernard Zinman, MDCM, FRCP(C), FACP, Director, tients with diabetes. The longer patients Leadership Sinai Centre for Diabetes, 600 University Ave., Suite 782, Toronto, Ontario, Canada. E-mail: have diabetes, the higher the prevalence [email protected]. of DR (2). In developed countries, DR is Received for publication 10 September 2002 and accepted in revised form 11 May 2003. recognized as the leading cause of blind- T.A.C. is a member of the PKC Eli Lilly Advisory Board and has acted as a consultant for Eli Lilly. A.G.A. serves on the editorial board of Ophthalmology Coding Alert, holds stock in Eli Lilly, and is a paid consultant ness in the working-age population for ReproGen. B.Z. is a member of the PKC Eli Lilly Advisory Board and is the chair of the Eli Lilly North (20–74 years old) and is responsible for American Diabetes Advisory Board; he has received consulting fees, honoraria, and grant support from Eli 12% of new cases of blindness each year Lilly. (3). Abbreviations: AGE, advanced glycation end product; ARI, aldose reductase inhibitor; CSME, clinically significant macular edema; DAG, diacylglycerol; DME, diabetic macular edema; DR, diabetic retinopathy; In patients with type 1 diabetes, the cumulative 14-year incidences of visual ETDRS, Early Treatment Diabetic Retinopathy Study; FA, fluorescein angiography; IC50, half-maximal inhibition concentration; PEDR, pigment endothelium-derived factor; PDR, proliferative diabetic retinopa- impairment (VA 20/40 or worse in the thy; PKC, protein kinase C; ROS, reactive oxygen species; VA, visual acuity; VEGF, vascular endothelial better eye), doubling of the visual angle, growth factor. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion and blindness were 12.7, 14.2, and 2.4%, factors for many substances. respectively (4). DME is a frequent man- © 2003 by the American Diabetes Association. ifestation of DR (5) and is a leading cause

DIABETES CARE, VOLUME 26, NUMBER 9, SEPTEMBER 2003 2653 Diabetic retinopathy and diabetic macular edema of legal blindness in patients with type 2 Table 1—International clinical diabetic retinopathy disease severity scale diabetes. Over a 10-year period, non– clinically significant DME and clinically Proposed disease significant DME will, respectively, de- severity level Dilated ophthalmoscopy findings velop in 14 and 10% of Americans with known diabetes (6). Approximately half No apparent retinopathy No abnormalities of patients with DME will lose two or Mild nonproliferative DR Microaneurysms only more lines of VA within 2 years (7). Moderate nonproliferative DR More than just microaneurysms, but less than Even in cases where retinopathy has severe NPDR not yet progressed to blindness, loss in VA Severe nonproliferative DR No signs of PDR, with any of the following: because of diabetes is a major problem ● More than 20 intraretinal hemorrhages in each of and may lead to significant reductions in four quadrants functional status. DR is the third leading ● Definite venous beading in two or more cause of severe visual impairment among quadrants inner-city adults Ն40 years of age (8). ● Prominent intraretinal microvascular anomalies Diabetes-related blindness and visual in one or more quadrants impairment places a significant burden PDR One or more of the following: on society. The federal budgetary cost of ● Neovascularization blindness was estimated to be $4.1 billion ● Vitreous or preretinal hemorrhage in the U.S. for the year 1990, and 97% of NPDR ϭ nonproliferative DR. these costs were accounted for by the working-age adult group (9). Health care and economic burdens of DR are further microaneurysm formation (15,20,23). stream nonperfusion in the diabetic reti- compounded by the resulting decline in Another common feature of DR is the nal microcirculation (27). Whereas quality of life (10); thus, the true impact thickening of the capillary basement leukostasis probably plays a key role in on society cannot be estimated on a mon- membrane and increased deposition of the pathogenesis of DR, platelets and etary basis alone. extracellular matrix components. This erythrocytes are also involved in this pro- feature may contribute to the develop- cess. Pathophysiology ment of abnormal retinal hemodynamics As a result of occluded capillaries, ret- Many studies have demonstrated that (24–26), including abnormal autoregula- inal ischemia stimulates a pathologic neo- chronic hyperglycemia, as well as hyper- tion of retinal blood flow. vascularization mediated by angiogenic lipidemia and hypertension, contribute to There is evidence that retinal leuko- factors, such as vascular endothelial the pathogenesis of DR (11–14). The ex- stasis may also play an important role in growth factor (VEGF), which results in act mechanisms by which elevated glu- the pathogenesis of DR. Leukocytes pos- proliferative diabetic retinopathy (PDR) cose initiates the vascular disruption in sess large cell volume, high cytoplasmic (29,30). This neovascularization is the retinopathy remain poorly defined, and, rigidity, a natural tendency to adhere to predominant feature of PDR. Hemorrhag- not surprisingly, several pathways have the vascular endothelium, and a capacity ing of new vessels into the vitreous may been implicated. The vascular disruptions to generate toxic superoxide radicals and also lead to tractional retinal detachment of DR/DME are characterized by abnor- proteolytic enzymes (27). In diabetes, (5). mal vascular flow, disruptions in perme- there is increased retinal leukostasis, Understanding the diabetes-induced ability, and/or closure or nonperfusion of which affects retinal endothelial function, mechanisms that contribute to pericyte capillaries. retinal perfusion, angiogenesis, and vas- loss, endothelial cell proliferation, neo- A hallmark of early DR is the change cular permeability. In particular, leuko- vascularization, and alterations in base- in the structure and cellular composition cytes in diabetes are less deformable, a ment membrane structure is therefore of the microvasculature (15–17). Endo- higher proportion are activated, and they central to the design of pharmacological thelial cells are responsible for maintain- may be involved in capillary nonperfu- therapeutic strategies to treat and prevent ing the blood-retinal barrier, and damage sion, endothelial cell damage, and vascu- early diabetes-related microvascular to them results in increased vascular per- lar leakage in the retinal microcirculation changes. meability. In early stages of DME, break- (27). A recent study showed that diabetic down of the inner blood-retinal barrier vascular leakage and nonperfusion are Diagnostic staging may occur, resulting in accumulation of temporally and spatially associated with Diabetic retinopathy. DR is a progres- extracellular fluid in the macula (7,18). retinal leukostasis in streptozotocin- sive disease that includes the following Pericytes are essential cellular compo- induced diabetic rats (28). There are stages: no apparent DR, nonproliferative nents in the regulation of retinal capillary many capillary occlusions by leukocytes DR, and PDR. Nonproliferative DR is perfusion, and damage to these cells in and capillary dropout or degeneration as- characterized by the presence of venous diabetes leads to altered retinal hemody- sociated with leukocytes in the diabetic dilatation, microaneurysms, retinal hem- namics, including abnormal autoregula- retina (27). Serial acridine orange leuko- orrhages, retinal edema, and hard exu- tion of retinal blood flow (19). Loss of cyte fluorography and fluorescein angiog- dates (5). Neovascularization in DR can retinal pericytes represents another early raphy (FA) show trapped leukocytes originate from the optic disk or elsewhere feature of DR (20–22) and correlates with directly associated with areas of down- (5). The gold standard for grading the se-

2654 DIABETES CARE, VOLUME 26, NUMBER 9, SEPTEMBER 2003 Ciulla, Amador, and Zinman verity of DR is stereoscopic fundus pho- agulation, can decrease vision loss (33, enced graders (46). A recent study tography through dilated pupils, using 37,38). However, it is generally not showed that four 45°field nonstereo- seven standard fields (31–33), and grad- possible to restore VA once it has dete- scopic color digital fundus photographs ing guidelines for these photographs es- riorated. Because DR can progress to ir- of each eye could be transmitted over the tablished by the Early Treatment Diabetic reversible stages with relatively few Internet and be used with great accuracy Retinopathy Study (ETDRS) group (34). symptoms (33), the optimal time for for the screening of DR (47). These meth- Although this staging system is used in treatment is before VA is impaired. Stud- ods have also been shown to have good research studies, it is rarely used clini- ies have confirmed that the clinical out- sensitivity and specificity when using a cally, given its complexity. To facilitate come is better if patients are screened and centrally based trained grader. communication between retina special- treated early (39). The benefits of early This ability to digitally photograph ists and health care professionals, Interna- management, such as intensive diabetes and transmit retinal images has led to ef- tional Clinical Diabetic Retinopathy and control, persist for years, even with sub- forts to develop complete telemedicine Diabetic Macular Edema Disease Severity sequent hyperglycemia (40). Thus, regu- screening programs for DR. The Joslin Di- Scales have recently been proposed (35) lar screening and early treatment for DR/ abetes Center in Boston has recently de- that were derived from the ETDRS (34) DME can potentially save years of vision veloped the Joslin Vision Network, which and the Wisconsin Epidemiologic Study and reduce societal costs (33). includes a remote imaging system, a cen- of Diabetic Retinopathy (14,36) studies. Fundus photography and telemedi- tralized grading center at the Joslin Dia- The International Clinical Diabetic Reti- cine. Current methods of color fundus betes Center, and a data storage system. nopathy Disease Severity Scale identifies photography use either a stereoscopic or One recent study validated the agreement five levels of DR that are clinically mean- nonstereoscopic camera to take seven between nonmydriatic Joslin Vision Net- ingful to practitioners and facilitate com- 30°, three wide-angle 60°, or nine over- work images and dilated ETDRS photo- munication between practitioners (Table lapping 45°fields (41,42). Fundus pho- graphs and suggested that this digital 1). tography can also be used to track the technique may be an effective telemedi- Diabetic macular edema. Some DR pa- progression of disease or efficacy of treat- cine tool for remotely determining the tients may develop vision loss from DME. ments. The utility of fundus photography level of DR, suggesting timing of next ret- Clinically significant macular edema as a large-scale screening procedure is inal evaluation and identifying the need (CSME) occurs if there is thickening of limited because of its cost and the require- for prompt referral to ophthalmology spe- the retina involving the center of the ret- ment for special equipment and trained cialists (44). There are also commercial ina (macula) or the area within 500 ␮mof personnel (32). Pupil dilation is another efforts underway, including Inoveon, it, if there are hard exudates at or within inconvenient aspect and may reduce based in Oklahoma City, and EyeTel, 500 ␮m of the center of the retina with compliance even further. Several technol- based in Virginia. Eyetel uses a novel ap- thickening of the adjacent retina, or if ogies that offer simple, low-cost, and proach that places an imaging system, there is a zone of retinal thickening one more accessible photographic screening called the Digiscope, in primary care of- disk area or larger in size, any part of for DR/DME are currently being fices to transmit images via a modem to a which is within one disk diameter of the evaluated. reading center at the Wilmer Eye Insti- center of the retina (37). This definition of To make fundus photography easier tute, Johns Hopkins Hospital, Baltimore, CSME generally refers to the threshold and more widely accessible, investigators Maryland. level at which laser photocoagulation is have evaluated the potential for the use of In addition to these efforts, newly de- carried out. However, it is important to digital cameras to obtain fundus images veloped automated methods for detection appreciate that the majority of visual loss through nondilated pupils. The sensitiv- of DR have sensitivity and specificity occurs when macular edema involves the ity and specificity of these nonstereo- ranges of 77.5–88.5 and 88.7–99.7%, re- center. scopic digital screening methods have spectively (48). However, tele-ophthal- The International Clinical Diabetic most often been compared with the ET- mology should not be currently viewed as Macular Edema Disease Severity Scale in- DRS seven standard field images. Overall, a substitute for comprehensive eye exam- cludes two major levels: absent and these methods where in substantial agree- inations. Photographic techniques can present. If DME is present, it is divided ment with the ETDRS classification for miss disease occurring outside the photo- into mild (some retinal thickening or hard the grading of DR and in fair to moderate graphic fields and are less effective than exudates in the posterior pole, but distant agreement for the grading of DME (43,44). angiography at detecting capillary closure from the center of the macula), moderate Another advantage of digital technol- and leakage (see below). Given the lower (retinal thickening or hard exudates ap- ogies is the ability to transmit images to a sensitivity of nonstereoscopic digital pho- proaching the center of the macula but centralized reading center for grading. E- tography to detect DME, supplemental not the center), and severe (involving ret- mailed digital images from dilated pupils measurement of VA may also be war- inal thickening or hard exudates involv- were found to be suboptimal for detecting ranted (45). A more appropriate use of ing the center). DME, but sensitive and specific enough to these technologies is the identification of detect sight-threatening DR (45). Al- patients with retinal lesions that warrant Recent screening techniques and though image quality is reduced com- further evaluation by an ophthalmologist technologies pared with that of 35-mm photographs, (44). Early detection of retinal abnormalities is telemedicine-transmitted images appear Ophthalmoscopy. Ophthalmoscopy is essential in preventing DR/DME and loss to be useful for the detection of sight- a useful screening procedure, easy to use of vision. Treatments, such as photoco- threatening DR in the hands of experi- and accessible to ophthalmologists and

DIABETES CARE, VOLUME 26, NUMBER 9, SEPTEMBER 2003 2655 Diabetic retinopathy and diabetic macular edema other physicians, and requires no special- parable for the detection of no or mild and Diabetes Control and Complications Trial ized equipment. Compared with fundus moderate DR (57). Similar results were and the U.K. Prospective Diabetes Study photography, ophthalmoscopy by an ex- reported for comparing digital color pho- showed that optimal metabolic control perienced examiner was found to agree tography and oral FA (sensitivity for DR, could reduce the incidence and progres- with grading by fundus photography 87% for both methods), although FA was sion of DR (67,68). The benefits of inten- Ͼ85% of the time (49). In the hands of more sensitive for detecting DME (sensi- sive glycemic control persisted over an primary care physicians, ophthalmos- tivity 48% for photography and 87% for extended follow-up (40). Thus, optimal copy was less sensitive than fundus pho- FA; P Ͻ 0.01) (43). In the Diabetes Con- metabolic control should be an important tography in detecting both any DR and trol and Complications Trial, FA was able treatment goal and should be imple- sight-threatening DR (sensitivity 63 vs. to detect “preretinopathy” in 21 and 42% mented early and maintained for as long 79% and 66 vs. 87%, respectively) (50). of adults with diabetes, deemed negative as it is safely possible (40). Rigid control With additional training, however, oph- with photography or ophthalmoscopy, of hypertension is also effective in reduc- thalmologic screening by primary care respectively (58,59). ing disease progression (69–71). Hyper- physicians may be a clinically acceptable Drawbacks to using FA as a screening lipidemia has been linked to the presence and cost-saving strategy to refer patients procedure are its invasiveness, time con- of retinal hard exudates in patients with for evaluation by an ophthalmologist. straints, expensive equipment, and ad- DR (13,72), and some evidence suggests Ophthalmoscopy compared favorably verse reactions. Allergic-type reactions to that lipid-lowering therapy may reduce with fundus photography, with 100% sodium fluorescein have been reported in hard exudates and microaneurysms (73). sensitivity for referral or follow-up within patients undergoing FA, although the in- The recommended values for HbA1c, 1 year (51). cidence of serious complications are rare blood pressure, and LDL cholesterol are Even in the hands of experienced (60). In general, the use of FA is limited to Ͻ6.5–7%, Ͻ130/Ͻ 85 mmHg, and ophthalmologists, ophthalmoscopy is less determining method and location of laser Ͻ100 mg/dl, respectively (32,74). How- sensitive than photography for detecting photocoagulation for DME and for assess- ever, many patients fail to achieve or some of the earliest lesions of retinopathy ing the extent of nonperfusion. It has lim- maintain these levels of metabolic con- (52). Ophthalmoscopy was less sensitive ited value over photography as a trol. In patients who do achieve a signifi- than photography for detecting DR/DME diagnostic tool and is not recommended cant reduction in HbA1c, there is an in patients with only a few microaneu- for routine use. associated increased risk of severe hypo- rysms (53). Fundus photography and Screening for DR: current guidelines. glycemia (67,68,75). Primary care physi- ophthalmoscopy can be viewed as com- Recent data indicate that annual dilated cians need to recognize correctable risk plementary techniques and may be eye examinations should be implemented factors (i.e., hyperglycemia, hyperten- particularly informative when used ad- from the initial diagnosis of both type 1 sion, and/or hyperlipidemia) so that ap- junctively (31). and type 2 diabetes (32,61). Referral to an propriate monitoring and referral for eye Fluorescein angiography. FA is gener- experienced ophthalmologist is required care can be implemented. ally used for treatment planning. It is a if any level of DME, severe nonprolifera- Treatment. Once sight-threatening DR method in which sodium fluorescein is tive DR, or PDR is detected in the exami- has been detected, the treatment options intravenously administered followed by nation (32). Regular follow-up is also are limited. Laser photocoagulation ther- rapid sequence photography of the retina essential to ensure early detection, even if apy has proven effective in reducing DR to evaluate its circulation. A method using no DR was found initially; this is espe- progression, and vitrectomy can in many orally administered fluorescein has also cially important for high-risk patients cases prevent severe vision loss in patients been developed (54). Normally, fluores- (32). with advanced stages of DR. Unfortu- cein cannot pass through the tight junc- Adherence to American Diabetes As- nately, both treatments carry a risk of ad- tions of retinal capillaries; however, in sociation guidelines for annual ophthal- ditional vision loss, and neither is some disease states, such as DR and DME, mic examination is poor, ranging only effective at reversing loss of VA. dye leakage occurs. The method is useful from 34 to 65% (62–65). Even among Laser photocoagulation. Laser photoco- in detecting early alterations of the blood- patients at high risk for vision loss (pre- agulation is used to treat both DR and retinal barrier, capillary closure, and mi- existent DR or long duration of diabetes), DME. The goal of macular laser photoco- croaneurysm formation (55). The major the rates of adherence were only 61 and agulation for DME is to limit vascular advantage of FA over fundus photogra- 57%, respectively (62). These findings leakage through a series of focal laser phy is its ability to detect macular isch- suggest a need for practitioner and patient burns at leaking microaneurysms or grid emia denoted by nonperfusion of the education about DR and its conse- laser burns in regions of diffuse break- retinal capillaries and to detect subtle quences. A standardized method of refer- down of the blood-retinal barrier. The ra- DME as evidenced by fluorescein leakage ring patients with diabetic eye disease for tionale of panretinal photocoagulation for from the capillaries (55). An automated further evaluation may also be of great DR is to ablate ischemic areas of the pe- method of quantitating microaneurysms value in improving early detection. ripheral retina and thereby reduce the in- from digitized fluorescein angiograms duction of angiogenic growth factors. was shown to reliably detect microaneu- Management and treatment Results of the Diabetic Retinopathy Study rysms with a sensitivity of 82% (56). Fur- Prevention. Control of the metabolic demonstrated that panretinal photocoag- ther improvement and automation may abnormalities of diabetes has a major ef- ulation effectively reduces the risk of vi- increase the utility and accessibility of FA. fect on the development of diabetic mi- sion loss in a majority (60%) of patients FA and fundus photography are com- crovascular complications (66). The with PDR (38,76). The ETDRS compared

2656 DIABETES CARE, VOLUME 26, NUMBER 9, SEPTEMBER 2003 Ciulla, Amador, and Zinman outcomes in eyes assigned to either defer- ral of macular laser photocoagulation or immediate treatment for clinically significant DME (37). Results showed that macular laser photocoagulation reduced the risk of vision loss by 50% for patients with clinically significant DME (33,37,77, 78). Macular focal and grid laser photocoagulation is indicated for clinically significant DME, and panretinal photocoagulation is indicated for high-risk PDR (37,38,79,80). Vitrectomy. In more severe cases of DR, specifically those with tractional retinal detachment or severe nonclearing vitreous hemorrhage, vitrectomy is indicated to prevent blindness and/or severe visual loss (80–83). During vitrectomy, inci- Figure 1—Metabolic pathways impli- sions are made at the pars plana, a portion cated in the development of diabetic of the sclera located posterior to the cor- microvascular complications. nea and lens but anterior to the retina. The procedure may also be used to release vitreoretinal traction by excising mem- cataract formation and includes risks of Role of sorbitol accumulation and branes causing tractional detachments of retinal detachment and endophthalmitis, use of aldose reductase inhibitors the retina (38). In addition, panretinal which fortunately are rare (88). In some The hyperglycemia of diabetes leads to an photocoagulation can be applied during patients treated with photocoagulation, increased flux through the polyol path- pars plana vitrectomy to treat the under- DR continues to progress and ongoing way, resulting in elevated levels of sorbi- lying PDR. This is typically performed treatment is necessary. DME can also re- tol (91). The net effect is a buildup of with a fiber optic endolaser probe intra- occur. intracellular sorbitol and fructose. The operatively. ensuing disruption of the osmotic balance Vitrectomy is clearly beneficial for the POTENTIAL in the cell is believed to result in cellular treatment of advanced active PDR (84). PHARMACOLOGICAL damage (91), which may be important in Early vitrectomy increased the percentage THERAPIES — Because of the limita- the loss of integrity of the blood-retinal of eyes with a VA of Ն10/20 to 44%, tions of current treatments, new pharma- barrier, among other complications. Loss compared with 28% in a conventionally cological therapies are being developed, of retinal pericytes in the earliest stages of managed group (84). The use of early vit- targeting the underlying biochemical DR may be due to their sensitivity to poly- rectomy is also warranted for eyes with mechanisms that cause DR/DME. The ra- ols (20,21,92). The “myo-inositol deple- very severe PDR, but not for patients with tionale behind the use of these agents is tion hypothesis” has also been put forth to less severe DR (84,85). However, recent the prevention of diabetes-induced dam- explain the physiological impairment of advances in surgical techniques and tech- age to the retinal microvasculature. The retinal pigment epithelial cells and peri- nology since the Diabetic Retinopathy mechanisms that contribute to cellular cytes by hyperglycemia (93–95). Retinal Vitrectomy Study have led to enhance- damage in the retina include increased pigment epithelial cells grown under high ment of the risk-to-benefit ratio for pars flux through the polyol pathway leading glucose conditions show marked in- plana vitrectomy and widening indica- to sorbitol accumulation, production of creases in sorbitol and decreases in myo- tions for this procedure. advanced glycation end products (AGEs), inositol content, which were prevented Benefits and disadvantages. Given the increased oxidative stress, and activation by sorbinil, an aldose reductase inhibitor risk of blindness without treatment, laser of the protein kinase C (PKC)-␤ pathway (ARI) (93). Pericytes grown under high photocoagulation and/or vitrectomy will (Fig. 1). Each of these mechanisms has glucose conditions also demonstrate ARI- continue to have a major role in the man- been targeted with specific inhibitory and myo-inositol–reversible alterations in agement of DR/DME. Both laser photoco- compounds, some of which may become inositol phospholipid metabolism and agulation and vitrectomy improve quality viable therapies to treat DR/DME. Blood DNA synthesis (94). Reducing the intra- of life for patients with DR and are cost- vessel formation plays a pivotal role in the cellular load of sorbitol in the retina and effective (86,87). However, these inter- development of PDR, and various anti- other tissues susceptible to microvascular ventions are indicated only when DR has angiogenic agents are also under investi- damage (e.g., nerves and kidney) is a goal progressed to a measurably advanced gation as potential therapies for DR. of these experimental therapies. stage in which some VA may already be Because there is considerable overlap Clinical trials of ARI (sorbinil, ponal- lost. Side effects, such as loss of periph- among these and other pathways in the restat, and tolrestat) have been conducted eral, night, or color vision, are rarely pathogenesis of DR (89,90), combina- for the treatment of DR (96–99). Unfor- noted by some photocoagulation-treated tions of therapies may prove to be more tunately, ARIs have shown little therapeu- patients (77). Vitrectomy can accelerate effective in preventing DR. tic promise for DR thus far. Treatment

DIABETES CARE, VOLUME 26, NUMBER 9, SEPTEMBER 2003 2657 Diabetic retinopathy and diabetic macular edema

effects, such as decreases in microaneu- rodent model of DR, aminoguanidine re- tion concentration (IC50) values ranging rysm count (96) and fluorescein leakage duced retinal oxidative stress and PKC ac- from 22 to 31 nmol/l and may be useful in (99), are observed in patients. However, tivity caused by diabetes or galactosemia the treatment of DR and other disorders there appears to be little significance of (106), suggesting that these pathways (120,121). The kinase domain of the hu- these effects on the progression of DR may also be involved in its beneficial ef- man VEGF receptor-2 (KDR) and the (97,98). One study found that ARI treat- fects on DR. In diabetic dogs, aminogua- platelet-derived growth factor receptor ␤ ment normalized nerve conduction ab- nidine effectively prevented the are also inhibited by PKC412 at IC50 val- normalities in diabetic dogs but had no development of DR but did not have a ues ranging from 20 to 100 nmol/l (120). effect on the development of DR significant effect on AGE formation (107). In an animal model of neovascularization, (99,100). Despite numerous attempts to The utility of these compounds for the PKC412 inhibited ischemia-induced target inhibition of the aldose reductase prevention of DR remains to be proven in angiogenesis as well as retinal vessel for- pathway alone, it appears that this is in- humans (108). mation during development (120). How- sufficient to impact diabetic microvascu- ever, early pharmacodynamic studies of lar complications. Role of the PKC-␤ pathway and use PKC412 have resulted in some adverse of PKC-␤ inhibitors outcomes, which may reflect PKC412’s Role of AGEs and use of AGE Experimental studies have shown that relative lack of specificity (122). Further inhibitors PKC activity and levels of diacylglycerol trials will be needed to determine whether Carbohydrates interact with protein side (DAG), an activator of PKC, are increased this compound will be useful in the treat- chains in a nonenzymatic fashion to form after exposure of vascular tissues to ele- ment of DR in humans. Amadori products, and these may subse- vated glucose (109,110). Diabetes- quently form AGEs, especially in the pres- induced DAG may derive from hydrolysis Role of oxidative stress and use of ence of high glucose (101,102). Excessive of phosphatidylinositides, metabolism of antioxidant compounds formation of AGEs has been proposed as phosphatidylcholine, or de novo synthe- Production of reactive oxygen species another biochemical link between diabe- sis of phosphatidic acid (26). PKC activity (ROS) has been implicated in the devel- tes and the development of microvascular is also increased after exposure of vascular opment of diabetic complications (123). complications. AGEs may affect such endothelial cells to oxidative stress, an- Diabetes may cause ROS production functions as enzyme activity, binding of other mechanism implicated in the devel- through glucose auto-oxidation, in- regulatory molecules, and susceptibility opment and progression of diabetic creased flux through the polyol pathway, of proteins to proteolysis (101). The microvascular complications (90,111). and increases in protein glycation (123). chronic interaction of these products with PKC-␤ and -␦ have been identified as the ROS may activate aldose reductase and at least one specific cell surface receptor predominant isoforms activated in vascu- PKC and increase AGE production and for AGEs (AGE-specific receptor) may lar tissues in response to hyperglycemia DAG formation (90). perpetuate a proinflammatory signaling (26,109). PKC-␤ has been shown to have The pervading role of ROS in the process and a pro-atherosclerotic state in an important role in regulating endothe- biochemical processes leading to microvascular tissues (103,104). In vitro, the lial cell permeability (112) and is an im- vascular damage has prompted an inves- AGE–AGE-specific receptor interaction portant signaling component for VEGF tigation of antioxidants as preventive has been associated with oxidative stress (113). Transgenic animals overexpressing therapy for diabetic complications (124). and the activation of nuclear factor-␬B, PKC-␤ in vascular tissues developed reti- Inhibition of superoxide production can which leads to hyperexpression of pro- nal hemodynamic abnormalities similar effectively block sorbitol accumulation, inflammatory cytokines, lymphocyte to those observed in human DR (114). AGE formation, and PKC activation adhesion molecules (e.g., V-CAM-1), va- The role of PKC in many cellular pro- (125). These findings suggest that ROS soactive mediators, and pro-coagulant cesses suggests that inhibition of all PKC production is associated with at least factors (104). These processes may result isoforms would cause unacceptable toxic- three mechanisms of diabetes-induced in disruptions of retinal hemodynamics ity (115). Ruboxistaurin (LY333531), a vascular damage. Antioxidants are effec- and/or damage to vascular endothelial specific inhibitor of PKC-␤1 and -␤2 tive inhibitors of pericyte loss secondary cells. Accordingly, strategies to reduce (115), has been shown to prevent and re- to diabetes in experimental models AGE formation in the absence of achiev- verse microvascular complications in an- (21,126). Tocopherol also inhibits hyper- ing euglycemia have been investigated as imal models of diabetes (116), to block glycemia-induced DAG production and potential preventive therapies for diabetic neovascularization associated with retinal PKC (124,127). Tocopherol prevents ret- microvascular complications (102). ischemia (117), and to inhibit the effect of inal hemodynamic abnormalities in dia- The inhibition of AGE formation us- VEGF on retinal permeability and endo- betic rats (127). In patients with type 1 ing compounds such as aminoguanidine thelial cell growth (118). In patients with diabetes and little or no baseline retinop- has been investigated to prevent some of minimal DR, ruboxistaurin reversed reti- athy, retinal blood flow was significantly the diabetic vascular abnormalities. AGE nal blood flow abnormalities and was well increased after 4 months of tocopherol accumulation in the retinal capillaries of tolerated (119). Additional trials are eval- therapy (P Ͻ 0.001) (128). Recent results diabetic rats can be blocked with the use uating the utility of ruboxistaurin for the of the Heart Outcomes Prevention Evalu- of aminoguanidine (105). The reduction treatment and prevention of DR and ation study and other trials showed a lack in AGE accumulation was also associated DME. of effect of tocopherol in the prevention of with a reduced number of acellular capil- PKC412 inhibits the ␣, ␤, and ␥ iso- cardiovascular risks, despite suggestive laries and pericyte loss (105). In another forms with similar half-maximal inhibi- evidence to the contrary (129–131).

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Role of angiogenic factors and the some evidence for resistance to the drug Staging and assessing efficacy of use of anti-angiogenic agents was noted (137,139). In a recent trial of potential therapies New blood vessel (angiogenesis) forma- patients with severe nonproliferative DR Limitations of current staging meth- tion is central to the pathology of PDR and or early PDR, therapy with octreotide (a ods. The evaluation of pharmacological is stimulated by such factors as VEGF in somatostatin analog) decreased the need interventions for a given condition re- response to retinal ischemia, which oc- for retinal photocoagulation compared quires standardized clinically meaningful curs because of capillary loss and/or mi- with conventional treatment (1/22 vs. end points that can be assessed in a quan- croaneurysm formation (29). VEGF is a 9/24 eyes) (138). However, the incidence titative manner. In the case of DR, the key mediator of angiogenesis in the retina of progression to severe PDR was not sig- scale most widely used is the ETDRS DR (30). Clinical studies have shown that nificantly different between the treatment severity scale (34). As discussed above, this scale has been used to assess the se- VEGF levels increase in patients as they arms (138). Additional controlled trials progress from nonproliferative DR to ac- verity of retinopathy in major interven- will determine whether somatostatin an- tive PDR (29,30). Successful panretinal tion trials for diabetes control (67). Other alog therapy is a viable therapeutic option photocoagulation has been found to re- trials evaluated the effects of diabetes con- duce intraocular VEGF levels by 75% for patients with more advanced stages of trol on the development and progression (P ϭ 0.008) in patients treated for ocular DR. of DR, using such end points as the need neovascularization (29). This suggests Experimental results indicate that for photocoagulation or the development that specific inhibition of VEGF activity high-dose aspirin suppresses diabetes- of PDR or severe nonproliferative DR. The may prevent retinal neovascularization induced retinal TNF expression, nuclear use of these clinical end points implies and associated blood flow abnormalities. factor-␬B activity, and leukocyte cell ad- that some degree of sight-threatening DR Inhibition of VEGF signaling using hesion molecule expression, which are already exists in a subject, and end points ruboxistaurin prevented VEGF-induced implicated in endothelial cell injury and such as these are of limited value in dis- increases in vascular permeability (118). breakdown of the blood-retinal barrier cerning the effects of pharmacological The importance of angiogenesis in the (140). There is evidence that aspirin alone therapies on early DR. A more efficient pathology of DR has prompted the inves- or in combination with dipyridamole way to assess these earlier stages in clini- tigation of angiostatic therapies for the could decrease the yearly increase in mi- cal trials would be to assess stepwise pro- treatment of DR and DME (132). Early croaneurysms in patients with early DR gression on the ETDRS scale. Data from results in mice have been encouraging (141). However, among patients with the Wisconsin Epidemiologic Study of (133). The role of VEGF in retinal neovas- mild to severe nonproliferative DR, aspi- Diabetic Retinopathy demonstrate that a cularization has also prompted the devel- rin therapy (650 mg/day) was shown to progression of one or more steps on the opment of VEGF-specific inhibitors such have no significant effect on DR progres- ETDRS scale is predictive of the develop- as antibodies to VEGF (134). These anti- sion nor to confer any increased risk of ment of PDR or clinically significant DME bodies may be especially useful for the vitreous hemorrhage (142). Thus, where- (relative risk, 5.9 and 3.8, respectively) (36). The use of the Ն1 step ETDRS pro- prevention of neovascularization during as aspirin prophylaxis may be useful in the very early stages of PDR. Another po- gression as an end point in clinical trials of the early stages of DR and DME, this ben- tent endogenous inhibitor of angiogenesis new pharmacological agents will reduce efit appears to be lost in later stages of is pigment endothelium-derived factor the sample size and trial duration needed (PEDF). PEDF inhibits angiogenesis in- disease. to assess efficacy (36). Although the duced by a wide variety of growth factors There is evidence suggesting that in- ETDRS staging system is widely used in in addition to VEGF (135,136). In a hibitors of the renin-angiotensin system clinical trials, it is rarely used clinically, mouse model of ischemia-induced reti- may have additional effects on DR that are given its complexity. Consequently, phar- nopathy, systemic administration of re- independent of their hypotensive abilities macological agents that alter the risk of combinant PEDF completely inhibited (69,71,143). Lisinopril, an ACE inhibitor, progression along steps of the ETDRS the development of ischemia-provoked reduced retinal neovascularization, scale may not be clinically meaningful to retinal vascular anomalies without affect- VEGF, and VEGF type 2 receptor expres- practitioners. It will be necessary to cor- ing the development of normal retinal sion in a rat model of retinopathy of pre- relate changes in steps of ETDRS progres- vessels (136). These findings suggest that maturity (144). Similarly, diabetes- sion to the International Clinical Diabetic PEDF may be useful as a primary inter- induced retinal VEGF expression and Retinopathy and Diabetic Macular Edema vention in the treatment of early DR. hyperpermeability were also inhibited by Disease Severity Scales. a similar treatment (145). Whether these Surrogate outcomes. As new treat- Other potential therapies for ments become available, alternative out- beneficial effects are independent of the retinopathy prevention comes must also be devised that can hypotensive action of these compounds is Somatostatin activity is linked with the accurately predict the progression of DR progression of DR (137,138), and hy- not yet known; nonetheless, their inhibi- from its initial stages. For example, the pophysectomy has been proposed as an tory effects on VEGF expression may be detection and quantitation of microaneu- intervention for severe treatment- especially important in the early stages of rysm formation and/or other retinal cap- resistant DR. Consequently, somatostatin PDR. Candesartan, a potent angiotensin II illary abnormalities using FA may be a has been evaluated for the treatment of receptor antagonist, decreases VEGF ex- sufficiently sensitive means to evaluate DR (137–139). Early results in patients pression and ameliorates retinal abnor- the effect of pharmacological therapy on with PDR were encouraging, although malities in diabetic rats (146). early changes in the blood-retinal barrier

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(55). The situation is greatly complicated more access to proper screening and may ley NA, Murphy RP, Chantry K, Hoog- by the nonlinear progression of DR. Clin- make this a more achievable goal. werf BJ, Miller D: ETDRS Research ical signs may spontaneously resolve and Group: association of elevated serum thus may mask true progression of the lipid levels with retinal hard exudate in disease (55). There is no straightforward Acknowledgments— The authors thank Drs. diabetic retinopathy: Early Treatment of Diabetic Retinopathy Study (ETDRS) method to address this issue at present Erin A. Kingshill and Peter D. Ho for their help with the manuscript. Report No 22. Arch Ophthalmol 114: and more research is needed in this area. 1079–1084, 1996 The use of multiple surrogate end points, 14. Klein R, Klein BEK, Moss SE, Cruick- such as a two-step ETDRS progression, References shanks K: The Wisconsin Epidemiologic measurement of retinal thickness, and as- 1. 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