Current Concepts in the Diagnosis and Treatment of Diabetic Retinopathy,
Including Diabetic Macular Edema

 

Diabetes mellitus reached a global prevalence estimated at 2.8% in 2000 and is projected to reach 4.4% in 2030.[1] The total number of people with diabetes is predicted to rise from 171 million to 366 million during the same period.[1] These increases are expected to affect every country (Figure 1). Diabetes can lead to a number of microvascular complications, including diabetic retinopathy, diabetic peripheral neuropathy, and diabetic nephropathy. Diabetic retinopathy is a common cause of vision loss in the US and in most other industrialized countries. Recent estimates of prevalence among patients with diabetes in a large US managed care organization were 40.3% for any degree of retinopathy, and 8.2% for severe retinopathy.[2] Although advances in the diagnosis and treatment of diabetic retinopathy have improved its once-poor prognosis,[3] it is still the leading cause of legal blindness among adults aged 20-74 years, resulting in 12,000-24,000 new cases annually in the US.[4,5] Diabetic retinopathy is also a common cause of moderate vision loss (MVL), defined as a doubling of the visual angle, or the loss of 3 lines on an eye chart.

 

Because it is a progressive disease, early and effective treatment of diabetic retinopathy, increases the likelihood of improved vision outcomes for patients. If current eye examination and treatment recommendations are followed, the risk of severe visual loss from diabetic retinopathy is less than 5%.[3] Delay in seeking medical attention has been cited as a key reason for the relatively high incidence of diabetic retinopathy among patients with diabetes.[3] Regrettably, the explosive recent and projected increases in the number of individuals with diabetes 1 suggest that diabetic retinopathy, including DME, will continue to contribute to vision loss for years to come. [5,6,7,8]

 

Theories linking hyperglycemia to diabetic retinopathy

At the cellular level, the chronic hyperglycemia characteristic of diabetes has been associated with a host of effects that may contribute to diabetic retinopathy, including loss of the cells that support the capillaries (pericytes), basement membrane thickening, increased adhesion of endothelial cells, increased leukostasis, platelet dysfunction, and coagulopathy. [9,10,11] These changes ultimately lead to the accumulation of fluid within the layers of the retina that characterize diabetic macular edema (DME), the distortions of the vascular walls that characterize nonproliferative diabetic retinopathy (NPDR), and the neovascularization that characterizes PDR.

 

Potential metabolic pathways leading to diabetic microvascular complications

Diabetes activates multiple, interacting metabolic pathways that can induce cellular and extracellular changes leading to tissue damage throughout the body, including the eye, as shown in Figure 2.[12] Substances potentially involved in these pathways include protein kinase C β (PKC β ), vascular endothelial growth factor (VEGF), angiotensin-II (A-II), endothelin-1 (ET-1), platelet-derived growth factor (PDGF), and many others, and may affect both neural and vascular tissues in the retina.[12,13,14,15] The potential pathways are of more than academic interest, as every substance along each pathway is a potential treatment target. Familiarity with the pathways is essential to understanding the modes of action of emerging treatments for diabetic retinopathy.

 

Molecular basis of investigational treatments for diabetic retinopathy, including DME

Treatments that inhibit pathogenic pathways can potentially address the underlying cause of diabetic retinopathy, delay progression of vision loss, and improve healthcare outcomes. However, compounds currently in late-stage clinical trials for diabetic retinopathy act upon only a few of the numerous potential pathogenic targets. The pathways that have been most closely scrutinized for their contribution to diabetic retinopathy have targeted polyol, A-II, VEGF, and PKC. Pathogenic treatments include oral treatments to limit PDR, DME, or both,[16,17,18] injectable systemic treatments to limit PDR,[19] and intravitreal injections to reduce DME.[20] Other treatments targeting local factors that contribute to the progression of DME or loss of visual acuity are also being investigated. These local treatments may reduce inflammation or edema in DME,[21] or clear persistent vitreous hemorrhage.[22] Clinical trial results, if published, for both pathogenic and other treatments for diabetic retinopathy will be discussed elsewhere in this article.

 

Overview of purpose, benefits, and limitations of diagnostic techniques

Standard clinical ophthalmic diagnostic instrumentation can adequately diagnose and stage most cases of diabetic retinopathy, as shown in Figure 3. Dilated stereo funduscopy with slit-lamp biomicroscopy and a handheld lens is considered the “gold standard” method for retinal assessment from the posterior pole to the peripher. Using this instrument, all the characteristic signs of NPDR, PDR, and DME can be detected. Stereo imaging is particularly important for diagnosing DME. Other stereo instruments that may be useful in certain situations include the indirect ophthalmoscope for assessing the peripheral retina, and color stereo photographs for documenting retinal status or transmission to a centralized diagnostic service. Centralized fundus reading centers, with or without telemedicine capability, may be especially well-suited for remote areas.[23]

 

Ancillary testing

Additional diagnostic procedures may be used to confirm an equivocal diagnosis, to quantify DME, or to detect obscure presentations of PDR or DME. Some of these procedures are listed in Figure 4.

 

Ultrasonography permits gross evaluation of retinal structure and the vitreous cavity in the presence of media opacity such as a vitreous hemorrhage. Ultrasound can assess whether vitreoretinal surgery should be performed, and if so, how urgently. The ultrasound B-scan mode provides cross-sectional images major eye structures, as shown in Figure 5.

 

Fluorescein angiography

Fluorescein angiography (FA) may help determine the cause of reduced visual acuity in a patient with an apparently normal retina, but is not used routinely to diagnose DME. FA uses an intravenous dye injected into a peripheral vein. A series of fundus images are obtained in rapid succession, permitting analysis of the retinal and choroidal circulation. A photographic fundus image and the corresponding FA image are shown in Figure 6. These images may be obtained on film or as digital images. FA is the best tool to determine whether PDR is present, as it can reveal neovascularization and areas of ischemia, but it is inadequate for determining optimal treatment for DME. For example, DME may be complicated by hyaloidal traction or epiretinal membranes (ERM) within the edema that cannot be detected by FA. FA is not useful for determining the success of therapy in DME because leakage can occur without retinal thickening (due to the retinal pigment epithelium's ability to resorb fluid[24]), and persistent thickening may occur in the absence of active leakage.[25,26]

 

Optical coherence tomography (OCT)

Instrumentation is currently available that improves the ophthalmologist's ability to image and quantify macular thickening, determine appropriate treatment, and gauge the success of therapy. OCT, a technology in clinical use since 1996, permits noninvasive, high-resolution, cross-sectional retinal imaging. Third-generation devices (OCT3), available since 2002, permit images with a resolution of 8-10 microns to be acquired in seconds.[27] Images can be compared with normative data for retinal thickness in the device's built-in database. Four types of DME can be diagnosed with OCT, as shown in Figures 7-10. Sponge-like fluid accumulation in the outer retina (Figure 7) affects approximately 60-96% of eyes with DME, and corresponds to focal/diffuse DME defined by the Early Treatment of Diabetic Retinopathy Study (ETDRS). Cystoid macular edema (CME) occurs in about 50% of eyes with DME (Figure 8); CME cannot be distinguished from other types of focal DME using indirect ophthalmoscopy or slit-lamp biomicroscopy. DME due to mechanical causes—hyaloidal traction and/or ERM—occurs in about 16% of patients (Figure 9), while serous macular detachment with or without traction occurs in about 15% of patients (Figure 10). Of these, CME, hyaloidal traction and/or ERM may only be detectable via OCT.[28,29]

 

OCT can help secure the proper diagnosis, suggest the best therapy, and confirm the anatomic success of any DME treatment. For example, it has been found that DME with hyaloidal traction and/or ERM does not respond well to laser, but responds very well to vitrectomy. The architectural features of this type of DME may be too subtle to see with biomicroscopy or FA, but are readily visualized with OCT.[30,31] CME is another form of DME that may be difficult to distinguish from other types of focal DME; CME also responds better to pars plana vitrectomy (PPV) than to laser photocoagulation.[32]

 

Neither OCT nor FA can completely replace the function of the other instrument. FA is sensitive to leakage, and can detect leakage even when retinal thickening is absent. However, visual acuity (VA) correlates better to macular thickness on OCT than it does to FA leakage. OCT, unlike FA, can also detect persistent thickening even if leakage is not active.[33,34]

 

Overview of signs and symptoms

Manifestations of diabetic retinopathy include a variety of defects within the layers of the retina or on its surface, and sometimes within the vitreous.[3,35] The progressive dysfunction of the retinal vasculature associated with diabetic retinopathy causes the classic clinical signs of the disease, but retinal function may be altered before the onset of visible vascular lesions, affecting blue-yellow color perception and contrast sensitivity.[36,37] Because retinal neurons and glial cells—although comprising most of the retinal mass--are transparent, their structure and function are invisible on clinical exam.[38] The clinical signs and symptoms associated with each form of diabetic retinopathy are listed in Figure 11. Significantly, even severe, sight-threatening diabetic retinopathy may be asymptomatic.

 

Both type 1 and type 2 diabetes place patients at risk for the same kinds of retinal complications, but in type 1 diabetes severe vision loss is usually due to PDR, while the main cause of MVL in type 2 diabetes is DME. Approximately half of patients with DME will lose 2 or more lines of visual acuity within 2 years.[8] Type 2 diabetes is about 20 times more prevalent than type 1 diabetes, so DME causes more cases of vision loss than PDR.[39] Over a 10-year period, clinically significant macular edema (CSME)—sight-threatening DME close to the fovea--will develop in 10% of Americans with diabetes.[5] The risk of MVL from CSME is 33% after 3 years.[39]

 

Nonproliferative diabetic retinopathy

Microaneurysms are the first manifestation of NPDR, and probably represent the outpouching of capillary walls. Small hemorrhages—sometimes described as “dot and blot” hemorrhages—and exudates are also seen in the least sight-threatening stage of NPDR. Microaneurysms and the smallest dot hemorrhages may be indistinguishable on clinical exam, but larger hemorrhages may have irregular borders, unlike microaneurysms.[35] See also Figure 12.

 

Cotton-wool spots appear as white patches with poorly defined borders (Figure 12). These were once called “soft exudates,” but it is now known that they represent nerve fiber layer infarcts and do not have an exudative cause, so the term “soft exudates” has been abandoned. The least severe manifestation of so-called “hard exudates” (lipoprotein deposits) appear as round, yellowish pinpoints with well-defined borders. Other manifestations of NPDR include large, deep intraretinal hemorrhages and intraretinal microvascular abnormalities (IRMA).[35] IRMA may represent either intraretinal shunts or intraretinal new vessels. Unlike the new vessels associated with PDR, IRMA may not leak on FA, except at their tips. IRMA usually appear as irregular loops of new vessels within the retina that straddle normal vessels. They are frequently observed adjacent to ischemic areas of the retina. Deep intraretinal hemorrhages are infarcts caused by retinal arteriolar occlusion.

 

Venous abnormalities such as loops, beading, or reduplication are associated with longstanding hypoxia. Loops are oxbow-like deviations of a vein. Beading gives a “string of pearls” contour to the walls of veins. Reduplicated veins appear to divide into 2 segments over short distances. These are ominous signs that neovascularization is imminent.[35]

 

Proliferative diabetic retinopathy

Neovascularization is the hallmark of PDR.[35] Vessels form on the surface of the retina at the vitreoretinal interface, as shown in Figure 13. Neovascularization may develop on the optic disc (NVD) or elsewhere (NVE) when there is widespread capillary bed closure. The new vessels proliferating into the vitreous may appear as fine, netlike mesh originating from a vein. These vessels are fragile and weak; as the vitreous moves and contracts, the weak vessels shear and bleed, and causing temporary or permanent vision loss. The vitreous hemorrhage may eventually clear, but fibrovascular tissue forms between the damaged vessel and the vitreous gel. The term “diabetic vitreopathy” has been introduced to describe this condition.[3] Over time, the fibrovascular tissue contracts, exerting traction on the retina, which may eventually lead to a retinal tear or detachment, resulting in severe, and possibly sudden, vision loss.[40]

 

Diabetic macular edema

DME is characterized by retinal thickening due to fluid accumulation between retinal layers in the macula, which may occur at any stage in the progression of diabetic retinopathy. Two primary fluid leakage patterns have been observed: focal, from leaking microaneurysms; or diffuse, due to increased vascular permeability. Focal DME is usually associated with a circinate pattern of hard exudates with microaneurysms at the center, as shown in Figure 14. Diffuse DME may be difficult to visualize with biomicroscopy, as shown in top left image in Figure 15, but is clearly seen in the OCT image in the lower right image in Figure 15. (Compare the OCT image in Figure 15 with the ultrahigh resolution OCT of a normal retina in Figure 16.) CME may result from diffuse leakage from the entire retinal capillary network.[3] Each type of DME has different prognostic implications.

 

ETDRS scale

For over 20 years, the evidence base established by the ETDRS and the Diabetic Retinopathy Study (DRS) have guided the diagnosis, staging, and treatment of diabetic retinopathy, including DME. Using ETDRS criteria, clinical diagnosis is made using a slit-lamp biomicroscope and a 60-, 78-, or 90-diopter handheld lens.[41] The ETDRS used a complex numerical scale, sometimes in conjunction with letter modifiers, to describe the type and degree of severity of diabetic retinopathy and DME from stereo fundus images. Some examples of these grades are shown in Figure 17. A trained photographer and a trained reader are required to prepare and grade fundus images. Because a large database of images has been graded with the ETDRS scale, it continues to be used in research settings. However, its complexity has limited its clinical appeal.

 

International Clinical Disease Severity Scales

The International Clinical Diabetic Retinopathy Disease Severity Scale (ICDRDSS) and the International Clinical Diabetic Macular Edema Disease Severity Scale (ICDMEDSS) were developed to promote the use of common terminology and definitions of different degrees of diabetic retinopathy and DME, respectively.[42,43] These scales are shown in Figures 18 and 19. According to the ICDMEDSS, diabetic retinopathy is classified as apparently absent or apparently present. If present, it is graded as mild, moderate, or severe, depending upon how close it is to the center of the macula. The ICDRDSS recognizes 5 levels of severity of NPDR/PDR. In this scale, NPDR is only classified as mild if there are no abnormalities other than microaneurysms. “Moderate NPDR” covers all forms of background retinopathy and maculopathy that involve more than microaneurysms, but lacking high-risk features for progression. Severe NPDR corresponds to the stage at which progression to PDR is imminent. PDR is diagnosed by the presence of any degree of neovascularization, or any degree of vitreous or preretinal hemorrhage. Although the international scales were not intended as treatment guides,[42] the American Academy of Ophthalmology uses ICDRDSS and ICDMEDSS definitions in their management recommendations for diabetic retinopathy.[43]

 

OCT-based severity scales for DME

Both the ETDRS and ICDMEDSS scales rely upon diagnostic instrumentation and procedures for staging DME that is no longer state of the art. Because OCT allows more precise classification of DME, and may be able to detect retinal thickening prior to loss of visual acuity or fluorescein leakage,[44] several authors have proposed new OCT-based classification scales for DME.[28,45] Future treatment guidelines for DME may use these or similar scales in place of the ETDRS or ICDMEDSS scales. An OCT-based classification scale may eventually be used to assign patients with DME to pharmacological, laser, or surgical treatment.[44]

 

Small hemorrhages, exudates, cotton-wool spots, and DME may resolve spontaneously due to normal metabolic and fluid regulatory processes within the retina.[35] As diabetic retinopathy progresses, these normal regulatory mechanisms are overwhelmed, leading to retinal hypoxia. Compensatory neovascularization results in the development of PDR and a high risk of severe vision loss. New treatments for diabetic retinopathy, including DME, are being developed to prevent, delay, or reverse the progression of the disease.

 

Current pharmacological treatments for diabetic retinopathy, including DME

While there are currently no pharmacological treatments specifically approved for diabetic retinopathy, intensive glycemic and blood pressure control are of paramount importance to reduce its incidence and progression.[46,47,48] The landmark Diabetes Control and Complications Trial (DCCT) established the critical role of intensive glycemic control in reducing the incidence and progression of diabetic retinopathy in patients with type 1 diabetes.[46] The United Kingdom Prospective Diabetes Study (UKPDS) confirmed the importance of intensive glycemic control in patients with type 2 diabetes, and further determined that patients who maintained tight blood pressure control (<150/85) significantly reduced the risk of retinopathy progression and vision loss compared to patients who maintained less tight blood pressure control (<180/105).[49] The degree of risk reduction afforded by tight glycemic and blood pressure control may be appreciated from Figures 20-22.

 

A1C, the new designation for the fraction of glycated hemoglobin A 1c , reflects average glucose control over the preceding 2-3 months. Intensive glycemic control means that blood glucose levels are reduced by diet, oral medications, insulin, or a combination thereof to maintain A1C at or below a goal of 6.0-7.5%.[46,47,50,51] For patients with type 1 diabetes, maintaining this degree of control requires multiple daily insulin injections based on the results of multiple daily self-monitored blood glucose (SMBG) assessments; for patients with type 2 diabetes, it may require combination therapy with 2-3 oral medications or oral medications plus insulin (the routine use of SMBG in non–insulin-using patients with type 2 diabetes is controversial[51]). Paradoxically, retinopathy may temporarily worsen with sudden improvements in glycemic control, but the long-term benefits of intensive glycemic control on retinopathy outcomes are undisputed.

 

Current evidence-based guidelines for diabetes developed since the UKPDS recommend that blood pressure be maintained at or below 130/80.[50,51] Most patients with diabetes will require at least 2 different antihypertensive medications to attain this level of control; many will require 3 or more,[50] and even 5 different antihypertensives may not be enough to lower blood pressure below 140/90.[51] Nevertheless, diabetic retinopathy often develops and progresses despite intensive control, and such control is difficult to sustain over long periods of time.[47,48,52]

 

Current surgical treatments for diabetic retinopathy, including DME

Several laser photocoagulation techniques are used to treat diabetic retinopathy. Indications for the 2 types used in the ETDRS are listed in Figure 23. Panretinal or scatter photocoagulation (PRP) involves applying hundreds of laser burns over multiple treatment sessions to the retina outside of the vascular arcades. This treatment may work by destroying retinal tissue that produces VEGF. Focal laser photocoagulation uses laser burns applied only to leaking microaneurysms, but sometimes the term is also used to encompass grid photocoagulation, which applies dozens of laser burns to areas of diffuse leakage. Grid photocoagulation is less extensive than PRP and uses a smaller burn size, and may optionally be applied to areas of nonperfusion.[41] Laser photocoagulation can sometimes improve visual acuity but may have deleterious effects on peripheral, color, and night vision.[55]

 

PPV is a treatment option for severe PDR. Some indications for vitrectomy are listed in Figure 24. The surgery is performed using miniature instruments contained within the lumen of 23- or 25-gauge needles through the sclera. A single intravitreal injection of a corticosteroid such as triamcinolone has been found to improve postoperative outcomes by preventing macular edema as a complication of the surgery.[53] Vitrectomy safety has improved over time, but the procedure is associated with serious complications, including risk of progression of iris rubeosis and neovascular glaucoma.[54]

 

Laser photocoagulation and vitrectomy are indicated only for severe or imminently sight-threatening disease. While these surgical options can preserve vision, their risks do not outweigh their benefits until retinopathy has already progressed to an advanced stage.[55]

 

Potential pharmacological treatments for diabetic retinopathy, including DME

Several medical treatments for diabetic retinal disorders are currently being investigated, each of which targets 1 or more of the functional derangements that lead to retinal tissue damage.

 

Intravitreal treatments

Intravitreal injections have recently emerged as a pharmacological intervention for diabetic retinopathy. The intravitreal route offers the theoretical advantages of rapid response to treatment and localized treatment effect. Currently, 2 classes of intravitreal injections, corticosteroids and growth factor inhibitors, are being evaluated for use as diabetic retinopathy treatments.

 

Corticosteroid intravitreal injections

Triamcinolone* is a crystalline cortisone under investigation as a chronic treatment for DME (eg, multiple injections over time).[56] The largest study of intravitreal triamcinolone in patients with diabetes reported to date is a retrospective, interventional case series of 210 eyes of 174 patients with diffuse DME.[21] NPDR was present in 154 eyes (75%) and PDR was present in 56 eyes (27%). Either 1 or 4 mg intravitreal trimcinolone was administered up to 4 times over 6 months, although most eyes (81%) were treated only once. Improved VA relative to baseline was observed at 1, 3, and 6 months. Resolution of DME was noted in approximately 40% of eyes at 1 month and about 63% of eyes at 6 months. Improvement with incomplete resolution of DME was noted in approximately 52% of eyes at 1 month and about 15% of eyes at 6 months. No change in DME was observed in approximately 6% and 19% of eyes at 1 and 6 months, respectively. These results are shown graphically in Figure 25. Elevated intraocular pressure (IOP) was a common, persistent adverse effect. Postinjection IOP =28 mm Hg affected approximately 14% of eyes; the mean increase in IOP was 5 mm Hg. Six months postinjection, mean IOP was elevated 1.3 mm Hg, with a wider range than at baseline (±6.0 mm Hg vs ±3.4 mm Hg). Other ocular adverse events were cataract progression (3.3% of eyes) and sterile endophthalmitis (2.9% of eyes). Peripheral iridotomy was performed on 1 eye (0.5%) without a history of glaucoma.

 

Some investigators have suggested that sub-Tenon triamcinolone injection may avoid the adverse events associated with intravitreal injections of triamcinolone. Sub-Tenon injections are performed with a curved rigid needle or a flexible cannula inserted through the previously sterilized, anesthetized conjunctiva until the tip enters Tenon's capsule (a dense, vascular layer of connective tissue that surrounds the globe except for the cornea). The drug is injected into the space between Tenon's capsule and the globe after the needle or cannula tip is inserted beyond the equator of the globe. A 24-week prospective, controlled trial of 31 eyes with diffuse DME found that a single sub-Tenon injection of 20 mg triamcinolone in conjunction with grid photocoagulation improved best-corrected VA (BCVA) by 2 ETDRS lines (P = .024) and improved contrast sensitivity by 21% (P = .01) without a significant increase in IOP.[57] A 12-month retrospective, interventional case series of 63 eyes of 50 patients with CSME persisting after ≥1 focal laser treatment found that after an average of 1.2 sub-Tenon injections of 40 mg triamcinolone, BCVA improved from 20/80 to 20/63, with a transient significant increase in IOP and ptosis noted in 2 patients.[58]

 

VEGF inhibitors

VEGF is well known as an inducer of angiogenesis, vascular permeability, and inflammation in diabetic retinopathy and other retinal vascular disorders.[59,60,61] Anti-VEGF treatments are being intensively investigated as retinal disease treatments.[62] Pegaptanib*, ranibizumab*, and bevacizumab* are anti-VEGF compounds under investigation as DME treatments. Clinical trial results for several investigational agents are discussed below.

 

In addition to its pathogenetic role in diabetic retinopathy, VEGF levels in intraocular fluid may have prognostic value in diabetic retinopathy treatment, and are correlated with the degree of fluorescence on FA. For example, diffuse DME appears to be associated with higher VEGF levels than dome-shaped (focal) DME. Elevated VEGF levels may predict the risk of a poor vitrectomy outcome.[63] To date, intraocular VEGF levels have only been measured in research studies, but these findings suggest a potential future application in refining clinical treatment selection.

 

Pegaptanib

Pegaptanib is an anti-VEGF pegylated aptamer that selectively blocks a single isoform (165) of VEGF. In a randomized, double-masked, multicenter, controlled, dose-ranging trial of 172 adults with either type 1 or type 2 diabetes and CSME confirmed by OCT and FA, 0.3 mg intravitreal pegaptanib administered at least 3 times over 24 weeks resulted in about a 68 micron decrease in retinal thickness at the center point of the central subfield, as shown in Figure 26.[21] Patients receiving sham injections experienced an approximate increase in retinal thickness of 4 microns at the same time (P= .02). Improved VA (≥10 letters) was noted in 34% of patients receiving 0.3 mg pegaptanib and 10% of patients receiving sham injections (P= .003) after 36 weeks of treatment, as shown in Figure 27. Eye pain and vitreous complications were the most common adverse events, as shown in Figure 28. A subgroup of 16 patients with PDR were assessed for regression of neovascularization.[64] These patients received 3-6 intravitreal injections of 0, 0.3, 1, or 3 mg pegaptanib for 12-30 weeks and were evaluated at 36 weeks. Neovascularization regressed in 8 out of 16 patients, was unchanged in 7 patients and progressed in 1 patient.

 

Bevacizumab and ranibizumab

Bevacizumab and ranibizumab are structurally related nonselective anti-VEGF recombinant humanized monoclonal antibodies. Each molecule of bevacizumab can bind 2 molecules of VEGF, while each molecule of ranibizumab can bind 1 molecule of VEGF. Clinical trials of ranibizumab in diabetic retinopathy are ongoing and have not yet reported. Bevacizumab is currently approved as a colon cancer treatment.[65] To date, the only published study of bevacizumab in diabetic retinopathy is a case report on 2 patients with PDR and vitreous hemorrhage precluding PRP.[66] One month after a single intravitreal injection of 1.25 mg bevacizumab, both patients had near-complete resolution of vitreous hemorrhage and partial regression of neovascularization. Recurrence of neovascularization was noted at 3 months in 1 patient. One patient experienced a 2-line improvement in VA, while the other experienced a 5-line improvement. No adverse events were reported. While this report is limited by a small number of patients and limited short-term follow-up, similarly encouraging results and a low rate of adverse events have been noted by other investigators for several other retinal vascular disorders.[67,68,69]

 

Systemic treatments

A number of oral medications are being investigated for their specific effects on diabetic retinopathy. Several of these are drugs currently marketed for other indications, such as candesartan* and atorvastatin*. A drug targeting the polyol pathway, epalrestat*, has been evaluated in small trials. Two novel compounds targeting PKC, midostaurin* and ruboxistaurin*, are in late-stage clinical trials.

 

A-II

There are two current classes of drugs targeting A-II: A-II converting enzyme (ACE) inhibitors and A-II receptor blockers (ARBs). A third class, renin inhibitors, is in development; renin inhibitors block 2 types of A-II receptors.[70] ACE inhibitors and ARBs are currently used to treat hypertension. There is some evidence from clinical trials of these drugs in patients with diabetes that they may benefit retinopathy outcomes as well.[71,72] However, some have argued that the observed benefits are due to blood pressure reduction, and not a specific therapeutic effect of A-II inhibition. A large, ongoing trial of the ARB candesartan in patients with diabetes is intended to distinguish between benefits due to blood pressure reduction versus a specific pathogenetic effect.[73] Balanced against the potential benefit of ARBs in diabetic retinopathy is a concern that these drugs may increase the short-term risk of DME in patients with type 2 diabetes.[74]

 

Statins

Accumulating evidence supports aggressive lipid control to treat exudates. Multiple observational studies support a relationship between elevated triglycerides and/or low-density lipoprotein cholesterol with the presence or number of hard exudates. Small interventional studies and case reports support aggressive lipid control. The ongoing Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non Insulin Dependent Diabetes Mellitus (ASPEN) study, a prospective, randomized, controlled study of 2,421 patients with type 2 diabetes, will examine ocular endpoints in a substudy.[75]

 

Aldose reductase inhibitors

Drugs targeting the polyol pathway were the first pathogenic treatments developed to treat diabetic retinopathy and other diabetic microvascular complications independent of metabolic control (eg, blood glucose, blood pressure, and lipids). These drugs are called aldose reductase inhibitors (ARIs). One ARI, epalrestat, is currently licensed for use in Japan. Another ARI, tolrestat, was briefly marketed as a diabetic neuropathy treatment, but was withdrawn in 1997 due to toxicity.[76] The most recent trial of an ARI for diabetic retinopathy, zenarestat, was mentioned in 2004.[77]

 

A 3-year, comparative, parallel-group, prospective controlled trial of 127 patients with NPDR treated with 100 mg epalrestat administered 3 times daily showed a trend toward reduced retinal vascular leakage as evaluated by FA.[78] FA was improved or unchanged in 97% of eyes of treated patients versus 72% of eyes of controls with mild to moderate NPDR, as shown in Figure 29. Among patients with severe (preproliferative) NPDR, 58% of eyes of treated patients and 20% of eyes of controls had improved or unchanged FA. Liver enzyme elevations were noted in 1% of patients (Figure 30).

 

PKC inhibitors

PKC is a family of related enzymes that act as signal transducers for various growth factors, hormones, neurotransmitters, and cytokines.[79] PKC β, particularly the β2 isoform, has been implicated in the development of diabetic neuropathy, nephropathy, and retinopathy.[80] Two PKC inhibitors currently in late-stage trials as treatments for diabetic retinopathy are discussed below.

 

Midostaurin

Midostaurin (PKC412) is a nonselective kinase inhibitor that inhibits all PKC isoforms, as well as VEGF and a number of other substances. A randomized, multicenter, double-masked, parallel-group study of 141 adults with type 1 or type 2 diabetes, NPDR (or no more than mild PDR), and CSME in the study eye treated for 3 months with 0, 50, 100, or 150 mg/d midostaurin showed a reduction in foveal thickness and an improvement in VA.[18] The maximum reductions in foveal thickness (approximately 45 microns) were attained by the patients assigned to 100 and 150 mg/d midostaurin (P = .015 and P = .039, respectively), as shown in Figure 31. Foveal thickness increased in these patient groups following treatment cessation. Mean VA improved by about 1 line at 3 months in the 100 mg/d treatment group, as shown in Figure 32. Gastrointestinal and hepatic adverse events were common, as shown in Figure 33.

 

Ruboxistaurin

Ruboxistaurin is a selective PKC β inhibitor currently under FDA priority review for the treatment of diabetic retinopathy.[81] Recently, it was confirmed in human clinical trials that some of the deleterious hemodynamic changes that contribute to retinal damage in experimental models of diabetic retinopathy can be ameliorated by ruboxistaurin.[15] A randomized, multicenter, prospective, double-masked, parallel-group study of 252 adults with type 1 or type 2 diabetes and moderately severe to very severe NPDR with or without DME treated for ≤42 months with 0, 8, 16, or 32 mg/d ruboxistaurin found that patients in the highest dose group had a significantly lower risk of MVL or worse loss than patients in the placebo group (P = .038), as shown in Figure 34.[16] No consistent trends in gastrointestinal, cardiovascular, pulmonary, renal, or dermatological adverse events were observed across treatment groups, as shown in Figure 35.

 

Summary

Diabetic retinopathy is a common, progressive, potentially sight-threatening disease. Landmark clinical trials have established the value of intensive control of blood glucose and blood pressure levels as the first line of defense against diabetic retinopathy. While prevention of diabetic retinopathy is paramount, these same studies have shown that even individuals with well-controlled systemic disease can still develop vision-threatening retinal disease. The current standard of care in diabetic retinopathy is to identify and treat diabetic retinopathy just before irreversible vision loss occurs. In practice, this means accurate, early diagnosis of severe NPDR and/or DME is needed to identify suitable candidates for laser photocoagulation or vitrectomy, as appropriate. Because diabetic retinopathy is frequently asymptomatic, and accurate diagnosis requires special training and instrumentation, annual comprehensive eye exams are recommended for all individuals with diabetes. [4,43,50,51]

 

However, the current standard of care for diabetic retinopathy does not yet include state-of-the-art diagnostic procedures and treatments. Inclusion of these advances into clinical care have the potential to further improve patient outcomes. Diagnostic instrumentation that permits precise measurement of retinal thickness is now available, and may refine treatment selection for advanced or complex retinal disease. Ongoing research into the molecular mechanisms of diabetic retinopathy has led to the development of wholly new drugs that may permit treatment of diabetic retinal disease before it reaches sight-threatening stages with less severe or fewer side effects than laser photocoagulation or vitrectomy. In short, the diagnosis and treatment of diabetic retinopathy appears to be on the threshold of the biggest change since the ETDRS.

 

*Not approved by the FDA for this indication.

 

A1C: hemoglobin A 1c ; expresses the percentage of glycated to total hemoglobin; also known as HbA 1c

A-II: abbreviation for angiotensin-II

ACE: angiotensin-II converting enzyme

ARB: angiotensin-II receptor blocker

ARI: aldose reductase inhibitor

BP: blood pressure, mm Hg

BCVA: best-corrected visual acuity

CME: cystoid macular edema

CSME: clinically significant macular edema

DCCT: Diabetes Control and Complications Trial

DME: diabetic macular edema

DRS: Diabetic Retinopathy Study

ERM: epiretinal membrane

ET-1: endothelin-1

ETDRS: Early Treatment Diabetic Retinopathy Study

FA: fluorescein angiography

HDL: high density lipoprotein, mg/dL

Hyaloidal traction: macular tension exerted by the shrinkage of fibrovascular tissue attached to the posterior vitreoretinal interface

ICDMEDSS: International Clinical Diabetic Macular Edema Disease Severity Scale

ICDRDSS: International Clinical Diabetic Retinopathy Disease Severity Scale

IOP: intraocular pressure

IRMA: intraretinal microvascular abnormality

LDL: low density lipoprotein, mg/dL

MVL: moderate visual loss, typically 3 lines on an eye chart (15 letters), or a doubling of the visual angle

NPDR: nonproliferative diabetic retinopathy, also known as background diabetic retinopathy

NVD: new vessels on the optic disc

NVE: new vessels elsewhere than on the optic disc

OCT: optical coherence tomography

OCT3: OCT scanner introduced in 2002

OD: right eye

OS: left eye

OU: both eyes

PDGF: platelet-derived growth factor

PDR: proliferative diabetic retinopathy

PKC: protein kinase C, a biomolecular signal transducer

PPV: pars plana vitrectomy

PRP: panretinal photocoagulation

SMBG: self-monitored blood glucose. This test is performed by the patient using a calibrated electronic device and disposable test strips. The blood sample is usually obtained after a lancet is used to pierce the fingertip.

TG: triglycerides, mg/dL

UKPDS: United Kingdom Prospective Diabetes Study

VA: visual acuity, often expressed as a Snellen fraction, eg, 20/20 is normal vision

VEGF: vascular endothelial growth factor, formerly known as vascular permeability factor

 

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