Experimental Treatments for Diabetic Retinopathy
HOMAYOUN TABANDEH, MD, MS, FRCOphth · DAVID BOYER, MD
Pharmacotherapeutic advances have resulted in more effective control of blood glucose and blood pressure in diabetic patients. Treatment modalities for diabetic retinopathy (DR), including retinal laser photocoagulation, vitreoretinal surgery, and intravitreal injections, have improved outcomes. Despite these advances, DR remains the most common cause of newly diagnosed vision loss in the working-age population.
Age at onset and the duration of diabetes are the major predictors for development and progression of DR. Blood-glucose and blood-pressure control are among the most important elements of management. The Diabetic Control and Complications Trial demonstrated that tighter glycemic control reduced vision loss in type 1 diabetics.1 The United Kingdom Prospective Diabetes Study found that every point decrease in hemoglobin A1C produced a 35% reduction in microvascular complications.2 This study also concluded that tight blood-pressure control reduced microvascular complications.
Laser therapy remains the mainstay for each form of DR. The Diabetic Retinopathy Study showed that panretinal photocoagulation significantly reduced risk of severe visual loss (5/200 or worse) in patients with high-risk characteristics.3 The Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated macular photocoagulation of clinically significant macular edema reduced the risk of moderate visual loss (doubling of visual angle) from 30% to 15% at 3 years.4 In addition, about 20% of patients undergoing laser treatment had some improvement in vision.
Though glucose control, blood-pressure control, and laser treatments are helpful, the number of patients who gain vision is low. New potential treatments are being evaluated for their effectiveness in controlling abnormal neovascularization, reducing macular edema and improving vision.
|Homayoun Tabandeh, MD, MS, FRCOphth, practices ophthalmology with Retina-Vitreous Associates Medical Group in Los Angeles. David Boyer, MD, also practices with Retina-Vitreous Associates Medical Group and is clinical professor at the Keck School of Medicine of the University of Southern California in Los Angeles. Dr. Tabandeh reports no financial interests. Dr. Boyer has minimal financial interest in Allergan, Genentech, Novartis, and iCo. Dr. Tabandeh can be reached via e-mail at email@example.com.|
DIABETIC MACULAR EDEMA
Intravitreal Triamcinolone Acetonide. Intravitreous triamcinolone acetonide (IVTA) has been used for treatment of diabetic macular edema (DME). IVTA has also been used as an adjunct for patients undergoing panretinal photocoagulation (PRP) to reduce postlaser macular edema — prior to macular laser photocoagulation to reduce the edema and intraoperatively to better visualize the posterior cortical vitreous — and to decrease postoperative vascular permeability. Limited studies have shown improvements or stabilization of visual acuity (VA) in the short term, especially in patients with cystoid macular edema.5-10 In a prospective, randomized trial, best-corrected visual acuity (BCVA) improved by >5 letters after 2 years in 56% of treated eyes compared with 26% of eyes in the placebo group.10 An increase in intraocular pressure (IOP) of >5 mm Hg was observed in 68% of treated eyes. Glaucoma medication was required in 44% of patients, and surgery was required in 5% of the treated eyes. Cataract surgery was performed in 54% of treated eyes within the 2-year follow-up period. There was 1 case of infectious endophthalmitis in the treatment group.
In another study, 88 eyes with DME were randomized to 4.0 mg IVTA or laser photocoagulation.11 Patients were assessed and treated every 4 months. Optical coherence tomography (OCT) showed a reduction in central subfield thickness (CST) of 82.0 μm with IVTA and 62.3 μm with laser at 12 months. The ETDRS scores remained the same in both groups. In the IVTA group, 22 of 43 eyes required ocular antihypertensives, and 1 eye developed sterile endophthalmitis. This study did not show a benefit from IVTA over conventional laser therapy for patients with chronic DME.
Higher-dose IVTA may be associated with improved outcomes, as well as increased side effects. In a study of 63 eyes of 63 patients with DME, the eyes were randomized to 4, 6, and 8 mg of IVTA. Although all groups demonstrated improvement of BCVA and macular thickness, the mean BCVA improvement at 6 months was significantly higher in the 8-mg group. Elevated IOP occurred in 39% of the 4-mg group and 55% of the 8-mg group.12
Combination of IVTA and macular laser photocoagulation was studied in 86 eyes with diffuse DME that were randomized to IVTA alone or IVTA, followed by macular laser photocoagulation 3 weeks later. The logMAR VA was significantly better in the combination group at 3 and 6 months.13
The Diabetic Retinopathy Clinical Research Network (DRCRnet) is a collaborative network dedicated to facilitating multicenter clinical research of diabetic retinal diseases. The network was formed in September 2002 and currently includes over 150 participating sites with more than 500 physicians. The network is funded by the National Eye Institute. DRCRnet recently reported on results of protocol B, comparing focal laser photocoagulation to IVTA 1 mg or 4 mg for treatment of DME. Eight hundred forty eyes with DME were randomized to macular laser photocoagulation, 1 mg IVTA, or 4 mg IVTA. Retreatment was given for persistent or new edema at 4-month intervals.
At 4 months, mean VA was better in the 4-mg triamcinolone group than in either the laser group or the 1-mg triamcinolone group. By 1 year, there were no significant differences among groups in mean VA. At the 16-month visit and extending through the primary outcome visit at 2 years, mean BCVA was better in the laser group than in the other 2 groups. OCT results generally paralleled the VA results. The study concluded that, over a 2-year period, focal/grid photocoagulation is more effective and has fewer side effects than 1-mg or 4-mg doses of IVTA and should be the benchmark against which other treatments are compared in clinical trials of DME.14
Sustained-release Fluocinolone Acetonide. Sustained-release fluocinolone acetonide (FA; Retisert, Bausch & Lomb) is an implantable, nonbiodegradable intraocular device that delivers 0.59 mg FA for up to 3 years at a rate of 0.5 μg per day.15 The implant is constructed of a 1.5 mm core of drug and a silicone/polyvinyl acetate–laminated coating affixed to a strut. Sustained-release FA implants are currently approved by the Food and Drug Administration (FDA) for chronic, noninfectious posterior uveitis. Its use for DME was evaluated in a phase 2 clinical trial that randomized 197 patients to receive either the 0.59 mg implant or standard of care (repeat laser or observation).16 At 3 years, the implant eyes had less macular edema than controls. Fifty-eight percent of the implant eyes showed no evidence of edema, compared to 30% of those receiving standard of care. VA improved by >3 lines in 28% of the implant group and in 15% of the standard of care group. The most common adverse events were cataract surgery in 95% of the phakic eyes and an IOP rise in 35%. Twenty-eight percent of the implanted eyes required a glaucoma filtering procedure, and 5% had the implant removed in order to control IOP.
Medidur FA. Medidur FA (Alimera Sciences, Inc. and pSivida) is an injectable device that delivers fluocinolone acetonide (FA) into the vitreous cavity. Unlike Retisert, which is placed in the operating room, Medidur is administered in the office setting, providing a low daily dose of FA for 24 to 36 months. It is inserted using a 25-g needle, which allows for a self-sealing wound.
Alimera recently reported on its interim month 3 safety and efficacy results from the first human pharmacokinetic study of Medidur FA, which it intends to market under the trade name Iluvien if approved by the FDA. The 36-month, open-label phase 2 study, running concurrently with the phase 3 Fluocinolone Acetonide in Diabetic Macular Edema (FAME) study, was designed primarily to assess systemic exposure of FA after administration of Medidur FA in patients with DME. Of the 37 subjects enrolled in the trial, 20 were on the low dose (approximately 0.23 μg/day) and 17 were on the high dose (approximately 0.45 μg/day). Preliminary results indicated that 20% of the low-dose patients and 18% of the high-dose patients showed improvements in BCVA of >15 letters. Mean macular thickness decreased in both groups. No adverse events related to IOP were observed in the low-dose patients; 12% of the high-dose patients experienced IOP elevation greater than 30 mm Hg. Cataract formation was reported in a patient in the high-dose group. Additional interim results will be published at months 6, 12, 18, 24, 30, and 36.
The FAME study consists of 2 masked, randomized, multicenter trials that are fully enrolled with 956 patients in the United States, Canada, Europe, and India who will be followed up for 36 months. The trials began in September 2005.
Posurdex. Posurdex (Allergan) is an intravitreous extended-release, biodegradable dexamethasone implant. A phase 2 multicenter trial showed significant improvement of vision in patients with DME. A total of 306 patients were randomized 1:1:1 to Posurdex 350 μm, Posurdex 700 μm, or observation. The patients' macular edema was secondary to DR, retinal vein occlusion, Irvine-Gass syndrome, or uveitis. At 6-month follow-up 36%, of the 700-μg group and 27% of the 350-μg group had at least a 2-line improvement in BCVA, compared to 19% of the observation patients. Nineteen percent of the 700-μg group had an improvement of >3 lines, compared to 8% of the observation group. The average change in CST was -142 μm for the 700-μg dose and -61μg in the 350-μg dose. There was an increase of 11 μm in the observation group. Seventeen percent of the 700-μg group experienced an increase in IOP of 10 mm Hg or higher at some point during the study, compared to 12% for the 350-μg patients and 3% for the observation group. The original study was performed with an implantable, biodegradable system placed in the operating room. An office-based, 22-g injector system is currently being used in phase 3 trials.
The Allergan 012 trial is a multicenter, randomized, double-blind clinical trial evaluating the safety and efficacy of the intravitreal implant of dexamethasone (700 μg every 6 months) in combination with laser macular laser photocoagulation compared with macular laser photocoagulation alone in patients with DME. Outcome measures include BCVA at months 12, CST, vascular leakage (fluorescein angiogram), and time to retreatment. This study started in May 2007 and is currently recruiting participants.
|Figure 1. Scanning electron microscopy of Posurdex immediately before implantation (left) and after 3 weeks (right).|
I-vation. The I-vation (SurModics) implant contains triamcinolone. In a multicenter phase 1 study, 31 patients were randomized to receive the 925-μg implant in either the slow-release or fast-release version. The interim data on 24 patients at 18 months showed no surgical complications and no uncontrollable IOP above 22 mm Hg.17 One patient developed endophthalmitis. No systemic side effects were noted. BCVA improved from a baseline of 46 letters (ETDRS) to 64 letters and CST decreased from a baseline of 395 μm to 158 μm at 18 months.
Nova63035. Nova63035 (Novagali) is an injectable emulsion containing a tissue-activated corticosteroid pro-drug that is converted into the drug by the enzymes present in the retina and choroid. A phase 1, nonrandomized open-label, dose-escalation clinical study to assess the safety and tolerability of Nova63035 in patients with DME is currently recruiting participants.
Ranibizumab. Ranibizumab (Lucentis, Genentech and Roche) is a humanized antigen–binding fragment against all isoforms of vascular endothelial growth factor (VEGF). Currently, it is the only FDA-approved anti-VEGF drug that has been shown to improve vision in patients with choroidal neovascularization (CNV). A single-center dose-escalating pilot study of ranibizumab for patients with central DME showed improved vision in the majority of patients, particularly at higher doses. Improvement of macular edema was observed with a reduction of 45.3 μm in the low-dose group and 197.8 μm in the high-dose group.18
In a phase I study, Ranibizumab for Edema of the mAcula in Diabetes (READ-1), Nguyen and associates reported an improvement in both VA and OCT in patients (n=10) who received 0.5 mg ranibizumab at baseline and at months 1, 2, and 6. At month 7, the mean improvement in BCVA was 14 ETDRS letters. The CST improved by 246 μm.19
The READ-2 study is a phase 2, randomized, multicenter clinical trial initiated in December 2006. It is designed to evaluate the long-term safety and effectiveness of injections of ranibizumab in patients with DME. In addition, the trial evaluates the efficacy of ranibizumab vs conventional treatment with laser photocoagulation therapy or a combination of ranibizumab and laser photocoagulation. One hundred twenty-six patients have been randomized to receive 1 of 3 interventions: ranibizumab, laser photocoagulation, or a combination of the 2 treatments. The study recently ended at 6 months, and patients will be monitored for an additional 2 years. The interim results reported at the 2008 meeting of the Association for Research in Vision and Ophthalmology indicated patients treated with ranibizumab experienced greater improvements in BCVA compared with patients receiving either of the other interventions. On average, the BCVA of ranibizumab-treated patients improved to 20/63 at month 6, compared with unchanged BCVA of about 20/80 in both the laser and the combination-treatment groups. In addition, patients treated with ranibizumab had a 56% reduction in excess retinal thickness, whereas only an 11% reduction was seen in those receiving laser treatments.
Protocol 1, run by DRCRnet, is an ongoing phase 3, randomized, multicenter clinical trial studying intravitreal ranibizumab or IVTA in combination with laser photocoagulation for treatment of center-involving DME (CST >250 μm). Outcome measures include BCVA at 12 months, change in CST and retinal volume measured by OCT, and number of injections in the first year.
Figure 2. Structure of the VEGF-Trap.
The RIDE and RISE studies are phase 3, double-masked, multicenter randomized sham-injection–controlled trials of the efficacy and safety of intravitreal ranibizumab injection 0.5 mg every 4 weeks for 24 months in patients with center-involving DME. The studies, sponsored by Genentech, started in May 2007 and are currently recruiting participants. Outcome measures include proportion of subjects who gain at least 15 letters in BCVA, mean change in BCVA and central foveal thickness, proportion of subjects with resolution of leakage, mean number of macular laser treatments, and change in contrast sensitivity.
RESOLVE is a randomized, double-masked, multicenter phase 2 study assessing the safety and efficacy of 2 concentrations of intravitreal ranibizumab injections compared with non-treatment control for patients with DME with center involvement.
This study is ongoing but not recruiting participants.
CAPTURE (DME) is a phase 1 randomized, open-label, dose-comparison, safety/efficacy study evaluating combination treatment using ranibizumab and efalizumab (Raptiva, Genentech) for DME. Efalizumab inhibits the binding of leucocyte function-associated antigen–1 to intercellular adhesion molecule–1, thereby inhibiting the adhesion of leukocytes to other cell types. Patients are randomized to ranibizumab 0.5 mg intravitreal alone every 4 weeks, efalizumab alone subcutaneously 1 mg/kg weekly, or combination. The study is currently recruiting participants and completion is expected by April 2010.
Bevacizumab. Bevacizumab (Avastin, Genentech) is a full-length humanized antibody against all isoforms of VEGF. Small series have shown short-term improvement in DME, regression of proliferative retinopathy (PR), clearing of vitreous hemorrhage, and regression of rubeosis.20-25 The DRCRnet study group recently reported on a phase 2 randomized clinical trial of intravitreal bevacizumab for DME.26 The group provided data on the short-term effect of intravitreal bevacizumab for DME. One hundred twenty-one eyes of 121 subjects with DME and BCVA ranging from 20/32 to 20/320 were randomized to 1 of 5 groups: (1) focal photocoagulation at baseline; (2) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks; (3) intravitreal injection of 2.5 mg of bevacizumab at baseline and 6 weeks; (4) intravitreal injection of 1.25 mg of bevacizumab at baseline and sham injection at 6 weeks; and (5) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks with photocoagulation at 3 weeks
At baseline, median CST was 411 μm and median BCVA was 20/50. Compared with group 1, groups 2 and 3 had a greater reduction in CST at 3 weeks and about 1 line better median BCVA over 12 weeks. There were no major differences between groups 2 and C3in CST reduction or BCVA improvement.
A CST reduction was present at 3 weeks in 43% of bevacizumab-treated eyes and 28% of eyes treated with laser alone and at 6 weeks in 37% and 50% of eyes, respectively. Combining focal photocoagulation with bevacizumab resulted in no apparent short-term benefit or adverse outcomes. DRCRnet results demonstrated that intravitreal bevacizumab can reduce DME in some eyes, but the study was not designed to determine whether treatment is beneficial.
Pegaptanib Sodium. VEGF levels have been found to be elevated in the vitreous and the anterior chamber samples in patients with DR.27 Pegaptanib sodium (Macugen, OSI/Eyetech, Pfizer) is an active aptamer that inhibits VEGF165. It was the first anti-VEGF treatment that the FDA approved for neovascular age-related macular degeneration (AMD). In a prospective, multicenter, randomized phase 2 trial of patients with DME, pegaptanib at 0.3 mg, 1 mg, and 3 mg vs sham injection was administered at 6-week intervals via intravitreal injection.28,29 Focal laser therapy was allowed prior to enrollment and after week 18. Patients received injections at baseline, week 6, and week 12, and additional injections were given as needed until week 30. There were 172 participants, with 39 assigned to the 0.3-mg dose. VA improvement of 10 or more letters was observed in 34% of study eyes compared with 10% of control. CST decreased by 64 μm in the 0.3-mg treated group vs a gain of 4 μm in the standard of care group. Regression of PR, less severe venous beading, reduction of intraretinal microvascular abnormalities, and reduced need for photocoagulation were also observed.
VEGF-Trap-Eye. The "VEGF-Trap" (Regeneron and Bayer Health Care) is a fully human soluble decoy smaller than an antibody consisting of the Ig-2 domain of VEGF receptor 1 and the Ig-3 domain of VEGF receptor 2 fused to an Fc fragment protein that binds all forms of VEGF isoforms, as well as placental growth factor.30 VEGF-Trap-Eye is now completing phase 2 studies for the treatment of CNV secondary to AMD. In a phase 1 study of VEGF-Trap-Eye for DME, the drug was administered as a single 4.0-mg intravitreal injection to 5 patients with longstanding diabetes and multiple prior treatments for DME. The single injection resulted in a decrease in mean CST and mean macular volume throughout the 6-week observation period. Phase 2 trials for the treatment of DME are expected to start in the near future.
Bevasiranib. Bevasiranib (OPKO) is a small interfering RNA drug designed to silence the genes that produce VEGF. The RACE trial was a pilot phase 2 study of the safety and efficacy of bevasiranib in patients with DME. The study indicated a trend for improvement in macular thickness between weeks 8 and 12.
It is hypothesized that posterior vitreous detachment may protect against development and progression of macular edema and proliferative diabetic retinopathy (PDR). Vitrectomy has been suggested as an adjunct to the treatment of DME in selected cases. The rationale for vitrectomy surgery includes relief of anterioposterior and tangential traction, removal of vasoproliferative and vasopermeable factors, and possibly improved oxygenation.
Pharmacological vitrectomy involves the dissolution of the vitreous by chemical means. The results of small uncontrolled studies have been encouraging. A purified form of hyaluronidase (Vitrase, ISTA Pharmaceuticals) was studied in phase 3 trials and showed a significant reduction in vitreous hemorrhage that allowed laser treatment.31,32 No serious safety issues were reported and the incidence of retinal detachment was not statistically significantly different between treated eyes and control groups. The study did not report on posterior vitreous detachment (PVD) induction. Animal studies of intravitreal hyaluronidase in rabbit eyes did not demonstrate an increase in induction of PVD.33 Vitrase is currently not FDA approved for treatment of vitreous hemorrhage, although it has been used off-label.
Plasmin is a nonspecific protease mediating the fibrinolytic process. It acts also on glycoproteins, including laminin and fibronectin, present at the vitreoretinal interface. Experimental studies indicate intravitreal injection of plasmin can induce PVD in some cases.34-36 Plasmin is not available for clinical application. Autologous plasminogen has been reported to assist vitreoretinal surgery by achieving spontaneous or easy removal of the posterior hyaloid.37-39 Recombinant microplasmin (ThromboGenics Inc., New York) is a truncated molecule containing the catalytic domain of human plasmin that is currently under clinical investigation. A phase 2 randomized trial (MIVI-II) is currently recruiting participants for nonsurgical PVD induction for treatment of patients with DME.
A phase 3 safety and efficacy study of intravitreous injection of carbamide (Vitreosolve, Vitreoretinal Technologies) for nonproliferative DR started in March 2008 and is currently ongoing. The primary outcome includes development of PVD confirmed by B-scan ultrasound. The study is expected to enroll 400 subjects.
iCo-007. Multiple growth factors are implicated in the etiology of DME and DR. The second-generation antisense drug iCo-007 (ISIS Pharmaceuticals) binds to the mRNA molecule, decreasing the production of C-raf kinase through which multiple growth factors, including VEGF, signal. This drug has the potential to inhibit the growth of new blood vessels and decrease vascular permeability. Antisense therapeutics may have increased target binding affinity and improved resistance to degradation, possibly resulting in less frequent dosing.
Sirolimus. Sirolimus (Rapamycin, MacuSight) is an FDA-approved antirejection drug used systemically following renal transplants. It has antiangiogenic, antipermeability, antifibrotic, and antiproliferative properties. Subconjunctival and intravitreal injections of sirolimus have been evaluated in a phase I study. The preliminary results showed a positive response in BCVA and CST with both routes of administration. A phase 2 trial utilizing the subconjunctival route is starting enrollment.
Infliximab. Infliximab (Remicade, Johnson & Johnson) is a genetically engineered antibody against tumor necrosis facto–α. A phase I nonrandomized, open-label study of intravitreal infliximab (0.5 mg/0.05 mL) in patients with refractory DME is currently recruiting participants.
Ruboxistaurin. Hyperglycemia increases serum and cellular levels of diacylglycerol, a physiologic activator of protein kinase C (PKC). Activated PKC levels are associated with both increased levels of VEGF and increased vascular permability.40,41 Ruboxistaurin (RBX; Arxxant, Eli Lilly) is a selective inhibitor of PKC. A phase 3 study indicated that RBX 32 mg/day taken orally was effective in delaying the occurrence of moderate visual loss. Moderate visual loss occurred in 9.1% of placebo-treated patients vs 5.5% of RBX-treated patients. Visual improvement of >15 letters was seen in 4.9% treated vs 2.4% placebo. Laser treatment for macular edema was reduced in the treated group, but a reduction in progression of DR from moderately severe to very severe was not observed.42
The PKC-DMES study group reported the 30-month results of a multicenter, double-masked, randomized clinical trial evaluating the safety and efficacy of orally administered RBX in patients with DME in which 686 patients received placebo or RBX orally (4, 16, or 32 mg/day) for 30 months. The primary study outcome was progression to sight-threatening DME or application of macular photocoagulation for DME. The delay in progression to the primary outcome was not statistically significant. RBX was well tolerated in this study.43 FDA has requested additional trials before approval of RBX.
Octreotide. Two phase 3 studies (study 802 and 804) utilizing the insulin-like growth factor antagonist octreotide (Sandostatin LAR, Novartis) have been completed. The purpose of the studies was to evaluate the 20-mg and 30-mg doses of Sandostatin LAR given intramuscularly monthly on progression of pre-existing DR. Secondary endpoints were time to development of macular edema and loss of VA. In study 802, patients from sites in the United States, Canada, and Brazil who received the 30-mg dose did show a delay in progression of retinopathy. No effect was observed for VA or progression to macular edema. The European study (802), however, did not confirm the delay in progression of retinopathy. Neither study showed a positive effect on VA or reducing the progression of edema. Side effects observed were significant and included diarrhea, cholelithiasis, and mild hypoglycemia.
Mecamylamine (Comentis) inhibits endothelial nACh receptors and decreases angiogenesis and vascular permeability. A phase 2 study of the safety and bioactivity of topical ocular mecamylamine administered twice a day for 12 weeks for the treatment of DME has recently been completed.
Bromfenac (Xibrom, ISTA) is a nonsteroidal anti-inflammatory drug that is currently undergoing a nonrandomized, open-label, uncontrolled phase 1 pilot study for treatment of DME.
PROLIFERATIVE DIABETIC RETINOPATHY
The Diabetic Retinopathy Study demonstrated a 50% decrease in risk of severe visual loss following panretinal laser photocoagulation in eyes with high-risk PDR. The Diabetic Retinopathy Vitrectomy Study (DRVS) showed that vitrectomy within 6 months of onset of nonclearing vitreous hemorrhage was associated with better visual outcomes in patients with PDR and type 1 diabetes mellitus. Since the start of the DRVS, there have been advances in the field of vitreoretinal surgery, such as the introduction of endolaser photocoagulation, small-gauge vitrectomy, and use of pharmacotherapeutic adjuncts such as triamcinolone and anti-VEGF agents. These advances have improved the surgical outcomes.
Bevacizumab has been used for treatment of PDR. It is particularly useful when vitreous hemorrhage obscures the view for panretinal laser photocoagulation, severe progressive proliferative disease despite panretinal laser photocoagulation, iris neovascularization, severe coexisting DME and PDR, and as adjunctive therapy before pars plana vitrectomy.22-24,44-46
In a study of 45 eyes with PDR treated with intravitreal bevacizumab (6.2 μg to 1.25 mg), all patients demonstrated a reduction in leakage of the neovascularization within 1 week after the injection. Complete resolution of angiographic leakage of neovascularization of the disc was noted in 73% of eyes. In 2 cases, a subtle decrease in leakage of neovascularization in the fellow uninjected eye was noted, raising the possibility that therapeutic systemic levels were achieved after intravitreal injection. Recurrence of fluorescein leakage varied.
Bevacizumab has also been used as an adjunct to PRP in patients with high-risk PDR. In a study of 22 patients, the adjunctive use of intravitreal bevacizumab with PRP was associated with a greater reduction in the area of active leaking neovascular complexes than PRP alone. There was no statistically significant difference in BCVA between the groups.47 A prospective, fellow-eye controlled study showed that intravitreal bevacizumab augmented the short-term response to panretinal laser photocoagulation in high-risk PDR, but the effect was short-lived, with many treated eyes showing recurrence.48 Tractional retinal detachment may develop or progress following intravitreal bevacizumab in patients with severe PDR.49
It is not known whether intravitreal steroid or anti-VEGF injections are beneficial in preventing vision loss after PRP treatment. DRCRnet protocol J is a phase 3, randomized, double-blind study evaluating use of intravitreal ranibizumab (IVTA) as an adjunct to PRP for PDR. The purpose of the study is to find out whether treatment with IVTA or an intravitreal injection of ranibizumab can prevent loss of vision caused by PRP photocoagulation treatment. Outcome measures include BCVA, change in thickness of OCT central subfield and retinal volume, presence and extent of new vessels, vitreous hemorrhage and need for additional PRP. The study started in March 2007 and is expected to be completed in 2010.
Rosiglitazone maleate, an oral peroxisome-proliferating activated receptor gamma agonist and oral insulin sensitizing agent with potential antiangiogenic activity, appears to delay the onset of PDR. A longitudinal medical record review of patients treated with rosiglitazone reported a 59% relative risk reduction for progression of severe non-proliterative DR to PDR. There was also a decrease in the number of subjects experiencing >3 lines of BCVA loss. The incidence of DME appeared unaffected.50
Diabetic retinopathy remains a major cause of blindness, despite improvements in management of blood glucose and pressure, use of laser photocoagulation, and improved vitreoretinal surgical techniques. With the addition of pharmacotherapy, either alone or in combination, improved visual outcomes may be possible. Currently, retinal laser photocoagulation remains an integral component of management of DR. RP
- Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med. 2000;342:381-389.
- Stratton IM, Cull CA, Adler AI, Matthews DR, Neil HA, Holman RR. Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75). Diabetologia. 2006;49:1761-1769.
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- Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985;103:1796-1806.
- Audren F, Erginay A, Haouchine B, et al. Intravitreal triamcinolone acetonide for diffuse diabetic macular oedema: 6-month results of a prospective controlled trial. Acta Ophthalmol Scand. 2006;84:624-630.
- Avitabile T, Longo A, Reibaldi A. Intravitreal triamcinolone compared with macular laser grid photocoagulation for the treatment of cystoid macular edema. Am J Ophthalmol. 2005;140:695-702.
- Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002;109:920-927.
- Nicolo M, Nasciuti F, Lai S, Ghiglione D, Borgia L, Calabria G. Intravitreal triamcinolone acetonide as primary treatment for diffuse diabetic macular edema: a prospective noncomparative interventional case series. Eur J Ophthalmol. 2006;16:129-133.
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- Gillies MC, Sutter FK, Simpson JM, Larsson J, Ali H, Zhu M. Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a doublemasked, placebo-controlled, randomized clinical trial. Ophthalmology. 2006;113:1533-1538.
- Ockrim ZK, Sivaprasad S, Falk S, et al. Intravitreal triamcinolone versus laser photocoagulation for persistent diabetic macular oedema. Br J Ophthalmol. 2008;92:795-799.
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- Pearson P, Levy B, Comstock T, Group. FAIS. Fluocinolone acetonide intravitreal implant to treat diabetic macular edema:3-year results of a multicenter clinical trial [abstract]. Invest Ophthalmol Vis Sci. 2006;47:E-Abstract 5442.
- Eliott D, Dugel PU, Cantrill HL, et a. I-vation TA: 18 months results from phase I safety and preliminary efficacy study. Paper presented at: Annual meeting of the Association for Research in Vision and Ophthalmlogy, April 27-May 1, 2008, Fort Lauderdale, FL.
- Chun DW, Heier JS, Topping TM, Duker JS, Bankert JM. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology. 2006;113:1706-1712.
- Nguyen QD, Tatlipinar S, Shah SM, et al. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol. 2006;142:961-969.
- Haritoglou C, Kook D, Neubauer A, et al. Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina. 2006;26:999-1005.
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