Diabetic Retinopathy: New Results, New Trials, New Opportunities

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Diabetic Retinopathy: New Results, New Trials, New Opportunities

Lloyd Paul Aiello, MD, PhD
Medscape

Approximately 16 million people in the United States, or 6.2% of the population, have diabetes. About 5.4 million of those with diabetes are unaware that they have the disease. Diabetic retinopathy is the most common microvascular complication of diabetes, affecting approximately 49% of those with diabetes. Of the 209 million Americans over the age of 18 years, diabetic retinopathy affects more than 5.3 million, or a little more than 2.5% of the entire adult US population.[1]

Although major advances in the clinical diagnosis and treatment of diabetic retinopathy and its associated complications have been achieved over the past 5 decades, diabetic retinopathy remains the leading cause of new blindness among working-age individuals in developed countries. In addition, although the mainstay of current treatment for advanced diabetic retinopathy and macular edema (laser photocoagulation) is remarkably effective at preserving vision in many cases, it is inherently destructive of the retina and has been associated with side effects (eg, nyctalopia, peripheral visual field loss). In rare cases, sight-threatening treatment complications can occur.

Extensive efforts are under way to evaluate the mechanisms underlying diabetic retinopathy. It is hoped that an understanding of these mechanisms will lead to new therapies with greater efficacy and fewer side effects.
An Era of New Therapy Evaluation

In recent years, extensive research initiatives have greatly expanded our understanding of the underlying mechanisms of diabetic retinopathy. This mechanistic information has suggested new molecular targets for which novel therapeutic agents have been developed. Several of these agents are now undergoing clinical trials, the results of which should begin to elucidate the potential of these new approaches to preserve vision.
Intervention Points in the Natural History of Diabetic Retinopathy

A longer duration of diabetes corresponds to increasingly common and severe changes in the retinal vasculature. In the first several years of diabetes, clinical evaluation of the retina may appear normal -- but significant biochemical and physiologic changes are already under way, including leukocyte adhesion and alterations in retinal blood flow. Although intervention at this early stage would likely preserve the greatest retinal function with potentially the greatest benefit, clinical trials at these early stages of retinopathy present significant challenges for drug evaluation in terms of efficacy and safety.

As the retinopathy progresses, microvascular abnormalities -- including retinal hemorrhages, microaneurysms, and intraretinal microvascular abnormalities (IRMA) -- become clinically apparent in the retina. Slowing, preventing, or reversing these changes would be of significant therapeutic benefit since they lead to subsequent, more severe complications (described below). Some of the ongoing clinical trials address this intermediate stage.

Progressive loss of retinal capillaries results in retinal ischemia. Retinal ischemia is thought to increase the release of growth factors, which subsequently result in abnormal proliferation of new vessels. These vessels are fragile, prone to bleeding, and undergo scarring and fibrosis -- which can lead to traction on the retina, retinal detachment, and severe visual loss. In addition, many of these growth factors increase retinal vascular permeability, another hallmark of diabetic eye disease. Consequently, much emphasis has been placed on evaluation of inhibitors of these angiogenic factors, and several ongoing or planned clinical trials are focused on them.

The retinal vessels may also become abnormally permeable at any stage in the disease process. This abnormal permeability results in transudation of blood serum components into the retina and a thickening of the retina called macular edema. When this edema involves or threatens the center of the macula, it is called clinically significant macular edema and it can result in visual loss. Macular edema affects half a million people in the United States alone. Although laser photocoagulation can reduce the risk of moderate visual loss from this condition by 50%, there are still considerable numbers of individuals who lose vision from macular edema, and the laser therapy does not usually restore vision once lost.
Potential New Drugs to Treat Diabetic Macular Edema -- Intravitreal Vascular Endothelial Growth Factor (VEGF) Inhibitors

In an effort to prevent the visual loss associated with proliferative diabetic retinopathy (PDR) and diabetic macular edema, and to avoid the side effects associated with destructive treatments such as laser therapy, studies have focused on blocking the growth factors thought to initiate the abnormal vessel growth and vascular leakage of the retina. VEGF is generally considered one of the most important of a diverse array of molecules that probably contribute to this complex biological process.

At present, 2 direct inhibitors of VEGF are being evaluated for the prevention of retinal neovascularization from age-related macular degeneration (AMD), which is also a VEGF-mediated disorder. These compounds are either in or approaching clinical trials for diabetic macular edema. Both approaches require administration by intravitreal injection.

One approach involves a humanized monoclonal anti-VEGF antibody fragment that selectively binds all isoforms of VEGF and prevents it from exerting its action. The compound, called rhuFab V2, is produced by Genentech. In a paper presented by Dr. J.S. Heier,[2] rhuFab V2 was evaluated in a multicenter randomized controlled trial for 3 treatment groups of patients with exudative AMD. Initial results in 24 of the patients demonstrated mild to moderate inflammation that was transient in nature. Visual acuity improved by 3 or more lines in 8 patients and was stable in 14 patients. In the overall study evaluating 64 patients, 53 patients received either 300 or 500 mcg of rhuFab V2 and 11 patients received standard of care. Of the 53 patients treated with rhuFab V2, 50 (94%) had stable or improved vision at day 98, and 26% had an improvement of 15 letters or more on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart.[3] On average, patients treated with rhuFab V2 gained 9.0 letters at day 98, compared with patients treated with standard of care who lost 4.9 letters. Again, the primary side effect was transient inflammation. These studies suggest that rhuFab V2 can inhibit VEGF after intravitreal injection and thus may be useful in preventing PDR or diabetic macular edema. But no conclusions can yet be drawn. Clinical trials to test this compound for treatment of diabetic macular edema are in the planning stages.

Another direct VEGF inhibitor is pegaptanib (Macugen), an anti-VEGF aptamer that was discussed in 2 sessions by Dr D. Guyer.[4,5] This compound, created by Eyetech Pharmaceuticals, binds one of the VEGF isoforms, and is administered by intravitreal injection. It had interesting preliminary results in its initial evaluation for AMD. Anecdotal case reports in patients with severe diabetic macular edema showed evidence of reduced retinal vascular leakage and possible improvement in vision. A phase 2 clinical trial evaluating pegaptanib's effect on diabetic macular edema is currently under way.
Potential New Drugs to Treat Diabetic Macular Edema -- Intravitreal Steroids

Recent studies have shown that steroids can reduce both the production and stability of VEGF mRNA. Thus, among many other actions, steroids could theoretically function as VEGF inhibitors. Numerous, uncontrolled case reports of rapid and extensive reduction in macular edema have fueled considerable interest in this therapy, and several studies are now evaluating the intraocular use of steroids for diabetic macular edema.

Dr. P.A. Pearson[6] presented results of a multicenter, randomized, clinical trial of a sustained release fluocinolone intravitreal implant (Bausch & Lomb) in 80 patients with diabetic macular edema. Eleven patients received a 2-mg implant, 41 a 0.5-mg implant, and 28 patients received "standard of care" (control). Only patients receiving the 0.5-mg implant showed statistically significant improvement in macular edema compared with those receiving standard of care (P = .03). More than 36% of the patients treated with the 0.5-mg implant had improved macular edema by 2 or more steps vs 7.7% in the control group. Retinal thickness in the implanted eye was reduced (P < .003) compared with the contralateral eye. Improvement in the severity of diabetic retinopathy compared with those treated with standard of care was also observed (P = .01), with more than 36% of patients treated with the 0.5-mg implant demonstrating a 1-step or greater improvement in their retinopathy severity scores vs 15% in the control group. Reduction in retinopathy severity scores in the eye receiving the implant was observed compared with the contralateral eye (P = .002). More than 80% of patients treated with the 0.5-mg implant had improved or stable visual acuity compared with 50% of the control group (P < .01).

Side effects were noted. More than 12% of patients in the implant group had an increase in intraocular pressure to 30 mm Hg or greater compared with none in the control group. Cataract progression at 6 months was also increased in the implant group to more than 17% compared with none in the control group. Additional studies are ongoing to further elucidate efficacy and the magnitude of the associated complications.

Dr. P.G. Massin[7] discussed another approach. In a randomized, controlled study, 4 mg of triamcinolone were intravitreally injected into 20 eyes with clinically significant macular edema resistant to laser photocoagulation. After 8 weeks, the mean macular thickness was reduced in all 10 treated eyes from 477 microns to less than 210 microns. There was no significant change over the course of the study in the control eyes. It should be noted that triamcinolone (Kenalog) is not currently formulated specifically for intraocular injection.
Potential New Drugs to Treat Diabetic Retinopathy and Macular Edema -- Oral Approaches

As discussed above, VEGF inhibitors should not only be theoretically effective as a therapy for diabetic macular edema, but also should prevent or ameliorate PDR. These approaches are not initially being evaluated for their effect on PDR, primarily because laser panretinal photocoagulation is a remarkably effective, relatively noninvasive therapy for this condition, reducing severe visual loss by up to 90%. When compared with the new approaches -- which might require repetitive intravitreal injections or surgical implantation for the chronic condition -- laser photocoagulation would probably be generally preferred.

However, orally administered agents that may ameliorate diabetic retinal complications are being evaluated. Protein kinase C (PKC) is an enzyme whose activity is increased early in diabetes. One isoform of this enzyme, the beta isoform, appears to be particularly important in the retina. PKC beta serves important roles in diabetes-induced vascular dysfunction, retinal blood flow abnormalities, VEGF expression, VEGF signaling, and retinal vascular permeability. It may also play pivotal roles in other diabetes-induced nonocular microvascular complications such as neuropathy or nephropathy. Thus, oral PKC beta inhibitors might provide an easily administered novel therapy for nonproliferative diabetic retinopathy (NPDR), PDR, or macular edema.

Two phase 2/3 multicenter, randomized, double-masked, placebo-controlled clinical trials evaluating once-a-day oral therapy with a PKC beta inhibitor manufactured by Eli Lilly (LY333531) have just been completed. Baseline demographic data were presented in a poster by L. P. Aiello for one of these trials.[8] Patients were randomized to placebo or 8, 16, or 32 mg LY333531 once daily and followed for 36-46 months. Because 58 of the 252 patients enrolled in the trial were initially screened for a similar trial that required the presence of diabetic macular edema and somewhat less severe retinopathy, they were excluded from analysis. An additional 7 patients were found to be ineligible subsequent to randomization. Baseline characteristics of the remaining group (N = 187) included a mean age of 56 +/- 12 years (range, 20-84), 68% men, 81% type 2 diabetes, mean HbA1c of 8.8 +/- 1.4%, mean duration of diabetes 16.5 +/- 7.5 years, and mean ETDRS visual acuity score of 80 letters (20/25 Snellen equivalent; range, 18 to 98 letters). Baseline retinopathy severity in the eligible eye of each patient was moderately severe NPDR (level 47B-D) in 41% of cases, severe NPDR (level 53A-D) in 38%, and very severe NPDR (level 53E) in 7%. Clinically significant macular edema was present in 65%, and macular edema not meeting clinically significant criteria was present in 14% of cases. Unmasked data release is expected by the middle of 2003.
Consensus Clinical Classification System for Diabetic Retinopathy

In order for clinicians to appropriately communicate the extent of retinal disease present in patients with diabetes, a consistent and established classification system is necessary. A spotlight session[9] was presented to describe a simplified diabetic retinopathy grading scheme called the "International Clinical Classification for Diabetic Retinopathy." This system utilizes the "4-2-1 rule," commonly employed by diabetic retinopathy experts for establishing the presence of severe NPDR.

Specifically, the classification recognizes the following retinopathy levels:

* No apparent diabetic retinopathy
* Mild NPDR
o microaneurysms only
* Moderate NPDR
o More than just microaneurysms but less than severe NPDR
* Severe NPDR
o See below for further description
* PDR
o Neovascularization and/or vitreous/preretinal hemorrhage

In addition, the presence or absence of macular edema is reported. The cutoff of severe NPDR is derived from the "4-2-1 rule" where presence of the following would qualify for this level if no PDR is present:

* 4 quadrants of hemorrhages or microaneurysms greater than ETDRS standard photograph 2A (> 20 retinal hemorrhages); or
* 2 quadrants of venous beading; or
* 1 quadrant of IRMA equal or greater than ETDRS standard photograph 8A (prominent)

A review of ETDRS data to determine if evaluation of IRMA could be dropped from the classification demonstrated that IRMA were independently a significant finding. Therefore, the classification could not be simplified further by eliminating IRMA evaluation and still appropriately reflect disease severity. Full details are expected to be published shortly.

This simplified classification should help with worldwide standardization of clinical care and communication regarding diabetic retinopathy. As new therapies enter the clinical arena, such a standardization will take on increasing importance. Since the classification is essentially a formalization of what diabetic retinopathy experts have been doing from a clinical standpoint for many years, and due to the international participation in its creation, the classification should become well accepted. However, in part due to the large span of retinopathy encompassed by each of these steps and due to variability of progression rates within each step, the formal ETDRS retinopathy classification will remain the "gold-standard" classification for detailed clinical trials in diabetic retinopathy.
The Future of Diabetic Retinopathy Therapy

The recent dramatic increase in our understanding of the mechanisms underlying diabetic retinopathy has resulted in the development of numerous potential therapeutic agents. Many of these approaches are now in or entering clinical evaluation. Results from these studies should shortly begin to define the potential efficacy and usefulness of these new modalities for the clinical care of patients with diabetes. Tantalizing preliminary data suggest that these novel agents may eventually prove beneficial and support the future promise for a substantially increased therapeutic armamentarium against the ocular ravages of diabetes.
References

1. National Eye Institute and Prevent Blindness America. Vision Problems in the US: Prevalence of Adult Vision Impairment and Age-Related Eye Disease. Available at:
http://www.nei.nih.gov/ eyedata/pdf/VPUS.pdf. Accessed November 7, 2002.
2. Heier JS. RhuFab V2 (anti-VEGF antibody) for treatment of exudative AMD. Program and abstracts of the American Academy of Ophthalmology 2002 Annual Meeting; October 20-23, 2002; Orlando, Florida.
3. Grading diabetic retinopathy from stereoscopic color fundus photographs--an extension of the modified Airlie House classification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991;98(5 suppl):786-806.
4. Guyer DR. Update on diabetic retinopathy: pharmacological approach to treatment of diabetic retinopathy. Program and abstracts of the American Academy of Ophthalmology 2002 Annual Meeting; October 20-23, 2002; Orlando, Florida.
5. Guyer DR. Pharmacotherapy for AMD: VEGF inhibitors and related agents. Retina Subspecialty Day. Program and abstracts of the American Academy of Ophthalmology 2002 Annual Meeting; October 20-23, 2002; Orlando, Florida.
6. Pearson PA. Fluocinolone acetonide intravitreal implant in patients with diabetic macular edema. Program and abstracts of the American Academy of Ophthalmology 2002 Annual Meeting; October 20-23, 2002; Orlando, Florida.
7. Massin PG. Intravitreal triamcinolone acetonide for diabetic diffuse macular edema. Program and abstracts of the American Academy of Ophthalmology 2002 Annual Meeting; October 20-23, 2002; Orlando, Florida.
8. Aiello LP, Sheetz MJ, Davis MD, Arora V, Milton RC. The PKC diabetic retinopathy study (PKC-DRS): study design and baseline patient characteristics. Program and abstracts of the American Academy of Ophthalmology 2002 Annual Meeting; October 20-23, 2002; Orlando, Florida; Scientific Poster 285.
9. Wilkinson CP. Achieving consensus on an international clinical classification for diabetic retinopathy. Program and abstracts of the American Academy of Ophthalmology 2002 Annual Meeting; October 20-23, 2002; Orlando, Florida.

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