here are currently a large number of people, particularly in the United States, who have some level of glucose impairment, if not frank diabetes. The estimated prevalence of diabetes in this country is currently 24 million people with the disease. These numbers are expected to grow as we see an increase in the aging population. Whether patients with diabetes have excellent control of their blood glucose levels or poor control, as longevity increases, many of these patients will develop some kind of retinopathy. It is estimated that 9 million people in the United States alone have diabetic retinopathy, which represents 3% of the entire US population, making eye disease one of the most, if not the most, prevalent comorbidity of diabetes (Figure 1). Because of the increase in patients who will experience some form of diabetic retinopathy in their lifetimes, it is crucial that the following information on diabetic retinopathy be understood by not only the ophthalmologist, but by all clinicians and health care providers involved in the care of patients with diabetes.

DIABETIC RETINOPATHY: A BRIEF HISTORY

The first documented description of diabetes was in approximately 1500 BC, and was described as a “melting down of flesh into the urine,” and it was in the early part of the 20th century with the advent of insulin, that people with diabetes could potentially survive. The increase in survival allowed clinicians to uncover morbidity associated with the disease, and for approximately 40 years from 1930 through 1970, many patients with diabetes became blind as a result. Fortunately, in the late 1970s, the development of ophthalmic lasers allowed for ablation of the peripheral retinal, what is called panretinal photocoagulation (PRP), and a subsequent reduction in the prevalence of blindness from proliferative diabetic retinopathy (PDR). This development led to a collaboration of a large group of vision scientists who put together the first classification of diabetic retinopathy.

The following 20 years witnessed a heyday of clinical research in diabetic retinopathy, beginning with the first clinical trial in retinal diseases, the Diabetic Retinopathy Study, which proved that PRP decreases the prevalence of blindness in the setting of proliferative retinopathy.1-14 This was followed 10 to 15 years later by the Early Treatment Diabetic Retinopathy Study (ETDRS), which provided further information about the timing of PRP in the setting of proliferative disease and more importantly, introduced the first treatment for diabetic macular edema which also involved laser treatment using a different technique, focal/grid photocoagulation.15-39 For the past 25 to 30 years, focal/grid laser photocoagulation has remained the gold standard for treatment for PDR. A few years later, the Diabetic Retinopathy Vitrectomy Study highlighted surgery for eyes with vitreous hemorrhage or tractional retinal detachment.40-44

UNDERSTANDING DIABETIC RETINOPATHY

The natural history of diabetic retinopathy can be viewed as an orderly progression from one phase to another. Nonproliferative diabetic retinopathy may not be associated with visual loss unless macula edema is present as part of it. It includes basement membrane thickening, loss of pericytes, and vascular hyperpermeability, and is categorized into mild, moderate, and severe levels. Macular edema, swelling in the retina, can occur at any one of the stages of mild nonproliferative retinopathy through proliferative disease. PDR is an advanced stage that includes retinal ischemia, neovascularization, retinal detachment and may have associated visual impairment. In PDR, abnormal blood vessels grow from the retina into the vitreous cavity.

Patients with diabetes lose vision from proliferative disease through various mechanisms. If the new vessels bleed and fill the vitreous cavity with blood (“vitreous hemorrhage”), vision will be affected but this can be addressed surgically with vitrectomy. They can also lose vision from traction retinal detachment whereby scarring, fibrous bands from neovascular proliferative tissue develop and pull the retina off the eye wall. This can also be corrected surgically; however, visual function will be returned only if the retina has been separated from its underlying blood supply for a brief period of time, and only if the blood supply within the retina is still intact. Unfortunately, most patients arrive at this point because of ischemia or nonperfusion. The ischemia that occurs in the severe nonproliferative phase of the disease leads to angiogenic factors, which allow proliferation to develop and leads to the endstage form of PDR. Thus, if the ischemia is profound, even in an attached retina, vision loss may not resolve.

Figure 1 shows an eye with severe macular edema. Lipid is a marker indicating leakage from the retinal vessels, which results from years of hyperglycemia. Hyperpermeability of the vessels can easily be seen with fluorescein angiography (Figure 2). On the left the microaneurysms are clearly visualized. On the right, 10 minutes after that bolus injection of fluorescein, all of the fluorescein is leaking out into the retinal tissue, showing why the retina might be thickened.

In the last 5 years, optical coherence tomography (OCT) has become a standard imaging technology. OCT is similar to ultrasound, but instead of using sound waves, OCT utilizes light to generate images, providing a virtual biopsy of the retina. Figure 3A shows a thickened macula where the fovea bulging forward from interstitial retinal fluid vs Figure 3B, which is a relatively flat macula after successful treatment. OCT is a useful tool for monitoring responsiveness to therapy for macular disorders.

In regard to visual acuity and diabetic retinopathy, ophthalmologists typically use the ETDRS eye chart to test vision. Significant loss of vision correlates to a 3-line loss in visual acuity on ETDRS testing; what a patient actually sees in relation to ETDRS testing can significantly affect his or her quality of life. Thus, it is important to address diabetic retinopathy before patients lose vision to such a degree.

THE DRCR.NET: OVERVIEW

The Diabetic Retinopathy Clinical Research Network (DRCR.net) was established 8 years ago in 2003 as a collaborative network to facilitate multicenter clinical research on diabetic retinopathy, diabetic macular edema and associated conditions. Funding for the DRCR.net comes from several sources, including a Cooperative Clinical Research Agreement (U10 Award) with National Eye Institute, which is now in its second 5-year cycle (2009 to 2013); the National Institute of Diabetes and Digestive and Kidney Diseases through Type 1 Diabetes Research; other foundations such as the Juvenile Diabetes Research Foundation; and industry collaborations. The DRCR.net priority initiatives include: the opportunity for all retina specialists to be involved at all levels of organization; establishment of community- based and academic-based clinical centers; ownership by investigators at front end (protocol development) and back end (publication and presentation) of clinical research; industry collaboration while maintaining academic integrity; establishment of control of design and operation of trials by the DRCR.net; ownership of data by the DRCR.net; and the ability of the DRCR.net to present and publish data independent of industry (not withstanding protection of intellectual property).

As of June 18, 2010, the DRCR.net has 103 active and 203 total research sites (community and academic centers), 66% (68) of which are community-based active centers. There are 300 active investigators (797 total), 862 active personnel (2352 total), and active participation is present in 36 states (47 total) of our country.

NEW PARADIGMS FOR TREATMENT

We are currently in a new era in the treatment of DR, in which we are administering anti-vascular endothelial growth factor (anti-VEGF) agents on a monthly basis into the vitreous. The DRCR.net completed a landmark study, a Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema, the results of which were published in 201045 and for which extended follow-up data were published in 2011.46

In this DRCR.net trial, Protocol I, 691 patients (854 eyes) were randomly assigned to 1 of 3 experimental treatments for diabetic macular edema (DME), and the results with each were compared to those with the gold standard of focal/grid laser photocoagulation. The 3 experimental arms included 1 using an anti-VEGF agent, ranibizumab (Lucentis, Genentech), injected into the vitreous cavity with prompt laser treatment; 1 using ranibizumab with deferred laser treatment, which was defined as deferring focal/grid laser treatment until such time that the DME may have persisted and was no longer improving; and 1 using intravitreal injection of a corticosteroid, triamcinolone acetonide, in combination with prompt laser treatment. All of these outcomes were compared to a fourth arm, in which sham injection with prompt laser was administered. Laser treatment is associated with a 50% reduction in risk of at least moderate vision loss when compared to no treatment per the results of the ETDRS. In addition, less than 20% of patients will experience moderate gain in visual acuity (improvement of at least 3 lines of acuity) when managed with focal/grid laser as a monotherapy.

In the more recent DRCR.net study the primary outcome was mean change in visual acuity 12 months after initiation of treatment. Figure 10 shows that the standard laser group, after receiving 1 treatment at entry and repeating laser every 3 to 4 months if the edema persisted, gained on average 3 letters (half of 1 line of vision) on the ETDRS eye chart at 12 months. In contrast, patients who were receiving ranibizumab with prompt laser or ranibizumab plus deferred laser gained an average of 9 letters (nearly 2 full lines of vision). In the group assigned to deferred laser twothirds of these patients did not require any laser through out the 12-month time period. The results for the patients who received corticosteroid plus laser were disappointing in that they did no better than with laser alone.

What is the importance of monitoring the statistic of or mean change in vision over time? Movement of the mean change in visions tells us that patients on the highest end of the spectrum are increasing in numbers. For example, the proportion of patients who have gained 10 or more letters over a period of time will be greater when the average change in vision, as measured in letters increases in one group vs another. A 10 letter increase (2 lines of acuity) represents a meaningful, or significant change in vision that more likely affects life style: a patient who was 20/50 at baseline has improved to 20/30, and a patient who was 20/100 at baseline has improved to 20/60 or getter. The 12-month results of Protocol I showed that with the use of ranibizumab, 50% achieved this amount of vision increase, whereas with standard laser, only 25% achieved these gains (Figure 4).

Figure 5 shows change in visual acuity at 2 years. The proportion of patients who manifest improvement of vision in the ranibizumab plus prompt or deferred laser groups is higher than the other groups, and this is true for improvements of 10 or 15 letters of acuity (3 lines of vision). It is important to also consider the patients who fared the worst-those who lost vision during the study. Despite laser treatment, approximately 10%-15% lost at least 2 lines of vision (Figure 6). In contrast, less than 5% in either of the ranibizumab groups lost vision, showing that ranibizumab plus prompt or deferred laser is very effective in preventing vision loss from DME.

The hidden pearl in this clinical trial is the possibility that anti-VEGF agents, such as ranibizumab, cannot only address hyperpermeability, but that they may also slow the process of ischemia and angiogenesis. When we looked at the patients treated in the same study, specifically at their general level of retinopathy and assessed progression or regression of that level of retinopathy, we saw a higher proportion of patients that improved their overall retinopathy level, meaning they manifested regression in regard to classification of their precise level of diabetic retinopathy, among the patients in the ranibizumab groups. This behavior was evident across a spectrum of entry levels of DR from mild NPDR thru PDR.

To answer the question of whether anti-VEGF agents can aid in slowing the process of ischemia and angiogenesis, the DRCR.net is embarking on a new trial that will evaluate anti- VEGF agents in the setting of proliferative disease to see if we can avoid using PRP.

CONSIDERATIONS REGARDING INTRAVITREAL INJECTIONS

Is there a downside to administering intravitreal injections of anti-VEGF? Frequent injections are required, often monthly, raising the risk for intraocular infection, or endophthalmitis. In our study, however, the incidence of infection was less than 1%. Retinal detachment is also a risk with intravitreal injection, but again, in our study, the incidence was low. The incidence of elevation in intraocular pressure and cataract was also low in the laser monotherapy and ranibizumab plus laser groups, as compared with the corticosteroids plus laser group, which had higher rates of both of these ocular adverse events. These findings are consistent with what we know about steroids and the increased risk of glaucoma and cataract. We did not see any increased mortality or systemic side effects in this trial, which is always a concern, as we are treating patients who have a larger number of co-morbidities than the general population, particularly with increased cardiovascular issues.

SUMMARY

In summary, intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser had superior visual acuity and OCT outcomes compared with focal/grid laser treatment alone for a period of at least 2 years. Approximately 50% of eyes had moderate improvement (≥10 letters) while approximately 30% gained ≥15 letters. Moderate visual acuity loss (≥10 letters) was uncommon, and the results were similar whether focal/grid laser was given starting with the first ranibizumab injection or it was deferred for 24 weeks or more and placed only if DME persisted.

For the first time in 25 years, we have a treatment that supersedes the gold standard of laser, and one with which ophthalmologists are accustomed to because of its widespread use in the neovascular form of age-related macular degeneration. Challenges with this treatment option exist, however. Frequent injections will place a higher burden on retina specialists and their patients, and so research efforts to address this issue are under way.

How can diabetologists and primary care physicians help to improve the eye health of their patients? The obvious answer is to control patients blood glucose levels, blood pressure, and lipid levels, all of which will decrease the number of patients who develop diabetic retinopathy and more severe disease. However, there will be patients who develop eye disease despite the best efforts of their health care providers. For these patients, the most crucial element is appropriate referral to a retinal specialist, who is armed with the highest level of medical training and expertise to treat and follow diabetic retinopathy.

Ophthalmologists can help by investing and participating in the research that is being performed to combat diabetic eye disease, such as the work that is performed by the DRCR.net. The DRCR.net is a success story, with approximately $4.5 million per year contributed by the National Eye Institute and approximately $1 million per year from the NIDDK through at least 2013. Through this and other generous funding (frequent collaboration with industry groups), the DRCR.net will continue to expand its research efforts to include increasing communication with basic science research to provide a wider platform for translational research; genetic research initiatives; and numerous new protocol ideas and protocols at various stages of development.

Susan B. Bressler, MD, is the Julia G. Levy, PhD, Professor of Ophthalmology at the Johns Hopkins University School of Medicine. She practices within the Retina Division of The Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore. Dr. Bressler reports that she is a paid consultant to GlaxoSmithKline and that her university receives grants from Notal Inc., Regeneron, Genentech, and Bausch + Lomb. She may be reached at +1 410 955 3648.

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