Diabetic retinopathy: a global epidemic.

From the days of the Airlie House classification of diabetic retinopathy, we have come a long way into the era of anti-vascular endothelial growth factor (VEGF) pharmacotherapies. Over the span of 50 years, we have witnessed four important changes in the field of the diabetic retinopathy management. First, diabetes has assumed the proportion of a global epidemic. According to the International Diabetes Federation, the number of diabetics in the world today is 350 million, and this number is being projected to increase to 600 million by 2035.1 Every seven seconds, one person dies from diabetes somewhere in the world.1 With that alarming proportion of increase in incidence of diabetes, its complication retinopathy has also increased accordingly. It is still the leading cause of blindness in middle-aged adults. Second, large randomized clinical trials have taught us the importance of tight control of systemic factors in the management of this disease. As ophthalmologists, we should stress the importance of tight control of blood glucose, blood pressure and blood lipid to our patients. Third, the introduction of the optical coherence tomography (OCT) has become an essential tool in the management of diabetic retinopathy. The improved resolution of this diagnostic tool for detection of fluid in layers of the retina has made it almost indispensable for our day-to-day practice. We are seeing less and less use of the more invasive fluorescein angiography. Finally, our treatment paradigm for clinically significant macular edema has completely changed in the recent 10 years. The anti-VEGF therapy has become the first-line of therapy in diabetic macular edema (DME). Several anti-VEGF and steroid drugs have been approved by the Food and Drug Administration (FDA) for use in DME. Many new drugs are in the pipeline for future use. We have never seen such an explosion of novel therapies and clinical trials in the field of ophthalmology before. With these changes in mind, this issue of MEAJO offers to review the current status on molecular pathways, diagnostic imaging, systemic factor control, laser therapy, novel pharmacotherapies, and telemedicine in the management of diabetic retinopathy.

Although hyperglycemia has been shown to contribute to the pathogenesis of diabetic retinopathy, the exact pathway through which it causes damage to the retinal blood vessels is not known. Many clinical trials based on the positive results focusing on these biochemical pathways in animal models have proved to be failures. No doubt inflammation plays a major role in initiating the inflammatory cascade with eventual release of cytokines including VEGF and alteration of the blood-retinal barrier.2 Coucha et al. in this issue has summarized the biochemical pathways responsible for pathogenesis of diabetic retinopathy, and nicely described the potential future therapeutic targets based on the basic science results.3 In the diagnosis of diabetic retinopathy, the clinical examination is still the gold standard method, but the OCT is a reliable, highly reproducible tool in measuring the outcomes of treatment with laser and anti-VEGF drugs. Salz and Witkin discusses the importance of this diagnostic modality as well as other modalities in following-up patients receiving a series of intravitreal pharmacotherapies.4

Many landmark clinical trials including Diabetes Control and Complications Trial, United Kingdom Prospective Diabetes Study, Epidemiology of Diabetes Intervention and Complications have shown the importance of tight blood glucose control in prevention and progression of diabetic retinopathy. However, the current results of the Action to Control Cardiovascular Risk in Diabetes study also pointed out that too tight control of blood glucose might be harmful with serious cardiovascular sequences.5 Frank, a pioneer clinician scientist, gives his insight into the role of systemic factors control in management of diabetic retinopathy.6 His analysis of the results of the clinical trials gives a new perspective to this controversial aspect of management of diabetic retinopathy.

With the advent of anti-VEGF and steroid therapies, DME patients are now being treated less and less with laser photocoagulation techniques. The Early Treatment Diabetic Retinopathy Study guidelines for management of DME have been vastly modified, and focal/grid laser has been indicated only in patients with noncenter-involving DME as well as a supplemental therapy in those poorly responding to the anti-VEGF therapies. However, panretinal laser photocoagulation (PRP) still remains the first-line of treatment in proliferative diabetic retinopathy (PDR), although a current clinical trial is comparing the efficacy of anti-VEGF injections with PRP laser in PDR patients.7 Adelman in this issue updates the current indication of laser therapy in management of diabetic retinopathy.8

Vascular endothelial growth factor remains to be a potent vas-permeability and angiogenic factor, and because of this dual effect VEGF has been targeted in DME as well as in PDR. At least for DME, the anti-VEGF drugs have been approved by the FDA and are being widely used as the first-line of treatment in center-involving DME. Two clinical observations can be pointed out here about anti-VEGF drugs in spite of their efficacy. First, the effect of anti-VEGF drugs is more robust in regression of new blood vessels (angiogenesis) in PDR patients compared to the effect in reducing vaso-permeability in DME patients. Second, it takes several anti-VEGF injections in DME patients for reduction of central retinal thickness, and also many patients respond poorly to these drugs. Dedania and Bakri have summarized the clinical trials involving pharmacotherapies in diabetic retinopathy, and also done an exhaustive review of the potential pharmacologic treatment modalities that target other molecules beyond VEGF.9

Given the alarming nature of the global epidemic of diabetic retinopathy, it becomes obvious that clinical examinations alone are unlikely to sustain the needs of clinical screening of this disease. Although telemedicine examinations cannot replace comprehensive eye examinations in management of diabetic retinopathy, they can help in immediate access to the underserved areas and can thus meet the demands of vast screening of diabetic retinopathy population.10 Das et al. emphasize this need in their review article on telemedicine, and how this inexpensive tool can be cost-effective in the health care costs for managing this epidemic.11

Over the last 5 decades, we have seen significant advances in the management of diabetic retinopathy. Large, randomized clinical trials have stressed the benefits of systemic factor control, laser therapy and novel pharmacotherapeutic approaches in the visual outcome of thousands of patients who are losing vision from this devastating disease. However, many questions remain unanswered. Is there a role of genetics in diabetic retinopathy? Why do some patients with long duration of diabetes have little retinopathy? Why does proliferative retinopathy develop in only about 50% patients with diabetic retinopathy? Are DME and PDR two different diseases as their responses to anti-VEGF drugs are so different? Still, a better understanding of the pathogenesis of diabetic retinopathy is needed to answer these questions. As diabetes becomes the fastest growing global epidemic, we all face a challenging question. Are we prepared enough to fight it?