Advancing Insights Into Diabetic Eye Disease: 5th Annual American Society of Retina Specialists Presidents’ Young Investigator Award Lecture

Introduction

The prevalence of diabetes mellitus (DM) has been increasing worldwide and continues to grow in numbers and significance. The increasingly high diabetes disease burden has been fueled by the global rise in the prevalence of obesity and unhealthy lifestyles. The latest estimates show a global prevalence of 382 million patients in 2013 and is expected to rise to 592 million by 2035. ¹ As of 2015, 30.2 million people in the United States, (9.4% of the population) had diabetes. Of this number, 7.2 million (23.8%) were unaware of having or did not report having diabetes.

Diabetic retinopathy (DR) is one of the leading causes of adult vision loss in the developed world, and hyperglycemia is the triggering factor for tissue alterations such as damage to capillary endothelial cells in the retina and blood-retinal barrier breakdown. ^2,3 The prevalence of DR in the US diabetic population is estimated to be approximately 35%. ⁴ In particular, diabetic macular edema (DME) is the most common cause of vision loss in diabetic patients and is present in 20% of individuals with younger-onset DM vs approximately 40% in older-onset DM. ^2,3

Since vision changes can be irreversible in DR, early detection and treatment are important to prevent vision loss from DR. Once DR is detected, surgical and medical interventions including photocoagulation, vitrectomy, and intravitreal drug injection can help preserve vision. However, the need for better detection methods and therapies that will allow earlier diagnosis and treatment remains apparent.

The Young Investigator Award recognizes an ASRS member age 45 or younger who has made substantial contributions to the field of retina that will potentially improve the lives of patients. The ASRS Presidents’ Young Investigator Award is given by the Foundation of the ASRS to honor past presidents of our Society by nurturing the development of next-generation retina leaders.

This overview summarize many of the research topics over the past year covering the current concepts of DR, including disease pathogenesis, diagnosis, and improving treatment outcomes.

New Imaging Modalities in DR

Before the introduction of optical coherence tomography (OCT) in clinical practice, the diagnosis and management of diabetic retinal disease was limited to ophthalmoscopy, fundus color photos, fluorescein angiography, and the examination of pathological specimens from enucleated eyes. In addition, advancements in OCT and OCT angiography have revolutionized the detection and diagnosis of DR. OCT angiography has allowed for noninvasive, rapid in vivo imaging of detailed microvasculature at distinct depths.

Recently, the emphasis on the pathogenesis of DR has expanded from focusing strictly on changes in the retinal vasculature that cause ischemia and macular edema (ME) to focusing on changes in the choroid. Studies have revealed histopathological vascular changes in the choroid of enucleated diabetic eyes, including neovascularization, capillary narrowing, and atrophy. ^5,6 Now, with improvements in image acquisition, better choroidal evaluation is possible in vivo. Vessel density changes and capillary perfusion density (CPD) have been reported in pathological specimens of the choroid in DR patients. ^7,8

To further examine when these pathological changes occur in the choroid and see how they correlate with retinopathy, Conti et al, in a retrospective study of 136 eyes, assessed choriocapillaris and retinal perfusion density changes in diabetic eyes in vivo. ⁹ Eyes with nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) presented significantly decreased choriocapillaris CPD compared with nondiabetic controls and patients with DM.

Choriocapillaris whole-image CPD was decreased by 8.3% (P < .001) in NPDR patients, and 7.1% in eyes with PDR (P = .005) compared with both sets of controls. Only eyes with PDR showed significantly decreased retinal whole-image, foveal, and parafoveal CPD. Additionally, they found a significant increase in foveal avascular zone (FAZ) area in eyes with PDR (increased by 50.9%; P = .001) compared with controls. Finally, eyes without DR showed a 3% decrease in choriocapillaris thickness (CT).

In summary, patients with NPDR and PDR manifest a decreased CPD in comparison with control patients. Capillary density reflects vascular integrity and may be useful as a measure to evaluate and monitor the evolution of diabetic retinal disease. Changes in choroidal capillary perfusion also might theoretically explain another reason why diabetic patients develop nonperfusion and ischemia and thus may indicate that the outer retina contributes to the pathogenesis of advanced DR.

DR and Blood Glucose Control

Intensive metabolic regulation remains a highly effective means of controlling retinopathy and other diabetes-related complications in diabetic patients. Several studies have been developed for evaluating the effects of different strategies for managing blood glucose and microvascular diabetes complications. ^{10 -12} However, intensive treatment of diabetes has consistently resulted in an initial and transient worsening of retinopathy. The first study to identify this finding was the Diabetes Control and Complications Trial. The intensive control group developed a statistically significantly higher level of retinopathy progression over the first 2 years of the study. ¹³ More recently, Feldman-Billard and colleagues in a meta-analysis reviewed the frequency, importance of, and risk factors for early worsening of diabetic retinopathy (EWDR) after dramatic decreases of serum hemoglobin A_1c values (HbA_1c) in all published studies between 1980 and 2017. ¹⁴ They described that EWDR arises within 3-6 months in approximately 10% to 20% of patients after rapid improvement of blood glucose with continuous subcutaneous insulin infusion, introduction of insulin in uncontrolled diabetes patients, or bariatric surgery.

The mechanisms behind this outcome have still not been completely elucidated. Previous studies have shown that high growth hormone and IGF-1 levels are associated with an increased prevalence and severity of DR. ^15,16 When initiating insulin and during pregnancy, the IGF-1 bioavailability increases, which can play an important role in the onset and progression of DR. However, growth hormone antagonists have not been studied in the specific context of EWDR following improved metabolic control. Another hypothesis concerns the effect of VEGF on EWDR.

High glucose ¹⁷ and insulin ¹⁸ have been said to stimulate VEGF production by vascular cells. However, more recently it has been shown that hypoxia-induced VEGF expression is impaired in diabetic tissues, rendering the link between diabetes and VEGF not as clear as it may have seemed. ¹⁹ However, it can be speculated that, in the ischemic retina, expression of VEGF is blunted as long as glucose concentrations are high, but will increase after normalization of glucose concentrations.

Intensive blood glucose control has been shown to improve glycemic control and cardiovascular risk when used specifically to treat diabetes. ^10,20 Bariatric surgery has also been shown to potentially reduce microvascular outcomes in these patient populations following surgery. Johnson et al in a retrospective cohort study compared microvascular outcomes in 2580 patients undergoing bariatric surgery and 13 371 controls who met the same inclusion criteria but did not have bariatric surgery.

Microvascular outcomes were defined as a new diagnosis of blindness in at least 1 eye, laser eye or retinal surgery, nontraumatic amputation, or creation of permanent arteriovenous access for dialysis. Surgery was associated with a significant reduction in microvascular events (adjusted hazard ratio 0.22, 95% CI 0.09 to 0.49). ²¹ Kashyap and colleagues showed a significant decrease in the urinary albumin-to-creatinine ratio from baseline at 5 years’ follow-up in the bariatric group compared with the medical therapy group (P < .001). ²²

To answer whether bariatric surgery patients experienced EWDR and/or exhibited improved retinopathy after 5 years, Schauer et al, in a nonblinded, single-center trial, randomized 150 diabetic, obese patients. These patients were divided into 3 groups consisting of intensive medical therapy alone, intensive medical therapy plus gastric bypass, and medical therapy plus sleeve gastrectomy. ²³ In the study with 5 years follow-up, bariatric surgery was superior to intensive medical therapy in terms of glycemic control, weight reduction, medication reduction, improvement in lipid levels, and quality of life. After surgery, there was a more rapid, larger, and more sustained reduction in HbA_1c and body mass index. The decrease was more dramatic in the first 3 months, with a net reduction of nearly 3% at 12 months and with persistent effects of 2.5% at 36 months.

In our analysis to determine whether EWDR was seen in patients following bariatric surgery, we found no transient worsening of retinopathy after surgical treatments for diabetes and, despite the significant reduction in HbA_1c, 86.5% of patients in all treatments groups had no change in retinopathy step progression. ²⁴ Bariatric surgery did not appear to change retinopathy outcomes at 2 years in comparison with medical management (P = .84).

Visual acuity (VA) also did not show significant change from baseline between groups (mean baseline and 2-year VA were the same in all 3 groups; P > .05). In addition, during the 5 years that ophthalmologic outcomes were assessed, no significant difference in retinopathy scores, incidence of ME, or step progression from baseline were observed between the 3 study groups (P > .05). ²³ In summary, although bariatric surgery resulted in large decreases in HbA_1c, there was no transient worsening of retinopathy nor significantly improved 2- and 5-year retinopathy outcomes.

Metabolic Factors in Treatment Outcomes With Anti-VEGF Therapy

Although historically DME and DR have been treated with laser photocoagulation and pars plana vitrectomy, advances in pharmacological therapies have recently demonstrated remarkable effectiveness in the treatment of ME and retinopathy. ²⁵ Intravitreal antivascular endothelial growth factor (anti-VEGF) agents have become the first-line treatment for patients with DME and certainly are considered equivalent to current therapies for DR. ^{26 -28} The 5-year results from the Diabetic Retinopathy Clinical Research Network’s Protocol S have shown that a low rate of severe vision loss or serious PDR complications were uncommon in the panretinal photocoagulation or ranibizumab group; however, the ranibizumab group had lower rates of developing vision-impairing DME and less visual-field loss. ²⁹

Some reports have suggested that abnormal values for metabolic factors related to severity of systemic diabetic disease potentially may affect the clinical response to anti-VEGF therapies. ^28,30 Matsuda et al assessed the critical role that systemic metabolic factors would have in the management of center-involving DME with anti-VEGF injections in a retrospective study of 124 patients. ³¹ Those patients with optimal DM control (≤7.0%) had a significant improvement in best-corrected visual acuity (BCVA) (20/66 to 20/43, P < .001). Central subfield thickness (CST) in this group showed a significant decrease (481.9 to 341.2, P < .001). The group with HbA_1c greater than 7.0% also had significant functional and anatomical improvement, but less robust reduction in CST. BCVA improved from 20/78 to 20/62 (P = .024), and CST decreased 83.3 μm (430.1 to 346.8, P < .001). Therefore in this limited study, glucose control may play an important role in the final outcomes of anti-VEGF therapy for DME. However, this relationship has conflicting findings based on the literature. Some analyses have shown no significant difference in BCVA gains or central foveal thickness reduction between patients with different HbA_1c levels. ³²

To study this further in larger prospective clinical studies, we conducted a post hoc analysis from the RISE and RIDE studies, which evaluated whether any baseline systemic or metabolic factors influenced BCVA improvement after anti-VEGF therapy with ranibizumab (Lucentis; Genentech, Inc) for DME treatment. ³³ Our analysis indicated there was no compelling evidence that nonocular factors such as glycemic control, blood chemistry, or renal function were associated with BCVA outcomes in response to ranibizumab. Similarly, we did not find evidence that BCVA outcomes differed according to class of antihyperglycemic medications being used for treatment of diabetes.

Similar findings from a post hoc analysis of VISTA and VIVID were reported by Dhoot et al when evaluating the systemic and local factors’ impact on DR outcomes. ³⁴ The authors evaluated whether baseline systemic and ocular factors influenced a 2 or more step improvement in diabetic retinopathy severity scale (DRSS) score after anti-VEGF. None of the baseline factors such as age, duration of diabetes, and HbA_1c values had been found to be related to treatment outcomes in these patients. Additionally, the analysis revealed a strong association between the baseline DRSS score and the 2 or more step DRSS score improvement from baseline at week 100 in the laser-treatment and intravitreal aflibercept injection-treated groups alike.

ME Following Cataract Surgery in Diabetic Patients

Cataract surgery is one of the most commonly performed surgical procedures in developed countries, and ME is a major cause of poor vision after uneventful cataract surgery and is especially seen in patients with diabetes. ^35,36 Patients with diabetes are at an increased risk of developing cataracts compared with those without diabetes, and the rising worldwide prevalence of diabetes further increases the risk for cataract development. With the advent of modern phacoemulsification techniques, the recently reported rates of postoperative ME are between 0.2% and 2.35%. ³⁷

Topical nonsteroidal anti-inflammatory drugs (NSAIDs) block cyclooxygenase (COX) enzymes responsible for prostaglandin. ^{38 -40} Some studies have shown that nepafenac (Alcon Research, Ltd), an NSAID, works to reduce and improve VA outcome after cataract surgery in eyes with DR. ^41,42 Nepafenac rapidly permeates into the cornea and sclera and is converted to its active metabolite, amfenac, primarily in the retina-choroid and the iris-ciliary body. Amfenac is a potent inhibitor of COX-1 and COX-2 that catalyzes the formation of pro-inflammatory prostaglandins. Both nepafenac and amfenac block the inflammation-mediated breakdown of the blood-retinal barrier that contributes to plasma extravasation and edema.

R.P.S. served as the study chair for 2 identical, phase 3, multicenter, vehicle-controlled, parallel-group studies that assessed the efficacy and safety of once-per-day nepafenac 0.3% ophthalmic suspension vs vehicle after cataract surgery. ⁴³ The study observed a significantly lower percentage of patients with ME within 90 days after surgery when treated with nepafenac vs vehicle (4.1% vs 15.9%; P < .001). In addition, the percentage of patients who maintained a day 90 improvement of 15 or more letters from baseline after achieving one through day 14 with nepafenac was 55.4% vs 46.7% (P = .003). Thus, NSAIDs are beneficial in improving visual outcomes and preventing ME in patients with a history of DR.

Future Challenges

Diabetic eye disease severely affects quality of life for patients with diabetes by decreasing VA and increasing the risk of blindness. The last few decades have established the importance of systemic risk factors in limiting the onset and progression of DR, and the role of anti-VEGF therapy has been clearly defined. Ultra-widefield retinal imaging has been shown to be an effective DR screening tool and has demonstrated potential in teleophthalmology screening programs, reducing screening and image evaluation time, increasing detection of pathology, and lowering the proportion of ungradable images. Artificial intelligence is being developed to make screening and early diagnosis even more efficient.

Anti-VEGF therapy has been shown to be highly effective in decreasing visual loss in eyes with center-involved DME. However, challeges remain, such as improving visual outcomes and decreasing the treatment burden associated with repeated intravitreal injections. In addition, not all eyes treated with anti-VEGF have resolution of DR or DME. ⁴⁴ Thus, there is an ongoing need to identify novel therapies that are effective for PDR and DME treatment that also avoid the potential adverse events or costs associated with current ocular interventions. Researchers have been exploring more continuous and more tightly controlled delivery systems of these agents ⁴⁵ and new agents that target alternate pathways and signaling molecules to provide patients additional therapeutic tools. ^46,47 Future improvements can potentially further reduce the risk of vision loss, support earlier disease detection, and lead to less-invasive treatments.