Diabetic Retinopathy: Halting and Reversing Progression
The first of three parts
STEPHEN J. SMITH, MD • MARGARET A. GREVEN, MD • PRITHVI MRUTHYUNJAYA, MD, MHS
Diabetic retinopathy, a microangiopathy secondary to the chronic effects of diabetes, is the leading cause of blindness among individuals between the ages of 25 and 74 years old in the industrialized world.
The costs of diabetic vision loss to patients and society are well documented,1 and the growing prevalence of diabetes in the developing world has led to an increased awareness such that DR is now a global health issue. Strategies to reduce the global burden of vision loss secondary to diabetes are critical if we are to meet the growing demand for eye care.
The anatomic signs of DR include loss of pericytes, capillary basement membrane thickening, microaneurysms, capillary acellularity, and breakdown of the blood-retina barrier. Multiple biochemical mechanisms and theories have been implicated, including the aldose reductase theory, the reactive oxygen intermediates theory, the advanced glycation end product theory, and more.
The cause of progression is not fully understood, but glucose levels, blood pressure, and lipid levels are known to play roles in the pathologic process. It has been postulated that capillary nonperfusion is a primary contributor to DR progression in patients with more advanced DR at baseline, indicating that VEGF is a primary contributor to the pathologic process.2
While numerous other factors, including insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), angiopoietin, and more, contribute, their roles have not been fully elucidated.
Various methods to assess DR progression and treatment response have been utilized in major clinical trials (Table). It is worth noting that some measures focus on structural assessment of progression, including the Diabetic Retinopathy Severity Score (DRSS), while others consider severity of DR (nonproliferative DR [NPDR] vs proliferative DR), and still others assess indirect measures that may be surrogates for DR progression, including changes in best-corrected visual acuity and structural changes as assessed by optical coherence tomography.
|DCCT3||≥3-step sustained retinopathy progression assessed by stereoscopic photos utilizing a modified Airlie House scale||Macular edema||Severe NPDR or PDR||Need for laser treatment|
|UKPDS4||Worsening of retinopathy assessed based on a modified Airlie House scale||Need for photocoagulation||Occurrence of vitreous hemorrhage||Worsening visual acuity|
|ACCORD5,6||ETDRS DRSS assessed by color fundus photography of seven standard stereoscopic fields at baseline and year 4||ETDRS DME severity scale changes||ETDRS BCVA||Need for intervention (laser, vitrectomy)|
|ETDRS7||Rate of moderate vision loss (decrease of three lines or more on a logarithmic visual acuity chart). Results were assessed to take into account presenting severity of DR.||Photographs and angiograms were used to assess macular edema and retinopathy level|
|DRS8||DR severity as assessed by color fundus photography of seven standard stereoscopic fields||BCVA||Occurrence of severe vision loss (<5/200)|
Published data have shown that there are several approaches for slowing or reversing DR progression, including intensive glycemic control, laser photocoagulation, surgical or medical vitreolysis, anti-VEGF therapy, and local corticosteroid delivery.
This article will briefly summarize some of the published data regarding intensive glycemic control, laser photocoagulation, and surgical and medical vitreolysis for DR. Part 2 of this series will focus on changes in DR progression induced by local anti-VEGF and steroid. Part 3 of this series will explore the clinical relevance of the treatment response seen with intravitreal anti-VEGF therapy, with additional discussion devoted to the economic impact of anti-VEGF therapy
Stephen J. Smith, MD, Margaret A. Greven, MD, and Prithvi Mruthyunjaya, MD, MHS, serve on the faculty of the Byers Eye Institute of the Stanford University School of Medicine in Palo Alto, CA. None of the authors reports any financial interests in products mentioned here. Dr. Mruthyunjaya can be reached via e-mail at email@example.com.
There is no longer any doubt that intensive glycemic control is crucial to slowing the progression of DR. The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Project (UKPDS) definitively showed the importance of tight glycemic control in the reduction of microvascular complications in type 1 and type 2 diabetes, respectively.3,9
Of perhaps greater importance, the protective effect of decreased A1C has been seen in long-term follow-up studies of DCCT and UKPDS patients, despite normalization of A1C between intensively treated and conventional treatment groups in these studies.4,10
For patients enrolled in DCCT, the Epidemiology of Diabetes Interventions and Complications (EDIC) study showed a 50% risk reduction of further retinopathy progression in the intensive glycemic control group despite rapid normalization of hemoglobin A1C to 8 after DCCT study completion.10
ACCORD and ACCORDION
In 2016, the Action to Control Cardiovascular Risk in Diabetes Follow-on (ACCORDION) research group released long-term follow-up from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study cohort.11
This study compared four-year outcomes of the patients with type 2 diabetes formerly assigned to the intensive blood glucose management group compared to the standard therapy group. The intensive glycemic control group had a mean A1C of 6.4% during the trial, while the standard therapy group maintained a mean A1C of 7.5% for the 3.5 year study.
Despite normalization of A1C between groups following study completion, only 5.8% of the patients in the intensive therapy group had a three-step Early Treatment Diabetic Retinopathy Study (ETDRS) scale worsening, compared to 12.7% for the standard therapy cohort. This represents a greater than 50% reduction in three-step DR progression despite normalization of A1C between the two cohorts.
The reason for the “metabolic memory” in intensively treated patients remains speculative. Recent evidence suggests that it may have to do with biochemical pathways involving advanced glycation endproducts and oxidative stress altering genes and proteins involved in the pathogenesis of diabetic retinopathy.12
Regardless of the mechanism, the protective effect of even a comparatively short period of intensive glycemic control is of great value to our patients and emphasizes the importance of patient counseling related to systemic management of diabetes.
The ACCORD trial also investigated the effects of lipid and blood pressure control on DR progression. This arm of the study was carried out in the patients randomized to standard glycemic control. Patients receiving fenofibrate demonstrated a reduction in DR progression, although this was only noted in patients with DR at baseline, not in patients with no DR at study initiation.
These findings were in keeping with the results of the effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD) study, suggesting that lipid control can reduce the rates of the ≥2 step DR progression in patients with pre-existing DR.13
While intensive glycemic control is undoubtedly of utmost importance, the ACCORD study was stopped early due to a higher rate of all cause mortality in patients receiving intensive therapy. In this cohort, cardiovascular disease (CVD) was the primary contributor to all-cause mortality, a result that was not found in the DCCT or UKPDS cohorts.14
The reasons for this discrepancy are not entirely clear, although it has been postulated that increased baseline CVD in patients in the ACCORD cohort combined with higher rates of three- to five-agent therapy in the ACCORD patients may have contributed. Based on the results of the DCCT, UKPDS, and ACCORD studies, it seems prudent to advocate for an A1C less than 7%, with avoidance of polypharmacy when possible.14 To achieve these goals, advances in diabetic management are needed.
There is hope that continuous glucose monitoring, the addition of newer antiglycemic agents, and an increased awareness of the importance of lipid control may help our patients achieve better systemic diabetes control, thus reducing the occurrence of DR progression.
For several decades, laser photocoagulation served as the standard of care for the management of both NPDR and PDR. The pivotal ETDRS demonstrated a 50% reduction in moderate vision loss in patients with clinically significant diabetic macular edema (CSDME) undergoing immediate focal laser photocoagulation.7 Combined immediate focal laser and scatter panretinal photocoagulation reduced severe vision loss by 50% in patients with severe NPDR or early PDR and macular edema.
The exact mechanism by which focal/grid laser exerts its treatment benefit is not entirely clear. However, it is known that focal laser frequently results in an incomplete treatment response, with failure to restore normal vision or completely resolve macular fluid in many cases. Part 2 of this series will discuss comparisons of focal laser, anti-VEGF, and steroid.
In light of these limitations, there has been recent interest in the role of subthreshold micropulse diode laser treatment for DME. Data from a recent meta-analysis of this technique suggested that subthreshold laser resulted in marginally better visual acuity, gains compared to conventional focal laser.15 However, the clinical relevance of these findings is still not entirely clear.
The Diabetic Retinopathy Study (DRS) conclusively demonstrated that PRP reduces the rate of severe vision loss in patients with PDR, particularly in patients with high risk PDR.8,16 PRP continues to be the standard of care for the management of PDR, although there is recent evidence that anti-VEGF therapy may offer similar efficacy albeit at a higher cost.17
Compared to anti-VEGF therapy, PRP has the distinct advantage of reduced treatment frequency, with many patients requiring only a single laser treatment. This is of great importance for patients with PDR, who are frequently lost to follow up. Data from upcoming clinical trials will help to clarify the role of PRP moving forward, but it remains the standard of care at this time.
In summary, focal/grid laser reduces moderate vision loss in patients with CSDME, although often with an incomplete treatment response. For this reason, focal laser has been supplanted by anti-VEGF for most patients with DME.
The role of subthreshold laser is an area of active research, but its role as primary or adjuvant therapy is not fully understood at present. PRP slows the progression of PDR and reduces the occurrence of severe vision loss in these patients. PRP remains the standard of care for patients with PDR, although anti-VEGF may play a larger role in the treatment of PDR moving forward.
Macular edema in diabetic patients can occur secondary to traction exerted by the posterior hyaloid face or epiretinal membrane, even in the absence of overt microvascular leakage on fluorescein angiography.
For patients with NPDR, mechanical forces may contribute to the pathology seen, while in PDR, the posterior hyaloid face plays a larger role in the pathology of disease progression. Studies have shown that the presence of a posterior vitreous detachment can reduce the occurrence of PDR, likely in part due to the lack of scaffold on which NV can grow into the vitreous.
Surgical therapy is the mainstay for tractional retinal detachment, but there has been longstanding interest in the role of vitrectomy to treat earlier-stage pathology, including DME. The DRCRnet prospectively investigated vitrectomy with or without ERM and internal limiting membrane peeling in a cohort of 87 patients with VMT and DME.18
Patients with NPDR and PDR were included in this cohort, and while VA gains of ≥10 letters were seen in just under 40% of patients, there was also a comparatively high rate of complications, including vitreous hemorrhage, RD, and endophthalmitis.
This study was conducted before small-gauge vitrectomy was the standard of care, making it more difficult to generalize these results. Prospective, randomized studies utilizing modern small-gauge vitrectomy systems are needed to examine the potential role of vitrectomy to slow DR progression and manage DME.
With the FDA approval of ocriplasmin (Jetrea, ThromboGenics, Iselin, NJ), there has been renewed interest in the role of early vitreolysis to slow or halt the progression of NPDR to PDR. A multicenter trial investigating pharmacologic PVD in diabetes is reportedly under way, although results have not yet been published.19 While intriguing, data are needed before any conclusions can be drawn regarding the potential role of ocriplasmin in slowing DR progression.
SUMMARY AND FUTURE DIRECTIONS
In summary, the single most important factor for slowing DR progression remains aggressive blood glucose control, with a target A1C of less than 7%. Continuing to educate our patients on the importance of blood glucose, blood pressure, and lipid control will not only improve their chances of preserving useful vision, but it will also decrease their risk of devastating systemic complications, including kidney failure and peripheral vascular disease.
For several decades, laser photocoagulation served as the primary treatment option for patients with NPDR and PDR. PRP induces regression of neovascularization, primarily through reduction of VEGF levels in eyes with extensive ischemic changes, and continues to be the standard of care for the treatment of PDR.
Additional therapies, including pharmacologic vitreolysis and subthreshold laser, may offer additional advantages, either as stand-alone treatments or adjuvant therapies. RP
1. Shea AM, Curtis LH, Hammill BG, et al. Resource use and costs associated with diabetic macular edema in elderly persons. Arch Ophthalmol. 2008;126:1748-1754.
2. Ip MS, Domalpally A, Sun JK, et al. Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for worsening retinopathy. Ophthalmology. 2015;122:367-374.
3. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-986.
4. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-1589.
5. Chew EY, Davis MD, Danis RP, et al. The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study. Ophthalmology. 2014;121:2443-2451.
6. ACCORD Study Group, ACCORD Eye Study Group; Chew EY, Ambrosius WT, Davis MD, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010;363:233-244.
7. 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.
8. Preliminary report on effects of photocoagulation therapy. The Diabetic Retinopathy Study Research Group. Am J Ophthamol. 1976;81:383-396
9. Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. Ophthalmology 1995;102:647-661.
10. Nathan DM, Bayless M, Cleary P, et al. Diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: advances and contributions. Diabetes. 2013;62:3976-3986.
11. Action to Control Cardiovascular Risk in Diabetes Follow-On Eye Study G and the Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION) Study Group. Persistent effects of intensive glycemic control on retinopathy in type 2 diabetes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) follow-on study. Diabetes Care. 2016;39:1089-1100.
12. Cooper ME. Metabolic memory: implications for diabetic vascular complications. Pediatr Diabetes. 2009;10:343-346.
13. Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet. 2007;370:1687-1697.
14. Ferris FL 3rd, Nathan DM. Preventing Diabetic Retinopathy Progression. Ophthalmology. 2016;123:1840-1842.
15. Chen G, Tzekov R, Li W, et al. Subthreshold micropulse diode laser versus conventional laser photocoagulation for diabetic macular edema. Retina. 2016 Apr 18. [Epub ahead of print]
16. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings. Ophthalmology. 1978;85:82-106
17. Lin J, Chang JS, Smiddy WE. Cost evaluation of panretinal photocoagulation versus intravitreal ranibizumab for proliferative diabetic retinopathy. Ophthalmology. 2016;123:1912-1918.
18. Diabetic Retinopathy Clinical Research Network Writing Committee; Haller JA, Qin H, Apte RS, et al. Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology. 2010;117:1087-1093.
19. Khoshnevis M, Sebag J. Pharmacologic vitreolysis with ocriplasmin: Rationale for use and therapeutic potential in vitreo-retinal disorders. BioDrugs. 2015;29:103-112.