Diabetic Retinopathy: Prevalence, Risk Factors and Early Detection

Diabetes Prevalence: United States

In the United States, estimates from 2015 indicate that more than 30 million people have diabetes, which is nearly 10% of the population. Of those, just over 23 million are diagnosed; more than 7 million, or nearly 24% of people with diabetes, are unaware they have diabetes, according to the Centers for Disease Control and Prevention (CDC).  These numbers include 193,000 children and adolescents younger than 20 years (0.24% of the total US population younger than age 20 years). ^1-4

Diabetes: Systemic Comorbidities

Diabetes is associated with a myriad of complications that require collaborative several medical specialties and subspecialties. The CDC estimates that patients with diabetes also have:

Ocular Complications of Diabetes

As mentioned, 28.5% of adults with diabetes age 40 and older have DR, which is caused by ongoing damage to the small blood vessels of the retina.  Patients with diabetes are also at higher risk for additional ocular complications. Compared with individuals without diabetes, patients with diabetes have a 60% higher risk of developing cataracts and a 40% increased risk of developing glaucoma. ^7-10

DR Prevalence and Predictions: Global

Worldwide, there were 145 million people with DR in 2015, with roughly one-third of those with severe vision loss, according to the International Diabetes Federation. By 2040, those numbers expected to rise to 224 million people with some form of DR and 70 million with vision-threatening DR.¹¹

Risk Factors

DR is the leading cause of vision loss in adults 20 to 74 years of age. The most common risk factors include duration of diabetes, poor control of diabetes, hypertension, nephropathy, obesity and hyperlipidemia, smoking, and pregnancy. Early detection and treatment are necessary to forestall vision loss from DR. A working group of ophthalmic and diabetes experts developed a consensus on the key principles of an effective DR screening program, which are based on analysis of a structured literature review. The recommendations for implementing an effective DR screening program are: (1) Examination methods must be suitable for the screening region, and DR classification/grading systems must be systematic and uniformly applied. Two-field retinal imaging is sufficient for DR screening and is preferable to seven-field imaging, and referable DR should be well defined and reliably identifiable by qualified screening staff; (2) in many countries/regions, screening can and should take place outside the ophthalmology clinic; (3) screening staff should be accredited and show evidence of ongoing training; (4) screening programs should adhere to relevant national quality assurance standards; (5) studies that use uniform definitions of risk to determine optimum risk-based screening intervals are required; (6) technology infrastructure should be in place to ensure high-quality images can be stored securely to protect patient information; (7) although screening for DME in conjunction with DR evaluations may have merit, there is currently insufficient evidence to support implementation of programs solely for DME screening. The working group concluded that utilization of these recommendations may yield more effective DR screening programs that reduce the risk of vision loss worldwide. ^9,12,13

Telemedicine

Telemedicine: Before and After the Pandemic Even before the 2020 COVID-19 pandemic began, fewer than one-third of patients returned for DR screening at least every 15 months. This was for a variety of reasons, but transportation issues were the most reported. In addition, after adjusting for demographics, those living more than 8 miles from the eye care facility were less likely to be compliant, according to a study by Lee and colleagues. Before social distancing mandates, 74% of patients were unaware of a telemedicine option in their physicians' practices. The COVID-19 pandemic has transformed this scenario, such that some leading telehealth platforms now report virtual patient visits have increased between 257% and 700%, according to the results of a 2020 study. The paper by Saleem and colleagues indicate that recent patient and provider interest in telemedicine, the relaxation of regulatory restrictions, increased remote care reimbursement, and ongoing social distancing practices related to the COVID-19 pandemic compel many ophthalmologists to consider virtualizing services. Telemedicine can be especially useful for patient discussions.^14-15

Telemedicine can be helpful for those patients most at risk for DR progression.  The American telemedicine Association recognizes four categories of telescreening:   1. The system that identifies none or or very mild NPDR2. The system that identifies patients with and without sight-threatening DR3. The system that identifies NPDR, PDR, and macular edema with sufficient accuracy for appropriate decision making4. The system that equals or exceeds the ability of ETDRS photographs to identify DR lesions   From a retina perspective, there is only one at-home monitoring system with imaging that is currently approved for use in the United States. It is intended to monitor patients with intermediate dry age-related macular degeneration (AMD) to determine if they progress to wet AMD.¹⁶

Duration of Diabetes = Highest Risk

Duration of disease is one of the greatest risk factors for the development of retinopathy. If a patient is diagnosed with diabetes at a young age, the longer the duration of disease, which means the patient is more likely to suffer complications. Epidemiological data from two major studies categorized by the duration of disease.  The graphs show the prevalence of DR by duration of type 1 diabetes and age at examination in the Wisconsin Diabetes Registry Study (1990–2002) and the Wisconsin Epidemiologic Study of Diabetic Retinopathy (1979–1980). Duration groups: 3 to 7 years (7- or 4-year examination), 8 to 11 years (9-year examination), and 12 to 15 years (14-year examination). T-shaped bars show 95% confidence intervals. The number of individuals in each age and duration group is noted above the bar. The percent of people with DR dramatically goes up after having the disease for 12 to 15 years compared with a duration of 3 to 7 years. If a patient is diagnosed at age 5, and he or she has the disease for 15 years, the chance of that patient having some retinopathy is roughly 90%.¹⁷

Disease Duration Plus Elevated A1c

As with type 1 diabetes, the Australian Diabetes, Obesity, and Lifestyle Study also demonstrated a relationship between disease duration, glycosylated hemoglobin (A1c) levels, and increasing DR prevalence in type 2 diabetes. At all levels of glycemic control, the likelihood of DR increased with duration of disease. Census identified national diabetes prevalence of 7%, and this survey included 11,247 adults age 25 and older from all over Australia. A total of 2,476 participants with diabetic complications and control group were included, and after exclusion of participants who were unable to be photographed or whose photographs were not gradable, data were available for 2,177 participants. Patients with type 1 diabetes were excluded from this analysis. The prevalence of DR in those with known type 2 diabetes versus those with newly diagnosed type 2 diabetes was 21.9% versus 6.2%, respectively. A similar relationship was shown for duration of diabetes, systemic blood pressure, and increasing DR prevalence in patients with type 2 diabetes.^18-20

Case 1

Widefield color fundus photography of this patient reveals evidence of numerous intraretinal hemorrhages/microaneurysms bilaterally without any signs of DME. Consistent with diagnosis of moderately severe NPDR (ETDRS-DRSS: 47)  

Widefield fluorescein angiography demonstrates numerous microaneurysms and midperipheral areas of vascular pruning and assocated intraretinal microvascular abnormalities (IRMA). There is some evidence of late angiographic perivascular leakage, but no frank neovascularization of the disc or elsewhere in either eye. Additionally, there is no angiographic leakage in the macula, further reinforcing this is a case of NPDR without DME.

OCT imaging confirms a preserved foveal contour without center-involving DME in either eye.

Prevention & Improvement

Prevention of Retinopathy Progression is Possible PDR may be classified as high-risk and nonhigh-risk. The hallmark of PDR is neovascularization, which occurs at the latter stages of the disease and can result in blindness; neovascularization is the consequence of abnormal fibrovascular proliferations with subsequent bleeding and retinal detachment.

• According to the Diabetic Retinopathy Study Research Group, high-risk PDR was defined as any one of the following:

• High-risk PDR was also defined as three or more of the following high-risk characteristics:

Patients in the study who had DME (n=759) were randomized to monthly sham, 0.3-mg ranibizumab, or 0.5-mg ranibizumab intravitreal injections. Macular laser was available per prespecified criteria. Fundus photographs, taken at baseline and periodically, were graded by a central reading center, and clinical examinations were performed monthly. The main outcome measures of this report were secondary/exploratory analyses including a 2-step or more and 3-step or more change on the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Score (DRSS) in the study eye and a composite DR progression outcome, including photographic changes plus clinically important events such as occurrence of vitreous hemorrhage, or need for panretinal laser. At 2 years, the percentage of participants with DR worsening by 2 or 3 steps was significantly reduced in ranibizumab-treated eyes compared with sham-treated eyes, and regression of DR by 2 or 3 steps was significantly more likely. The cumulative probability of clinical progression of DR as measured by the composite outcome at 2 years was 33.8% of sham-treated eyes compared with 11.2% to 11.5% of ranibizumab-treated eyes.^21-23

VIVID/VISTA: Improvement in DR Scores

Protocol T: 2-Year Results The DRCR.net Protocol T study was the first trial to compare the efficacy and safety of the commercially available anti-VEGF drugs used to treat DME. During the study, patients were randomized to receive 2.0 mg aflibercept, 1.25 mg bevacizumab or 0.3 mg ranibizumab up to every 4 weeks through 2 years following a retreatment protocol. A total of 650 participants were analyzed. Of those, 495 had nonproliferative DR (NPDR) and 155 had proliferative DR (PDR). The figure shows the percentage with improvement of retinopathy at 1 and 2 years by baseline DR status.  Part A in the figure shows NPDR at baseline. The respective levels of significance for the pairwise comparisons at the 1-year and 2-year visits were aflibercept vs bevacizumab, P = .004 and P = .85; aflibercept vs ranibizumab, P = .51 and P = .85; and ranibizumab vs bevacizumab, P = .01 and P = .85. Part B in the figure shows PDR at baseline. The respective levels of significance for the pairwise comparisons at the 1-year and 2-year visits were aflibercept vs bevacizumab, P < .001 and P = .01; aflibercept vs ranibizumab, P = .02 and P = .06; and ranibizumab vs bevacizumab, P = .09 and P = .73.

According to the study results, at 1 year, among 423 NPDR eyes, 44 of 141 treated with aflibercept, 29 of 131 with bevacizumab, and 57 of 151 with ranibizumab had improvement of DR severity. At 2 years, 33 eyes in the aflibercept group, 25 eyes in the bevacizumab group, and 40 eyes in the ranibizumab group had DR improvement; no treatment group differences were identified. For 93 eyes with PDR at baseline, 1-year improvement rates were 75.9% for aflibercept, 31.4% for bevacizumab, and 55.2% for ranibizumab. These rates and treatment group differences appeared to be maintained at 2 years.²⁵

Case 2

Anti-VEGF Improved DR Severity at All Stages

More recently, Wykoff and colleagues published a posthoc analysis of the phase 3 RIDE and RISE trials, with two-step or more or 3-step or more improvement or worsening on the ETDRS DRSS and time to new proliferative event (composite end point) as the primary endpoint. DR outcomes were assessed through month 36 by baseline DR severity level. At baseline, most patients were distributed evenly among mild or moderate nonproliferative DR (NPDR; ETDRS DRSS, 35/43), moderately severe or severe NPDR (ETDRS DRSS, 47/53), and proliferative DR (ETDRS DRSS, 60-75; 28.8%, 33.2%, and 31.1%, respectively).²⁶

At month 24, rates of 2-step or more improvement with ranibizumab 0.3 mg, ranibizumab 0.5 mg, and sham treatment were highest among patients with baseline DR levels 47/53 (78.4%, 81.1%, and 11.6%, respectively) compared with patients with baseline DR levels 35/43 (10.3%, 15.8%, and 1.4%, respectively) or 60 through 75 without panretinal photocoagulation (31.0%, 36.4%, and 6.7%, respectively; all ranibizumab vs. sham comparisons, P <  .05). In patients with baseline DR levels 47/53, ranibizumab treatment reduced the probability of patients experiencing a new proliferative event at month 36 by 3 times compared with sham treatment (12.4% and 11.9% vs. 35.2% for ranibizumab 0.3 mg, ranibizumab 0.5 mg, and sham, respectively). In patients with baseline DR levels 47/53 who achieved 2-step or more DR improvement, improvements were independent of all assessed baseline characteristics (P > .4). The figure shows that after 12 months of treatment, the DRSS level improved from level 53 to level 35, which is essentially a 3-step improvement.²⁶

Case 3

December 4, 2019

OCT shows center-involving DME with an ERM.

Key Considerations:

After 1 year: Better NPDR, ~1 line of vision gain   Key Considerations: 

The Sweet Spot

Anti-VEGFs appear to work best for patients in the moderate to severe NPDR stage. This falls to the 4-2-1 rule on clinical examination: four quadrants of hemorrhage or one quadrant of intraretinal microvascular abnormalities (IRMA), or two quadrants of venous beading. Therefore, Wykoff and colleagues concluded that ranibizumab treatment resulted in DR improvements in all three baseline DR severity subsets examined. The greatest benefits in DR improvement occurred in patients with baseline moderately severe to severe NPDR (DR levels 47/53). DR improvements were rapid, clinically meaningful, and sustained through month 36.²⁷

Clinical Questions: 1. Can early treatment of DR with anti-VEGF agents prevent progression to vision-threating DR?   2.. What is the window of maximum efficacy for treating DR with anti-VEGF agents?

PANORAMA: NPDR without DME

Case 4

Widefield color fundus photography of this patient reveals evidence of scattered intraretinal hemorrhages/microaneurysms bilaterally, along with scattered hard exudates in the macula, but did not have commensurate swelling to suggest DME. Consistent with diagnosis of moderate NPDR (ETDRS-DRSS: 43)

Widefield fluorescein angiography demonstrates numerous microaneurysms and midperipheral areas of vascular pruning and associated intraretinal microvascular abnormalities (IRMA). There is some evidence of late angiographic perivascular leakage, but no frank neovascularization of the disc or elsewhere in either eye. Additionally, there is no significant angiographic leakage in the macula, further reinforcing this is a case of NPDR without DME.

OCT imaging confirms a preserved foveal contour without center-involving DME in either eye (right eye does show exudates in the superior macula, while left eye shows exudates in superotemporal macula)  

Conclusions

PANORAMA: NPDR without DME From a practical perspective, by improving the DRSS score, there is a dramatic slowing of disease progression.

The figure shows that by not treating patients, there is a 58% chance of developing either PDR or center-involved DME. This can be reduced by nearly 80% with aflibercept injections every 4 months or by 75% with injections every 2 months.  These eyes still have an approximately 20% risk of progression.²⁸Case Study: Ranibizumab Improves VA

SUMMARY DME is a serious problem.  Most eye care providers are familiar with the high-risk NPDR stage without DME and the potential improvements to be gained from earlier therapy with anti-VEGFs.  However, not all NPDR patients need treatment and they can be monitored carefully. It is important to ensure these patients do not have PDR – many patients do have PDR that is only visible with angiography – and if they are in the NPDR high-risk, the conversation with the patient must begin earlier to they are ready for the treatment if the progression occurs.  

References

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