New Strategies for Managing Diabetic Retinopathy

Improving Referral Rates to Prevent the Onset of Proliferative Diabetic Retinopathy
Over 5 years, patients with severe nonproliferative diabetic retinopathy (NPDR) have a 75% to 81% chance of progressing to proliferative diabetic retinopathy (PDR).¹ In fact, a large 2021 retrospective analysis from the American Academy of Ophthalmology’s Intelligent Research in Sight (IRIS) Registry by Wykoff et al. showed that patients newly diagnosed with severe NPDR or PDR had a 3.6 and 4.0 times greater risk, respectively, for sustained blindness at 2 years than patients newly diagnosed with mild NPDR (Figure 1).² Thus, these findings indicate that patients who initially present with an advanced stage of diabetic retinopathy (DR)—either severe NPDR or PDR—are at a higher risk of sustained blindness, even with today’s effective treatment options.²

Figure 1. Risk of blindness with DR.² 

The results from the IRIS Registry analysis underscore the importance of detecting DR early to preserve vision and reduce the substantial risk for future blindness. Despite the many challenges that exist surrounding patient compliance, optometrists can play a vital role in educating patients on the importance of compliance with referrals, recommended appointments, and treatment.

Staging of Diabetic Retinopathy
Accurately classifying DR is necessary because the severity level drives the decisions that ensure timely referrals for potential treatment and vision preservation. A commonly used scale to assess the severity of DR is the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS). The DRSS employs a complex numbering system that is primarily used in clinical trials, and it may also be used clinically to classify the DR stage.

Moderate NPDR is characterized by the DRSS as findings that include intraretinal hemorrhaging, exudates, or cotton wool spots that are less extensive than moderately severe NPDR. Severe NPDR is characterized by the presence of pathology as generally stated in the “4-2-1” rule. The 4-2-1 rule is defined as any of the following without signs of PDR: severe intraretinal hemorrhages and microaneurysms in each of the 4 quadrants, definitive venous beading in 2 or more quadrants, and moderate intraretinal microvascular abnormalities (IRMA) in 1 or more quadrants.

Multimodal Imaging Is Key to Accurate Staging of Pathology
Identifying diabetic pathology is crucial to correctly classify the severity level of DR. However, accurate staging of DR can be clinically challenging, particularly in uncooperative patients or those with significant media opacities. Multimodal imaging technology, particularly wide-field and ultra-widefield fundus imaging, is an important diagnostic tool that can aid clinicians in efficiently and accurately identifying pathology. Additionally, this technology is valuable in detecting and documenting DR lesions not only in the posterior pole but also in the peripheral retina.

Peripheral Lesions on Ultra-Widefield Imaging Predict DR Progression
A 2015 study by Silva et al. evaluated predominantly peripheral lesions, defined as DR lesions located mostly outside the 7 standard ETDRS fields, for an association with increased DR progression in 200 eyes over 4 years.³ Notably, the study found that, independent of baseline DR severity and hemoglobin A1c (HbA1c) levels, eyes with predominantly peripheral lesions compared with eyes without predominantly peripheral lesions had a 3.2-fold increased risk of 2-step or more DR progression (34% vs 11% [P = 0.005]) and a 4.7-fold increased risk for progression to PDR (25% vs 6% [P = 0.005]).³ Also, eyes with an increasing extent of predominantly peripheral lesions had a markedly increased risk of 2-step or more DR progression (P = 0.004) and progression to PDR (P = 0.009), particularly in those with less severe DR at baseline.³ In summary, eyes with predominantly peripheral lesions had a nearly 5-fold increased risk for progression to PDR compared with eyes with lesions primarily confined to the posterior pole.

Optical Coherence Tomography Angiography Highlights Vascular Abnormalities
Even with the best clinical skills using indirect ophthalmoscopy, microvascular abnormalities may be quite subtle on a clinical fundus examination alone. More concerning, these abnormalities, such as microaneurysms, retinal nonperfusion, or mild IRMA, may be undetected and undiagnosed. Mid-peripheral retinal nonperfusion is a major concern because of its high risk of progression to PDR. Therefore, its presence may warrant earlier treatment because retinal ischemia is nonreversible and may progress. Fortunately, wide-field optical coherence tomography angiography (OCT-A) helps optometrists to readily identify microvascular abnormalities.  

Additionally, with its robust dataset, OCT-A can reliably differentiate between IRMA and preretinal neovascularization. IRMA are dilated telangiectatic capillaries within the retina, whereas preretinal neovascularization occurs on the retinal surface at the vitreoretinal interface. En face OCT-A isolates data at the vitreoretinal interface, making preretinal vascular proliferation clearly viewable and easily identifiable.

Pivotal Studies: PANORAMA and Protocol W
Findings from the 2021 randomized clinical trials PANORAMA and Protocol W have been critical in bringing about a paradigm shift in the management of patients with moderate and severe NPDR. PANORAMA evaluated the risk of vision-threatening complications (VTCs) and center-involved DME (CI-DME) in the eyes of 402 adults with moderately severe and severe NPDR without DME and with a best corrected visual acuity (BCVA) of 20/40 or better receiving anti-vascular endothelial growth factor (anti-VEGF) therapy up to 100 weeks.⁴ The participants received intravitreal injections as 1) 2.0 mg of aflibercept either every 16 weeks after 3 initial monthly doses and one 8-week interval (Q16W) or 2) every 8 weeks after 5 initial monthly doses with pro re nata dosing starting at week 56 (Q8W) or 3) received sham injections.⁴ The study found that significantly fewer eyes receiving aflibercept developed VTCs (Figure 2) and/or CI-DME through week 100 (16.3% Q16W and 18.7% Q8W) than eyes receiving sham injections (50.4%; P < 0.001 for both).⁴ In addition, significantly more eyes treated with aflibercept than sham were observed to have a 2-step or greater improvement in DRSS level at 24 weeks and 52 weeks (P < 0.001 for both) and a nominal improvement at 100 weeks.⁴ These findings indicate that earlier treatment may reduce the risk of developing DME and PDR and may improve the DR staging in patients with moderately severe and severe NPDR.

Figure 2. Anti-VEGF reduced the risk of VTCs in moderately severe to severe NPDR in the PANORAMA study.⁴

Protocol W studied the efficacy of intravitreal aflibercept injections in 328 adults with moderate to severe NPDR without CI-DME in reducing the risk of PDR or CI-DME compared with sham injections.⁵ Eyes randomly received injections of 2.0 mg of aflibercept or sham at baseline, 1, 2, and 4 months and then every 4 months through 2 years.⁵ At 2 years, eyes treated with aflibercept showed a reduced risk of PDR (13.5% aflibercept vs 33.2% sham) or CI-DME (4.1% aflibercept vs 14.8% sham) (Figure 3).⁵ Overall, data showed an 83% reduction in the risk of developing DR complications in patients receiving aflibercept.⁵ However, the mean change in visual acuity was not significant from baseline to 2 years between the group receiving aflibercept (-0.9 letters) and sham injections (-2.0 letters; P = 0.47).⁵ In the future, 4-year results will be important for assessing visual acuity outcomes over a longer term.⁵

Figure 3. Anti-VEGF reduced the risk of PDR or CI-DME in moderate to severe NPDR in the Protocol W study.⁵ y, year.

Key Message from PANORAMA and Protocol W
The new research from the pivotal PANORAMA and Protocol W trials indicates that it is critical to refer patients with DR earlier, ie, before the disease transitions to the proliferative stage. Any optometrist that lacks proper diagnostic modalities should refer patients with moderate DR to a retina specialist. Anti-VEGF therapy can stabilize and, in some cases, improve the stage of retinopathy. Therefore, optometrists have the opportunity to prevent VTCs by referring patients with moderate NPDR, particularly those with high-risk factors for progression like poor glycemic control and hypertension, for possible early treatment.

Case Study
A 58-year-old African American woman was recently diagnosed with diabetes. Her HbA1c was 10%, and her medical history also included hypertension and hypercholesterolemia. Her BCVA was 20/25 OD and OS. Fundus images showed a few cotton wool spots, exudates, and intraretinal hemorrhages (Figure 4). At this point in the examination, the DR classification was considered moderate stage.

Figure 4. Patient’s ultra-widefield imaging showing pathology in NPDR OD (top) and OS (bottom).

However, OCT-A imaging told a different story (Figure 5). Ultra-widefield FA showed significant capillary nonperfusion in the peripheral retina OD and an area of neovascularization OS. Therefore, the final staging based on OCT-A was severe NPDR OD and PDR OS, and the patient was referred to a retina specialist.

Figure 5. Patient’s OCT-A imaging showing pathology indicative of PDR OD (top) and OS (bottom).

Save Sight Key Takeaways
The recent results of PANORAMA and Protocol W underscore the consideration of earlier referrals for NPDR. Accurate staging of DR is essential to best manage patients and preserve their vision. Ultra-widefield imaging, including photos and dye-free fluorescein angiography, plays an important role in diagnosing and staging DR. It also helps identify eyes at an increased risk of disease progression. By referring earlier in the disease process of DR, optometrists offer patients the opportunity to preserve their vision and even reverse their stage of retinopathy.

References

1. Yonekawa Y, Modi YS, Kim LA, Skondra D, Kim JE, Wykoff CC. American Society of Retina Specialists clinical practice guidelines on the management of nonproliferative and proliferative diabetic retinopathy without diabetic macular edema. J Vitreoretin Dis. 2020;4(2):125-135.
2. Wykoff CC, Khurana RN, Nguyen QD, et al. Risk of blindness among patients with diabetes and newly diagnosed diabetic retinopathy. Diabetes Care. 2021;44(3):748-756.
3. Silva PS, Cavallerano JD, Haddad NMN, et al. Peripheral lesions identified on ultrawide field imaging predict increased risk of diabetic retinopathy progression over 4 years. Ophthalmology. 2015;122(5):949-956. 
4. Brown DM, Wykoff CC, Boyer D, et al. Evaluation of intravitreal aflibercept for the treatment of severe nonproliferative diabetic retinopathy: results from the PANORAMA randomized clinical trial. JAMA Ophthalmol. 2021;139(9):946-955. 
5. Maturi RK, Glassman AR, Josic K, et al. Effect of intravitreous anti-vascular endothelial growth factor vs sham treatment for prevention of vision-threatening complications of diabetic retinopathy: the Protocol W randomized clinical trial. JAMA Ophthalmol. 2021;139(7):701-712.