New Treatment Strategies for Diabetic Retinopathy: Sharpening the Focus

Introduction
A main goal of retina specialists in managing diabetic retinopathy (DR) is to initiate therapy before vision loss occurs. However, early treatment raises the question: When is treatment considered too early? Recent studies can provide insight to that answer. Here, 2 patient cases are discussed that use the results of these studies to guide retina specialists in their initiation of DR therapy.

Case Study 1
A 54-year-old man was referred for nonproliferative DR (NPDR) with no vision complaints. He had a medical history of type 2 diabetes for 20 years with a hemoglobin A1c (HbA1c) of 12% from 10 years ago—which was recently lowered to 6.3%. He also had a history of controlled hypertension and hyperlipidemia. The only medication he was taking was metformin. He was also a nonsmoker who consumed 2 drinks daily.

The patient’s best corrected visual acuity (BCVA) was 20/20 OD and 20/25 OS. His OD and OS 30° fundus photos were both consistent with moderate NPDR. His OD showed moderate intraretinal hemorrhages throughout the periphery and mild juxtafoveal exudates with a few foveal microaneurysms. Given the proximity of exudates to the fovea, this eye was also likely to have diabetic macular edema (DME). His OS showed a few foveal microaneurysms and moderate intraretinal hemorrhages in the periphery. No neovascularization was present OU. Fluorescein angiography (FA) showed a mildly increased foveal avascular zone with mild leakage from peripheral microaneurysms OU. The left eye did not show any leaking microaneurysms near the fovea; however, the right eye did show a few juxtafoveal leaking microaneurysms. Optical coherence tomography (OCT) imaging in both eyes was consistent with mild center-involved DME (CI-DME), which was more pronounced in his OS (Figure 1).

Figure 1. Patient’s FA and OCT imaging showing DR pathology OD (top row) and OS (bottom row).

Risk Factors for Vision Loss
This first case highlights the complexity of diabetes with a history of an elevated HbA1c that presents with other comorbidities, ie, hypertension and hyperlipidemia. The patient’s recently improved HbA1c is also a factor to consider for retinopathy prognosis. In DR, an accurate diagnosis is essential to determine the best course of management because the risk of blindness is greater with increasing severity of DR. In fact, patients with severe NPDR or proliferative DR (PDR) are twice as likely to develop severe vision loss or blindness compared to those with mild NPDR. Therefore, retina specialists need to classify or stratify risk of vision loss in patients with severe retinopathy for treatment purposes. In this case study, the patient had moderate NPDR and CI-DME with some ischemia and nonperfusion.

Pivotal Clinical Studies: Protocol W, PANORAMA, and Protocol V
Protocol W, an ongoing Diabetic Retinopathy Clinical Research (DRCR) Retina Network randomized clinical trial, is evaluating the effect of the anti-vascular endothelial growth factor (anti-VEGF) aflibercept on the prevention of PDR or CI-DME in eyes with moderate to severe NPDR without CI-DME.¹ The 2-year study included 399 eyes with moderate to severe NPDR receiving 2.0 mg of either aflibercept or sham injections at baseline, 1, 2, and 4 months, and then every 4 months through 2 years.¹ At 2 years, eyes treated with aflibercept had a significantly reduced risk of CI-DME with vision loss or PDR (16.3% aflibercept vs 43.5% sham) (Figure 2).¹ Eyes treated with aflibercept at 2 years also had an almost threefold reduced risk of CI-DME with vision loss (4.1% aflibercept vs 14.8% sham) and an almost twofold reduced risk of PDR (13.5% aflibercept vs 33.2% sham) (Figure 2).¹ In addition, Protocol W showed that eyes treated with aflibercept (45.8%) compared with sham (13.7%) had a ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) within 2 years (Figure 2).¹

Figure 2. Anti-VEGF therapy reduced the risk of CI-DME or PDR in moderate to severe NPDR in Protocol W.¹ 

The 100-week PANORAMA randomized clinical trial also analyzed the risk of DR progression in eyes with NPDR treated with anti-VEGF therapy.² This study included 402 adults with moderately severe to severe NPDR without DME and a BCVA of 20/40 or better.² Eyes received either intravitreal injections of 2.0 mg of aflibercept every 16 weeks after 3 initial monthly doses and one 8-week interval (Q16W); aflibercept every 8 weeks after 5 initial monthly doses with pro re nata (PRN) dosing beginning at week 56 (Q8W); or sham.² At 100 weeks, eyes treated with aflibercept had a reduced rate of developing vision-threatening complications (VTCs) (8.1% Q16W, 6.0% Q8W vs 27.1% control; nominal P < 0.001) (Figure 3).² In addition, more eyes treated with aflibercept at 52 weeks (65.2% Q16W, 79.9% Q8W) and at 100 weeks (62.2% Q16W, 50.0% Q8W) showed a ≥2-step improvement in the DRSS level than those treated with sham at 52 weeks (15.0%; P < 0.001 for both comparisons) and at 100 weeks (12.8%; nominal P < 0.001 for both comparisons) (Figure 4).²

Figure 3. Anti-VEGF therapy reduced the risk of VTCs in moderate to severe NPDR in PANORAMA.²

Figure 4. Anti-VEGF therapy improved the DRSS level ≥2 steps in moderately severe to severe NPDR in PANORAMA.²

Protocol V, the DRCR Retina Network randomized clinical trial, reported the outcomes of initial observation of eyes with CI-DME and a good visual acuity (VA) (20/25 or better) and of follow-up of these eyes with aflibercept only if VA loss occurred.³ Of the 236 eyes included in the study, 80 (34%) received aflibercept during the 2 years of follow-up.³ Eyes with a baseline central subfield thickness (CST) ≥300 mm were more likely to receive aflibercept than those with a CST of <300 mm (45% ≥300 mm vs 26% <300 mm; continuous P = 0.005).³ In addition, eyes with moderately severe NPDR and above at a DRSS severity level ≥47 (51%) were more likely to receive aflibercept than those with moderate NPDR and below at a DRSS severity level ≤43 (27%) (ordinal P <0.001).³

Patient Management
Considering the results of all 3 trials, management of this patient can vary. A full discussion with the patient that includes clinical trial data and their individual data is warranted to develop a personalized management plan. With the presence of CI-DME, anti-VEGF therapy is an option. However, because this patient has a good VA and controlled comorbidities, observation is also acceptable if the patient is willing to comply with frequent visits for careful monitoring. Anti-VEGF therapy should be initiated for any retinopathy progression or worsening of VA.

Case Study 2
A 63-year-old man was referred for a DR evaluation. He had type 2 diabetes and a recent HbA1c of 9%. His medical history included end-stage renal disease and hemodialysis therapy. His BCVA was 20/20-1 OD and 20/30-2 OS. Ultra-widefield imaging showed severe NPDR OU with numerous scattered intraretinal hemorrhages, exudates, and cotton wool spots throughout the peripheral retina (Figure 5). OCT imaging showed CI-DME with some preservation of the foveal contour OD<OS. 

Figure 5. Patient’s ultra-widefield and OCT imaging showing DR and DME pathology OD (top row) and OS (bottom row).

Patient Management
This case also highlights the importance of considering clinical trial data and the whole patient, particularly their comorbidities and ability to comply with follow-ups. This patient had a poorly controlled HbA1c and end-stage renal disease. He also had a nearly twofold higher risk of DR progression from severe NPDR and from a central OCT thickness of >300 mm, according to Protocol W and V, respectively. Anti-VEGF therapy was recommended to reduce the macular edema and to decrease the DRSS severity level, based on Protocol W and PANORAMA, possibly benefitting the patient for many years. Additionally, education with the patient and his family should emphasize the importance of controlling his HbA1c and other comorbidities and of patient compliance to treatment and follow-up. 

Most importantly, education should help patients understand how diabetes can affect their eyes. Patients need to know that hyperglycemia can cause the blood vessels in their retina to leak or bleed, possibly leading to permanent vision loss. They need to understand that regular eye examinations can detect diabetic eye disease and that today’s effective treatments may be initiated earlier, giving them the best chance to preserve their vision. Use this brief animation to help patients visualize the ocular effects of diabetes and the role of anti-VEGF treatment. 

Save Sight Key Takeaways
In moderately severe to severe NPDR, anti-VEGF therapy can prevent DR progression, complications of PDR, and CI-DME. It has also revolutionized clinicians’ ability to treat DR and save vision. The pivotal trials of Protocol V, Protocol W, and PANORAMA have established that physicians can customize anti-VEGF therapy to each patient for the best outcomes.

References

1. 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. 
2. 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. 
3. Glassman AR, Baker CW, Beaulieu WT, et al. Assessment of the DRCR Retina Network approach to management with initial observation for eyes with center-involved diabetic macular edema and good visual acuity: a secondary analysis of a randomized clinical trial. JAMA Ophthalmol. 2020;138(4):341-349.