Risk vs Reward: VEGF Inhibition in the Treatment of Nonproliferative Diabetic Retinopathy

Rishi P. Singh, MD
Cleveland Clinic Florida, Martin Health

Key Takeaways

  • Over 50% of patients with severe nonproliferative diabetic retinopathy (NPDR) experience disease progression. Clinicians should discuss the risks and benefits of anti-vascular endothelial growth factor (anti-VEGF) injections and consider them as a strong alternative to the watch and wait approach that currently is considered to be the standard of care. 
  • Early data indicates a 60% to 70% reduction in vision-threatening complications when patients with severe NPDR receive anti-VEGF treatment. While there may be cases for treating patients with anti-VEGF injections at earlier stages of retinopathy, earlier initiation may be less beneficial. 
  • Follow-up care for patients receiving anti-VEGF injections should include monitoring of widefield images, with or without angiography, to classify the treatment outcome and determine the continued frequency of anti-VEGF treatment. Patients also should be monitored for progression to PDR. 

Rishi P. Singh, MD, is president of Cleveland Clinic Martin North Hospital in Stuart and Cleveland Clinic Martin South Hospital in Martin County, Florida, a staff physician at the Cleveland Clinic Cole Eye Institute in Ohio, and a professor of ophthalmology at the Cleveland Clinic Lerner College of Medicine in Ohio. His clinical specialties include medical and surgical treatment of retinal diseases, such as diabetic retinopathy, retinal detachment, and age-related macular degeneration. Dr Singh has authored more than 180 peer-reviewed publications, books, and book chapters. He serves as the principal investigator of numerous national clinical trials advancing the treatment of retinal disease. 

With the goal of preventing vision-threatening complications in patients with NPDR, what key considerations and factors should be considered by clinicians prior to the initiation of intravitreal anti-VEGF treatment?

Approximately half of the patient population with NDPR is likely to develop PDR within 1 year.1 Therefore, the discussion around anti-VEGF treatment in NPDR often revolves around the risks and benefits of the injections over improved standard of care or wait and watch approaches to disease progression. Cost of the injection, patient discomfort after the procedure, and the need for continuous monitoring are key factors to consider before initiating intravitreal anti-VEGF treatment.

Can you comment on how underlying medical conditions such as hypertension, lung disease, and chronic kidney disease may impact treatment decisions? 

None of these systemic conditions affect treatment decisions to initiate anti-VEGF therapy because the therapy is generally well tolerated without any systemic side effects. However, we should try to optimize the health of the patient from a systemic standpoint since these underlying conditions are likely to play a role in disease progression. For this reason, we work with patients’ primary care physicians to ensure that these underlying conditions also are well managed.

There is a general consensus that patients with mild NPDR should not be treated unless there is clinically significant edema. As you mentioned, there is a risk of progression in a subset of patients. How do you recommend determining patient follow-up intervals?

For every level of retinopathy, there is a recommended follow-up period and it is based upon the level of disease. With mild or moderate retinopathy, a follow-up is recommended every 6 months and with severe retinopathy, the recommendation is to follow up every 2 to 3 months. It is recommended for patients with type 1 diabetes to have annual screenings for diabetic retinopathy beginning at year 5 after onset of the disease. For patients with type 2 diabetes, a screening for diabetic retinopathy is recommended at the time of diagnosis followed by annual screenings.2

What is the role of VEGF inhibition in preventing the transition of NPDR to proliferative diabetic eye disease? Is there a case to be made for using this delivery method in patients with early-stage NPDR?

Results from the PANORAMA study (ClinicalTrials.gov Identifier: NCT02718326) showed that intravitreal aflibercept injections caused a 2-step or greater improvement in the Diabetic Retinopathy Severity Scale. A reduction in vision-threatening retinopathy complications, including vitreous hemorrhage, center-involved diabetic macular edema, and neovascular glaucoma was also observed.3 With all levels of retinopathy, there is a benefit to using anti-VEGF medications; however, the benefit is lower when used in earlier stages of retinopathy. Regardless of the stage of retinopathy, I would advise patients to consult with a physician to discuss the risks and benefits of anti-VEGF treatment.

You mentioned the PANORAMA study, which found anatomic improvement with intravitreal aflibercept injections in patients with moderately-severe to severe NPDR. In the PANORAMA study, fixed dosing of injections was necessary into year 2 to maintain benefit. These results suggest that there is a need for ongoing VEGF inhibition, so addressing patient adherence to therapy is important. How do you assess and encourage adherence to injection therapy?  

It is key to educate the patient about the importance of continued treatment. We discuss with the patient how the treatment may prevent vision loss and vision-threatening events, such as vitreous hemorrhage. In addition to educating the patient about continuing therapy, we have regular follow-ups with them to see how they are doing. It can be challenging to achieve these follow-ups visits on a regular basis, however, because these patients tend to be busy, working adults. To help them stay motivated, we also share pictures taken with optical coherence tomography to show them how the ongoing therapy is benefiting them.

Based on findings you mentioned from the PANORAMA trial, can you comment on your approach to fixed interval dosing as opposed to dosing patients as needed?

Fixed interval dosing is difficult to do and we moved away from this model years ago because we wanted to reduce the treatment burden on patients. Dosing as needed is unpopular because it leaves gaps in care. For these reasons, we put most patients on treat and extend protocols until a certain given indication and then we continue treatment at regular intervals that are personalized to the patient.

What VEGF inhibitor treatment options are approved by the US Food and Drug Administration (FDA) for dosing flexibility in patients with diabetic retinopathy? Can you review the dosing schedules for VEGF inhibitors for diabetic retinopathy?

Ranibizumab and aflibercept have been approved for the treatment of NPDR.5,6 Bevacizumab is used off-label for this indication.7 For the dosing schedule, I would use the package insert as a reference, which includes the recommended frequency of treatment. 

With all levels of retinopathy, there is a benefit to using anti-VEGF medications; however, the benefit is lower when used in earlier stages of retinopathy.

What key considerations should be assessed during patient follow-up after intravitreal VEGF inhibitor treatment in patients with NPDR?

A key consideration during the patient follow-up is the outcome measurement of the anti-VEGF treatment. Physicians will typically get widefield images, with or without angiography, to classify the treatment outcome and determine the continued frequency of anti-VEGF treatment. Another key consideration is the progression to PDR, which should be monitored and noted in these high-risk patients.   

Ranibizumab adverse effects
Adverse effects commonly reported with ranibizumab injections include increases in intraocular pressure, endophthalmitis, retinal detachment, and iatrogenic traumatic cataract.

Can you speak to long-term visual acuity outcomes with VEGF inhibition in patients with NPDR and diabetic eye diseases in general?

Long-term data is currently unavailable. Many of these studies only had a 1- to 2-year outcome measurement. The longest study to date is the Protocol S study (ClinicalTrials.gov Identifier: NCT01489189), which for 2 years followed patients with PDR who were treated with anti-VEGF therapy.8 Study outcomes compared panretinal laser treatment with anti-VEGF therapy and found favorable results for both, albeit with lesser treatments in the panretinal laser group. Outcomes favoring the anti-VEGF group were visual field preservation and prevention of progression to other vision-threatening events.  

What roles do anti-VEGF therapy play in the management of NPDR and how do they differ from laser therapy?

In the past, focal laser treatment was given prior to VEGF inhibition but now, we are using it as a supplemental therapy. Focal laser treatment has been a part of many studies including the Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol T study in which patients still had significant edema despite VEGF inhibition.9 When applied at a strength of 20% to 30%, laser treatment dried the edema faster in patients who weren’t responding well to VEGF inhibition. In practice, laser treatment is given for far less time and at lower rates than what we observe in studies, but I believe it still has an important role in supplemental care.

This Q&A was edited for clarity and length.


Rishi P. Singh, MD, reported affiliations with Alcon Laboratories, Inc.; Bausch & Lomb Inc.; Genentech, Inc.; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc.; ZEISS Group; Aerie Pharmaceuticals, Inc.; Apellis Pharmaceuticals, Inc.; and Graybug Vision, Inc.


1. Singh R, Ramasamy K, Abraham C, Gupta V, Gupta A. Diabetic retinopathy: an updateIndian J Ophthalmol. 2008;56(3):178-188.
2. Flaxel CJ, Adelman RA, Bailey ST, et al. Diabetic retinopathy preferred practice pattern®. Ophthalmology. 2020;127(1):66-145. doi:10.1016/j.ophtha.2019.09.025
3. 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 trialJAMA Ophthalmol. 2021;139(9):946-955. doi:10.1001/jamaophthalmol.2021.2809
4. O’Day R, Ali N, Lim LL, Sandhu S, Chau T, Wickremasinghe S. A treat and extend protocol with aflibercept for crystoid macular oedema secondary to central retinal vein occlusion- an 18-month prospective cohort study. BMC Opthalmol. 2020;20(1):69. doi:10.1186/s12886-020-01346-8
 5. Lucentis. Prescribing information. Genentech, Inc; 2017. Accessed June 1, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125156s114lbl.pdf
6. Eylea. Prescribing information. Regeneron Pharmaceuticals, Inc; 2011. Accessed June 1, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125387lbl.pdf
7. Avastin. Prescribing information. Genentech, Inc; 2013. Accessed June 1, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125085s301lbl.pdf
8. Sun JK, Glassman AR, Beaulieu WT, et al; for the Diabetic Retinopathy Clinical Research Network. Rationale and application of the protocol S anti-vascular endothelial growth factor algorithm for proliferative diabetic retinopathyOphthalmology. 2019;126(1):87-95. doi:10.1016/j.ophtha.2018.08.001

9. Bressler NM, Beaulieu WT, Maguire MG, et al. Early response to anti-vascular endothelial growth factor and two-year outcomes among eyes with diabetic macular edema in protocol T. Am J Ophthalmol. 2018;195:93-100. 2018;195:93-100. doi:10.1016/j.ajo.2018.07.030

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Ophthalmology Advisor had no role in this content’s preparation.
                                                                                                                               Reviewed June 2022