Retina · Diabetic Retinopathy

Anti-VEGF Therapy in Diabetic Retinopathy

Mechanism, principal agents, clinical uses, treatment regimens and important safety considerations.

This companion note organises and updates the core concepts taught in the accompanying video.

Why VEGF Matters

Diabetic retinal capillary damage causes retinal ischaemia and hypoxia, increasing the production of vascular endothelial growth factor, particularly VEGF-A. [1]

Capillary closure Retinal hypoxia VEGF upregulation

Vascular permeability

Breakdown of the blood–retinal barrier causes vascular leakage and contributes to diabetic macular oedema.

Angiogenesis

Persistent retinal ischaemia promotes retinal or disc neovascularisation and proliferative diabetic retinopathy.

Receptor or ligand	Principal role	Clinical relevance
VEGFR-1	Angiogenic and inflammatory signalling	Also binds placental growth factor
VEGFR-2	Endothelial proliferation, permeability and angiogenesis	Principal receptor responsible for the major vascular effects of VEGF-A
PlGF	Acts mainly through VEGFR-1	Contributes to pathological vascular activity and inflammation

Effects of VEGF Blockade

Clinical setting	Main effects	What remains untreated?
Diabetic macular oedema	Reduced vascular leakage Reduced intraretinal or subretinal fluid Reduced central retinal thickness Improved or stabilised visual acuity	Macular ischaemia, chronic structural damage and traction may continue to limit visual recovery.
Proliferative diabetic retinopathy	Rapid regression of NVD or NVE Reduced neovascular leakage Control of associated DME Reduced bleeding before selected diabetic vitrectomy cases	Retinal ischaemia persists, and neovascularisation may recur after the drug effect declines.

Clinical Pearl: Anti-VEGF treatment suppresses leakage and neovascular activity; it does not reverse the underlying retinal ischaemia.

Principal Anti-VEGF Agents

Anti-VEGF agents differ in molecular structure, target profile, dose, durability, regulatory status and safety.

Agent	Molecular format	Principal targets	Common dose	Clinical position	High-yield point
Pegaptanib [19]	Pegylated RNA aptamer	VEGF-A₁₆₅	Not routinely used for diabetic retinal disease	First anti-VEGF drug approved specifically for intraocular use	No longer a principal agent in current diabetic-retinal practice
Bevacizumab	Full-length humanised monoclonal antibody containing Fab and Fc regions	VEGF-A	1.25 mg/0.05 mL	Widely used off-label because of its lower cost	Ophthalmic use depends on reliable sterile compounding
Ranibizumab [13]	Affinity-matured Fab fragment without a conventional Fc region	VEGF-A	0.3 or 0.5 mg/0.05 mL	Developed specifically for intraocular use	Approved dose varies by indication and jurisdiction
Aflibercept [14] [17]	VEGFR-1/VEGFR-2 receptor–Fc fusion protein	VEGF-A, VEGF-B and PlGF	2 mg/0.05 mL 8 mg/0.07 mL	Established VEGF-trap therapy; the 8 mg formulation is designed to provide greater durability	Both formulations use the same decoy-receptor principle; the difference is dose and formulation
Faricimab [8] [15]	Bispecific antibody with two different target-binding arms	VEGF-A and Ang-2	6 mg/0.05 mL	Dual-pathway treatment with extended-interval potential	Selected responding eyes may reach treatment intervals of up to 16 weeks
Brolucizumab [9] [16]	Compact single-chain variable fragment without a conventional Fc region	VEGF-A	6 mg/0.05 mL	Approved for DME in some jurisdictions	Associated with intraocular inflammation, retinal vasculitis and retinal vascular occlusion
Biosimilars [18]	Highly similar version of an approved reference biologic	Same target as the reference agent	According to the approved biosimilar product	May improve affordability and access	Not a new mechanism of action; approval and interchangeability vary by jurisdiction

How does the aflibercept decoy receptor work?

VEGF is released within the retina

VEGF binds the soluble receptor domains of aflibercept

Less VEGF reaches endothelial VEGF receptors

Doses, approved indications and interchangeability rules may vary by jurisdiction.

Clinical Indications for Anti-VEGF

Anti-VEGF therapy is used in:

Vision-impairing centre-involving DME — principal initial treatment. [2]
Proliferative diabetic retinopathy — regression of NVD and NVE. [6]
DME associated with PDR — treats macular oedema while suppressing neovascularisation.
Before diabetic vitrectomy — reduces neovascularity and intraoperative bleeding. [12]
Selected severe NPDR without DME — may reduce progression, but routine prophylactic treatment is not required. [7]

Remember: centre-involving DME with good visual acuity may be observed initially when follow-up is reliable, while PRP remains important in PDR when durable control is needed. [5]

Choosing an Anti-VEGF Agent

1. Vision and treatment objective

DME: improve vision and control macular fluid.
PDR: regress neovascularisation and prevent complications.
Baseline visual acuity may influence the choice of agent.

2. Previous response

Assess both visual acuity and OCT.
Persistent fluid may require a shorter interval or agent switch.
Exclude macular ischaemia, chronic damage and traction.

3. Safety

Consider previous intraocular inflammation.
Brolucizumab has specific inflammatory and vascular risks.
Recent major vascular events require individual assessment.

4. Practical factors

Durability: longer intervals may reduce visit burden.
Cost: bevacizumab is commonly selected for affordability.
Follow-up: unreliable attendance may favour PRP in PDR.

Protocol T [4]

Mild visual loss: outcomes were broadly similar with aflibercept, bevacizumab and ranibizumab.

Worse baseline vision: aflibercept produced a greater average early gain than bevacizumab.

Assessing Treatment Response

DME

Assess visual acuity, change in letter score, central subfield thickness, retinal fluid and any macular ischaemia or traction.

PDR

Assess regression or recurrence of NVD/NVE, new preretinal or vitreous haemorrhage, fibrovascular proliferation and retinal traction.

DRCR.net Protocol I: 10% CST and five-letter rule [3]

Response	Visual change	Anatomical change
Improvement	Gain ≥5 letters	CST reduction ≥10%
Stability	Neither improvement nor worsening by these thresholds
Worsening	Loss ≥5 letters	CST increase ≥10%

Five letters represent functional change; 10% CST represents anatomical change. These thresholds were used in the DRCR.net Protocol I retreatment algorithm for centre-involved DME; they are not universal stop or discharge rules.

Anti-VEGF Treatment Regimens

The key difference is what happens at each visit and whether the next treatment interval remains fixed or changes according to disease activity.

Fixed

Predetermined schedule

Scheduled review

Injection given

Same interval

Simple and consistent, but may increase treatment burden.

PRN

Reactive treatment

Regular review

Is disease active?

Inject if needed

Fewer injections do not necessarily mean fewer monitoring visits.

Treat-and-extend

Proactive treatment

Review and inject

Assess activity

Extend or shorten

Inject at each visit; adjust the next interval according to disease control.

Traditional treat-and-extend sequence

Extend in one- or two-week steps when control is maintained

4 weeks

6 weeks

8 weeks

10 weeks

12 weeks

Current update: 12 weeks is the traditional teaching ceiling, not a universal maximum. Selected faricimab and aflibercept 8 mg regimens may extend to 16 weeks. [8] [10]

Potential Complications

Most injections are uncomplicated. Adverse events may arise from the injection procedure, the ocular response to treatment or, less commonly, a systemic event.

Category	Potential complications
Common and usually minor	Subconjunctival haemorrhage Mild pain, irritation or foreign-body sensation Temporary floaters or visual disturbance Transient intraocular-pressure rise
Potentially sight-threatening	Infectious endophthalmitis Significant intraocular inflammation Retinal tear or retinal detachment Persistent or clinically important pressure elevation [13] [14] [15]
Systemic consideration	Potential arterial thromboembolic events, including stroke or myocardial infarction Assess the individual risk–benefit balance after a recent major vascular event [14] [15] [16]

Urgent review is required for increasing pain, marked redness, photophobia, sudden visual loss, new flashes or floaters, or a curtain-like field defect.

Discussed separately: brolucizumab-associated retinal vasculitis and anti-VEGF crunch are covered in the next safety section.

Safety and Important Precautions

Intravitreal anti-VEGF therapy is generally well tolerated, but safe use requires attention to ocular infection, inflammation, systemic history and tractional retinal disease.[2]

Check before every injection

Ocular or periocular infection

Defer injection when an active infection is present.

Active intraocular inflammation

Investigate and control inflammation before further treatment.

Recent major vascular event

Consider the systemic history and individualise the risk–benefit discussion.

Brolucizumab Specific safety warning

Brolucizumab is associated with intraocular inflammation, retinal vasculitis and retinal vascular occlusion.[16]

New pain, redness, photophobia, floaters or reduced vision after an injection requires prompt examination. Further brolucizumab should not be given while active intraocular inflammation is present.

Anti-VEGF crunch[11]

A tractional complication in proliferative diabetic retinopathy

Anti-VEGF injection in an eye with fibrovascular proliferation

Rapid involution and contraction of fibrovascular tissue

New or worsening tractional retinal detachment

When to be particularly cautious

Extensive fibrovascular proliferation, pre-existing traction, broad adhesions or a tractional detachment approaching the macula.

Typical clinical context

The complication usually develops within the first few weeks after injection and may present with sudden visual deterioration.[11]

Practical point: preoperative anti-VEGF can reduce neovascularity and intraoperative bleeding before diabetic vitrectomy, but in an eye with marked traction it should be used as part of a coordinated surgical plan rather than followed by an avoidable delay.[12]

Key Takeaways

VEGF promotes vascular leakage and neovascularisation. Anti-VEGF therapy suppresses these effects but does not reverse the underlying retinal ischaemia.[1]
Vision-impairing centre-involving DME is a principal indication for anti-VEGF therapy. Anti-VEGF treatment can also produce regression of neovascularisation in PDR.[2][6]
There is no single best agent for every eye. Baseline vision, previous response, durability, safety, cost and follow-up reliability all influence drug selection.[4]
Assess treatment response functionally and anatomically. Visual acuity, OCT findings, retinal fluid and neovascular activity should be interpreted together.[3]
Fixed, PRN and treat-and-extend regimens are different. They vary in when injections are given, how frequently the patient is reviewed and whether the next interval is adjusted.
Safety depends on the clinical context. Brolucizumab has specific inflammatory and retinal vascular risks, while extensive fibrovascular proliferation may predispose to anti-VEGF crunch and worsening traction.[11][16]

Clinical principle: treat the eye, not only the OCT. The treatment plan should reflect visual function, retinal anatomy, neovascular activity, tractional risk and the patient’s ability to maintain follow-up.

References

1.
Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480–1487. DOI: 10.1056/NEJM199412013312203
2.
Lim JI, Kim SJ, Bailey ST, et al. Diabetic Retinopathy Preferred Practice Pattern®. Ophthalmology. 2025;132(4):P75–P162. DOI: 10.1016/j.ophtha.2024.12.020
3.
Aiello LP, Beck RW, Bressler NM, et al. Rationale for the Diabetic Retinopathy Clinical Research Network treatment protocol for center-involved diabetic macular edema. Ophthalmology. 2011;118:e5–e14. DOI: 10.1016/j.ophtha.2011.09.058
4.
Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123:1351–1359. DOI: 10.1016/j.ophtha.2016.02.022
5.
Baker CW, Glassman AR, Beaulieu WT, et al. Effect of initial management with aflibercept versus laser photocoagulation versus observation on vision loss among patients with centre-involved diabetic macular oedema and good visual acuity. JAMA. 2019;321:1880–1894. DOI: 10.1001/jama.2019.5790
6.
Gross JG, Glassman AR, Liu D, et al. Five-year outcomes of panretinal photocoagulation versus intravitreous ranibizumab for proliferative diabetic retinopathy. JAMA Ophthalmol. 2018;136:1138–1148. DOI: 10.1001/jamaophthalmol.2018.3255
7.
Maturi RK, Glassman AR, Josic K, et al. Four-year visual outcomes in the Protocol W randomized trial of intravitreous aflibercept for prevention of vision-threatening complications of diabetic retinopathy. JAMA. 2023. DOI: 10.1001/jama.2022.25029
8.
Wong TY, Haskova Z, Asik K, et al. Faricimab treat-and-extend for diabetic macular edema: two-year results from the randomized phase 3 YOSEMITE and RHINE trials. Ophthalmology. 2024;131:708–723. DOI: 10.1016/j.ophtha.2023.12.026
9.
Wykoff CC, Garweg JG, Regillo C, et al. KESTREL and KITE phase 3 studies: 100-week results with brolucizumab in patients with diabetic macular edema. Am J Ophthalmol. 2024;260:70–83. DOI: 10.1016/j.ajo.2023.07.012
10.
Brown DM, Boyer DS, Do DV, et al. Intravitreal aflibercept 8 mg in diabetic macular oedema (PHOTON): 48-week results from a randomised, double-masked, non-inferiority phase 2/3 trial. Lancet. 2024;403:1153–1163. DOI: 10.1016/S0140-6736(23)02577-1
11.
Tan Y, Fukutomi A, Sun MT, et al. Anti-VEGF crunch syndrome in proliferative diabetic retinopathy: a review. Surv Ophthalmol. 2021. DOI: 10.1016/j.survophthal.2021.03.001
12.
Dervenis P, Dervenis N, Steel DHW, et al. Intravitreal bevacizumab prior to vitrectomy for proliferative diabetic retinopathy: a systematic review. Ther Adv Ophthalmol. 2021. DOI: 10.1177/25158414211059256
13.
DailyMed. LUCENTIS®—ranibizumab injection: prescribing information. Official label: DailyMed prescribing information
14.
DailyMed. EYLEA®—aflibercept injection: prescribing information. Official label: DailyMed prescribing information
15.
DailyMed. VABYSMO®—faricimab-svoa injection: prescribing information. Official label: DailyMed prescribing information
16.
DailyMed. BEOVU®—brolucizumab-dbll injection: prescribing information. Official label: DailyMed prescribing information
17.
DailyMed. EYLEA HD®—aflibercept injection: prescribing information. Official label: DailyMed prescribing information
18.
US Food and Drug Administration. FDA approves the first interchangeable biosimilars to Eylea. Source: FDA information
19.
US Food and Drug Administration. MACUGEN®—pegaptanib sodium injection: prescribing information. Official label: FDA prescribing information