Original Article

Ziv-aflibercept in Diabetic Macular Edema: Relation of
Subfoveal Choroidal Thickness with Visual and

Anatomical Outcomes

Siamak Moradian1, MD; Masoud Soheilian2, MD; Mahsan Asadi3, MD; Abdolreza Baghi3, MD; Hamid Safi3, MD
Seyed-Hossein Abtahi3, MD

1Ophthalmic Epidemiology Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti
University of Medical Sciences, Tehran, Iran

2Ocular Tissue Engineering Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti
University of Medical Sciences, Tehran, Iran

3Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of
Medical Sciences, Tehran, Iran

ORCID:
Siamak Moradian: https://orcid.org/0000-0002-5328-7565

Abstract
Purpose: To evaluate the effects of intravitreal ziv-aflibercept injections (IVZ) on subfoveal choroidal
thickness (SCT) as well as on central macular thickness (CMT) and on best corrected visual acuity
(BCVA) changes in eyes with center-involved diabetic macular edema (CI-DME).
Methods: Fifty-seven eyes of 36 patients with CI-DME were included in this prospective
interventional case series. Structural optical coherence tomography (OCT) and enhanced depth
imaging OCT were performed at baseline followed by three monthly 1.25 mg IVZ injections.
Changes of SCT, CMT, and BCVA at each follow-up session were assessed. The association
between baseline SCT and its monthly changes with final visual and anatomical outcomes were
also assessed.
Results: CMT at baseline, and at the first, second, and third month follow-up sessions were 396 ±
119, 344 ± 115, 305 ± 89, and 296 ± 101 μm, respectively (P-value < 0.001). SCT at baseline, and at
months one, two, and three were 236 ± 47, 245 ± 56, 254 ± 54, and 241 ± 54 μm, respectively (P-
value > 0.99). Corresponding figures for BCVA were 0.58 ± 0.29, 0.47 ± 0.31, 0.4 ± 0.24, and 0.37 ±
0.23 LogMAR, respectively (P-value < 0.001). There was a statistically significant positive correlation
between BCVA and CMT changes following IVZ injections (P-value < 0.001). However, there were
no significant correlations between SCT changes and visual acuity (VA) and CMT changes following
IVZ injections.
Conclusion: IVZ improved visual outcomes and macular thickness profiles in patients with CI-DME.
However, IVZ had no significant effect on SCT. Baseline SCT and its monthly changes had no
association with visual and anatomical outcomes.

Keywords: Center-involved Diabetic Macular Edema; Central Macular Thickness; Intravitreal; Subfoveal
Choroidal Thickness; Ziv-Aflibercept

J Ophthalmic Vis Res 2023; 18 (2): 164–169

Correspondence to:

Siamak Moradian, MD. Department of Ophthalmology,
Labbafinejad Medical Center, Shahid Beheshti University of
Medical Sciences, Paidarfard St., Boostan 9 St., Pasdaran
Ave., Tehran 16666, Iran.
Email: moradian33195@yahoo.com
Received: 25-10-2021 Accepted: 30-08-2022

Access this article online

Website: https://knepublishing.com/index.php/JOVR

DOI: 10.18502/jovr.v18i2.13182

This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

How to cite this article: Moradian S, Soheilian M, Asadi M,
Baghi A, Safi H, Abtahi S-H. Ziv-aflibercept in Diabetic Macular
Edema: Relation of Subfoveal Choroidal Thickness with Visual and
Anatomical Outcomes . J Ophthalmic Vis Res 2023;18:164–169.

164 © 2023 Moradian et al. THIS IS AN OPEN ACCESS ARTICLE DISTRIBUTED UNDER THE CREATIVE COMMONS ATTRIBUTION LICENSE | PUBLISHED BY KNOWLEDGE E

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Ziv-aflibercept for DME ; Moradian et al

INTRODUCTION

Diabetic macular edema (DME) is the main cause
of vision loss in diabetic patients.[1, 2]. The use
of anti-vascular endothelial growth factors (anti-
VEGFs) is currently the main therapeutic choice
for DME.[3] Ziv-Aflibercept (Zaltrap, Sanofi-Aventis
US, LLC, Bridgewater, New Jersey, USA and
Regeneron Pharmaceuticals, Inc, Tarrytown,
New York, USA) is an FDA-approved drug for
treatment of colorectal and metastatic cancers.
As an analogue of aflibercept, ziv-aflibercept is
a monoclonal antibody that binds to VEGF A
and B of various isoforms and placental growth
factor, which also possesses a good safety profile
and is of lower cost.[4, 5] There is a growing body
of evidence that intravitreal ziv-aflibercept (IVZ)
improves visual outcomes and macular thickness
profiles in patients with DME.[6–11] However, the
changes of choroidal thickness in eyes with DME
treated with IVZ and the effects of subfoveal
choroidal thickness (SCT) on visual and anatomical
outcomes remain unknown.

Subfoveal choroidal thickness measurement
performed by enhanced depth optical coherence
tomography (EDI-OCT) in DME cases treated with
anti-VEGFs has been proposed as a predictor of
therapeutic outcomes.[12] However, the correlation
between baseline SCT and treatment responses
in patients with DME remains controversial.[3, 13, 14]
Thinning of SCT might aggravate retinal hypoxia
and accentuate VEGF secretion resulting in
increased breakdown of the blood retinal barrier
(BRB) and consequent DME deterioration.[15, 16]
Therefore, the association of SCT with visual and
anatomical outcomes should be elucidated.

In this study, we investigated the effects of IVZ
on SCT as well as on central macular thickness
(CMT) and on best corrected visual acuity (BCVA)
changes in eyes with center-involved diabetic
macular edema (CI-DME). A possible correlation
between SCT changes and visual and anatomical
outcomes of DME cases treated with IVZ is
questioned.

METHODS

In this prospective interventional case series,
cases of CI-DME were enrolled for intravitreal
pharmacotherapy at Labbafinejad Medical Center,
Tehran, Iran between April 2019 and April 2020.

The study protocol was reviewed and approved
by the Ethics committee, Ophthalmic Research
Center, Shahid Beheshti University of Medical
Sciences, Tehran, Iran, and the approval number
was IR.SBMU.ORC.REC.1394.05. In addition, the
protocol of the study complied with the guidelines
for human studies and the tenets of Declaration of
Helsinki. Informed consent was obtained from all
participants.

Based on the standard protocols, all patients
underwent three monthly IVZ injections (1.25
mg/0.05 ml).[17] Complete ocular examinations,
Spectralis EDI-OCT (Heidelberg Engineering,
Heidelberg, Germany), and SD OCT were
performed at baseline and repeated one month
after each IVZ injection. All visits and imaging
procedures took place between 9 am and 12
am. BCVA was evaluated using the Snellen
chart. CMT was assessed based on previously
described OCT software methodology (the 1-
mm Early Treatment Diabetic Retinopathy Study
(ETDRS) circle centered on the fovea).[18] SCT was
measured manually as the distance between the
RPE hyperreflective line and the chorio-scleral
junction. Only patients with CMTs of >250 µm
and BCVA readings between 20/40 and 20/320
were included. Patients with proliferative diabetic
retinopathy (PDR), concomitant macular disease,
a history of intravitreal injections of anti-VEGFs or
corticosteroids or retinal photocoagulation within
three months of enrollment, a history of pars
plana vitrectomy, refractive errors higher than ±5
diopters, a history of cardiovascular accidents,
glaucoma, pregnancy, and uncontrolled systemic
hypertension were excluded.

Statistical Analysis

Data were presented using mean, standard
deviation, median and range, frequency, and
percentage. Paired T-test was used to assess the
improvement within the groups and T-test was
used to evaluate the difference among the groups.

Minimal sample size needed for all variables
was calculated as ≥45 individuals (G*Power
software [latest ver. 3.1.9.7; Heinrich-Heine-
Universität Düsseldorf, Düsseldorf, Germany])
to achieve a certain power (effect size dz =
0.5; α error probability = 0.05; power [1-β error
probability] = 0.95). We also used generalized
estimating equations (GEE) to consider the possible

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Ziv-aflibercept for DME ; Moradian et al

correlation of the results in the eyes. Correlation of
variables was assessed using Pearson’s correlation
coefficient. All statistical analyses were performed
using the SPSS (IBM Corp. Released 2017. IBM
SPSS Statistics for Windows, Version 25.0. Armonk,
NY: IBM Corp.). P-value < 0.05 was considered
statistically significant.

RESULTS

Fifty-seven eyes of 36 patients with CI-DME were
included in this prospective interventional case
series. During the study period, no patient missed
follow-up sessions or required further treatments
(e.g., laser photocoagulation, vitrectomy) and no
complications related to IVZ were recorded in
patients (signs of intraocular inflammation, change
in the lens status, and systemic complications). Past
medical history and ocular examination findings
were summarized in Table 1.

CMT decreased progressively through IVZ
monthly injections. A marginally significant
decrease was recorded at the one month follow-up
(P = 0.057); however, compared to the baseline
a significant decrease was recorded after the
second and third months. Progressive BCVA
improvement was also observed after monthly
IVZ injections. Significant changes were recorded
after the second and third months as compared to
the baseline. No significant changes in SCT were
observed after monthly IVZ injections as compared
to baseline [Table 2].

At each follow-up interval, the level of
improvement of BCVA was correlated with the
amount of CMT reduction. However, SCT did
not correlate with changes in BCVA and CMT at
follow-up visits [Table 3].

DISCUSSION

Ziv-aflibercept (Zaltrap) is a monoclonal antibody
approved for the treatment of metastatic colorectal
cancer. Like its analogue, aflibercept, Ziv-
aflibercept blocks all isoforms of VEGF A, B,
and placental growth factor (PlGF). While Ziv-
aflibercept (Zaltrap) has higher osmolarity than
aflibercept, studies showed no difference between
the two drugs in the safety profile. Malick et
al compared the toxicity of aflibercept, Ziv-
aflibercept, bevacizumab, and ranibizumab on
RPE cells in media culture. They observed mild

mitochondrial toxicity following bevacizumab and
ziv-aflibercept injections.[19] In an experimental
study, 0.05 ml IVZ had no deleterious effect on
the osmolarity of the vitreous.[20] Mansour et al
showed the effect of IVZ in patients with DME
without any intraocular toxicity.[9] Chhablani et al
demonstrated the effect of IVZ injection on patients
with neovascular AMD with no intraocular toxicity
or retinal electrophysiological abnormalities.[21]
Additionally, no significant adverse effects related
to IVZ were detected, at least in a short-term
follow-up. However, long-term adverse effects of
IVZ remains unknown.

Variable results have been reported regarding
choroidal thickness changes in patients with
DME.[14, 15, 22] There are reports of reduced
choroidal thickness in these patients, which
may be the consequence of choroidal vascular
obstruction and development of non-perfusion
areas similar to retinal vascular alterations.[15, 22]
A histopathological study revealed thinning and
attenuation of the choriocapillaris layer with
subsequent reduction of choroidal thickness in
diabetic retinopathy.[14] Meanwhile, some studies
showed increase of choroidal thickness in patients
with DME. VEGF overexpression causes dilation
and congestion of choroidal vessels that result in
thicker choroid in patients with DME. Therefore,
anti-VEGFs for DME treatment could theoretically
reduce the permeability and thickness of choroidal
layers. However, no significant association was
found between anti-VEGF therapy and choroidal
thickness changes in patients with CI-DME.

The effect of anti-VEGF treatment on
choroidal thickness in DME has already been
evaluated.[3, 12–14, 23–25] Several studies reported
reduction of choroidal thickness following
intravitreal injection of bevacizumab (IVB).[3, 12, 23]
Rayess et al revealed that thicker baseline SCT
was associated with better anatomic and functional
responses. They suggested baseline SCT as a
predictor of DME treatment response to IVB.[12]
Yiu et al reported no correlation between SCT
reduction and changes in visual acuity (VA) and
macular thickness.[3] In a clinical trial, no significant
changes were observed in choroidal thickness
following IVB injection in DME.[24] Recently, it has
been shown that intravitreal aflibercept had more
effect on SCT in DME as compared to intravitreal
ranibizumab.[25]

Despite previous investigations using various
forms of anti-VEGFs, the effect of IVZ on choroidal

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Ziv-aflibercept for DME ; Moradian et al

Table 1. Baseline characteristics and demographic features.

N (%)

Eye OD 30 (52.6%)

OS 27 (47.4%)

Lens status Pseudophakic 20 (35.1%)

Phakic 37 (64.9%)

History of MPC No 31 (54.4%)

Yes 26 (45.6%)

History of injection No 28 (49.1%)

Yes 29 (50.9%)

Naïve No 36 (63.2%)

Yes 21 (36.8%)

Age Mean ± SD 63.3 ± 5.93
Number of injection Mean ± SD 3.93 ± 1.03
Duration of diabetes (yr) Mean ± SD 12.37 ± 4.23

MPC, macular photocoagulation; OD, right eye; OS, left eye; SD, standard deviation

Table 2. Best-corrected visual acuity, central macular thickness, subfoveal choroidal thickness before and at one, two, and three
months after monthly injection of intravitreal ziv-aflibercept.

Baseline Month 1 Month 2 Month 3

Values Values Changes P-value Values Changes P-value Values Changes P-value

BCVA 0.58 ± 0.29 0.47 ± 0.31 –0.15 ± 0.22 0.202 0.4 ± 0.24 –0.19 ± 0.26 0.002 0.37 ± 0.23 –0.22 ± 0.27 <0.001

CMT 396 ± 119 344 ± 115 –52 ± 123 0.057 305 ± 89 –91 ± 132 <0.001 296 ± 101 –102 ± 144 <0.001

SFCT 236 ± 47 245 ± 56 9 ± 55 >0.99 254 ± 54 18 ± 55 0.197 241 ± 54 7 ± 61 >0.99

P-value calculated using paired T-test
BCVA, best-corrected visual acuity; CMT, central macular thickness; SFCT, subfoveal choroidal thickness

Table 3. Correlation between central macular thickness changes, best corrected visual acuity changes, and subfoveal choroidal
thickness changes at one, two, and three months after monthly injection of intravitreal ziv-aflibercept.

Time CMT and BCVA SFCT and CMT SFCT and BCVA

Month 1 Pearson Correlation 0.436** 0.186 –0.025

P-value 0.002 0.165 0.864

Month 2 Pearson Correlation 0.446** 0.006 0.028

P-value 0.001 0.966 0.845

Month 3 Pearson Correlation 0.456** 0.104 0.047

P-value 0.001 0.453 0.743

**Correlation is significant at the 0.01 level (2-tailed)
BCVA, best-corrected visual acuity; CMT, central macular thickness; SFCT, subfoveal choroidal thickness

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Ziv-aflibercept for DME ; Moradian et al

thickness in DME has not been evaluated so far.
In our study, SCT did not significantly change after
IVZ injection in patients with CI-DME. In addition,
despite adequate sample size and statistical
power of the analysis, we observed no correlation
between SCT and changes of CMT and BCVA
after IVZ injections. It might be related to different
receptor density and sensitivity of retinal and
choroidal vasculature to VEGF. It is believed that
choroidal thickness reduction in DME may be
related to factors other than VEGF. Hence, VEGF
may not be the sole contributor to choroidal
thickness changes in DR.[26]

There were few limitations in the current study.
It lacked a contralateral eye comparison. The
absence of correlation between IVZ and changes
in choroidal thickness might be related to the short
follow-up time of the study. In addition, we did
not compare the effect of IVZ with other forms
of anti-VEGFs. SCT changes might not represent
the changes of the entire choroidal tissue. A
more detailed assessment of the choroidal vascular
index and stromal area could be a better way to
assess the choroidal structure changes in response
to intravitreal anti-VEGF injections.

In summary, IVZ is a promising form of
anti-VEGF drug used to improve visual and
anatomical outcomes in patients with CI-DME
without significant short-term toxicity. The visual
and anatomical effects of IVZ on DME are not
correlated with any changes in SCT.

Financial Support and Sponsorship

None.

Conflicts of Interest

None of the authors have any conflicts of interest
to declare.

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