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Year : 2019  |  Volume : 32  |  Issue : 4  |  Page : 1447-1451

Evaluation of intravitreal injection of ranibizumab in diabetic macular edema

1 Department of Ophthalmology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Ophthalmology, Health Insurance Organization, Shobra El Kheema, Qalubeya, Egypt

Date of Submission13-Dec-2018
Date of Decision09-Jan-2019
Date of Acceptance26-Jan-2019
Date of Web Publication31-Dec-2019

Correspondence Address:
Ahmed Z Zayed
El Bajour, El Menoufia 32821
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mmj.mmj_410_18

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The aim of this study was to evaluate the intravitreal injection of antivascular endothelial growth factor of ranibizumab in patients with diabetic macular edema (DME).
The study evaluated short-term and long-term effects of ranibizumab on the morphology and function of the retina.
Patients and methods
Fifty eyes of 44 patients with DME were enrolled in this prospective study. After intravitreal ranibizumab injection, central macular thickness (CMT) and best-corrected visual acuity (BCVA) were measured before, 1, 2, 3, and 6 months later.
The mean CMT and logarithm of minimum angle of resolution BCVA improved significantly (P < 0.001) after the first, second, and third injections. Three eyes did not show improvement in CMT while seven eyes did not show improvement in BCVA. The most significant (P < 0.0001) correlation in mean CMT and logarithm of minimum angle of resolution BCVA is seen after the first month. In addition, significant change is seen in CMT (P = 0.001, 0.002) and BCVA (P = 0.0001, 0.001) between the first and second month and second and third month, respectively. Three months after the last injection, mean CMT insignificantly (P = 0.24) increased, and mean BCVA insignificantly (P = 0.51) decreased, but they were still significant with baseline. There was a significant correlation (P < 0.001) between the mean change in CMT and BCVA at all stages of the study.
In DME, intravitreal ranibizumab effectively decreased CMT as a structural aspect and hence improved BCVA as a functional aspect. Evaluation of the short-term effects of ranibizumab can predict the therapeutic outcome 1 month after injection.

Keywords: antivascular endothelial growth factor, central macular thickness, diabetic macular edema, intravitreal injection, ranibizumab

How to cite this article:
Sarhan ARE, Mandour SS, Zayed AZ. Evaluation of intravitreal injection of ranibizumab in diabetic macular edema. Menoufia Med J 2019;32:1447-51

How to cite this URL:
Sarhan ARE, Mandour SS, Zayed AZ. Evaluation of intravitreal injection of ranibizumab in diabetic macular edema. Menoufia Med J [serial online] 2019 [cited 2020 Jun 6];32:1447-51. Available from: http://www.mmj.eg.net/text.asp?2019/32/4/1447/274274

  Introduction Top

Diabetic retinopathy (DR) is the leading cause of preventable blindness among individuals of working age. Visual loss develops secondary to complications of DR, such as diabetic macular edema (DME) [1].

DME is defined as a retinal thickening involving or approaching the center of the macula. The pathological process of DME formation has several principal components; a primary event is the breakdown of the blood–retinal barrier. One of the causes of the breakdown of the blood–retinal barrier seems to be an increase in vascular endothelial growth factor (VEGF) [2].

The recent introduction of the anti-VEGF ranibizumab represents an important improvement in the treatment of DME. It is a Fab fragment of a humanized monoclonal antibody against VEGF-A. It was the first approved drug for DME [3].

A second anti-VEGF, aflibercept, was submitted for European Union marketing authorization on November 2013 [4]. The efficacy and safety of the pegylated anti-VEGF aptamer pegaptanib in the treatment of DME were investigated in phases II and III studies, but the license application was withdrawn in 2011 [5]. Bevacizumab, a full-length anti-VEGF-A antibody developed for the treatment of cancer, has not been developed or licensed for intravitreal injection use [6].

In several randomized clinical trials, patients treated with ranibizumab had a better visual outcome than those treated with other injections and/or laser. In addition to its effect on vision, it markedly decreased retinal thickness [7].

In 1996, the first commercially available optical coherence tomography (OCT) device made it possible to objectively quantify retinal thickness, proving to be sensitive for the detection of DME [8]. The aim of this study was to evaluate the intravitreal ranibizumab injection in DME.

  Patients and Methods Top

A prospective, nonrandomized, and interventional study was conducted on 50 eyes of 44 patients with DME within 20 months starting in January 2017 and ending in August 2018. The study was approved by the organization's institutional ethical committee, and informed patient written consent was obtained.

Patients included were 18 years or older, diagnosed with type I or II diabetes mellitus (DM), with best-corrected visual acuity (BCVA) range of 6/12–3/60, and baseline central macular thickness (CMT) of 350 μm or more by OCT.

The exclusion criteria were eyes with epiretinal or traction membranes, previous vitreoretinal surgeries, panretinal or macular photocoagulation, or use of intraocular steroids or anti-VEGF drugs within the previous 6 months. In addition, eyes with ocular conditions interfering with CMT, such as cataract surgery or YAG capsulotomy, uncontrolled hypertension (systolic >160, diastolic >90 mmHg), uncontrolled DM with glycosylated hemoglobin more than 10%, ocular infection, or history of hypersensitivity reactions were also excluded.

The patients underwent ophthalmologic examinations including measurement of BCVA using Snellen chart at 6 m, and the values were converted to logarithm of minimum angle of resolution (LogMAR) for statistical analyses and slit-lamp biomicroscopy with fundus examination. Investigations included fundus fluorescein angiography (Topcon TRC-50; Topcon Corporation, Japan) and spectral-domain OCT (Topcon 3D OCT-2000;, Topcon Corporation, Tokyo, Japan).

Three intravitreal consecutive monthly injections of anti-VEGF of ranibizumab (Lucentis; Novartis, Basel, Switzerland) at a dose of 0.5 mg/0.05 ml were administered in a sterile manner using a 30-G needle toward the center of the vitreous at 4 mm in phakic or 3.5 mm in pseudophakic eyes and inferotemporally from the limbus.

CMT and BCVA were measured before injection (baseline), at least 28 days after the first, second, and third injections and 6 months from baseline for follow-up. Data were analyzed by SPSS 24 (IBM, New York, New York, USA) using repeated measure analysis of variance, and P value less than 0.05 was considered statistically significant.

  Results Top

The study was conducted on 50 eyes of 27 male patients and 17 female patients with a mean age of 60.27 ± 5.77 years (48–73 years). Fifty-eight percent (29) of injections were administered at right eyes, whereas 42% (21) were administered at left eyes. Twenty-five patients were proven hypertensive. The mean systolic blood pressure was 127.8 ± 9.08 mmHg, while the mean diastolic was 83.14 ± 7.72 mmHg. All patients were diagnosed with type II DM with a mean duration of 15.33 ± 4.49 years and mean glycosylated hemoglobin of 8.37 ± 0.65%. According to fundus fluorescein angiography, three patients were diagnosed with proliferative DR, whereas 41 patients were diagnosed with nonproliferative DR.

The mean baseline CMT was significantly (P < 0.001) decreased from 501.24 ± 90.76 to 417.38 ± 80.85, 380.16 ± 89.5, and 347.8 ± 90.48 μm after the first, second, and third injections, respectively. Three eyes did not show improvement in CMT [Figure 1]. The most significant decrease of CMT (P < 0.0001) was between baseline and after the first injection by 83.86 μm, and a significant decrease (P = 0.001, 0.002) was seen with a difference between the first and second injections by 37.22 μm and between the second and third injections by 32.4 μm, respectively. Three months after the last injection, the mean CMT increased by 3.3 μm. It was insignificant (P = 0.24) in comparison with after the third injection but still significant (P < 0.001) in comparison with baseline [Table 1].
Figure 1: Comparison according to the central macular thickness (n = 50).

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Table 1: Central macular thickness comparison between baseline, 4 weeks after the three injections and 6 months from baseline (n=50)

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The mean LogMAR of unaided visual acuity (VA) of the studied eyes was 1.28 ± 0.25 (≈3/60 Snellen equivalent). The mean baseline LogMAR BCVA was significantly (P < 0.001) improved from 1.03 ± 0.13 (≈6/60 Snellen equivalent) to 0.85 ± 0.19, 0.74 ± 0.22, and 0.64 ± 0.26 (≈6/36, 6/36, 6/24 Snellen equivalent) after the first, second, and third injections, respectively. Seven eyes did not show improvement in BCVA [Figure 2].
Figure 2: Comparison between different injections according to the best-corrected visual acuity in logarithm of minimum angle of resolution (n = 50).

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The most significant improvement of LogMAR BCVA (P < 0.0001) was between baseline and the first injection by 0.18, and a significant improvement (P = 0.0001, 0.001) was seen with a difference between the first and second injections of 0.11 and between the second and third injections of 0.10, respectively. Three months after the last injection, the mean BCVA decreased by 0.03. It was insignificant (P = 0.51) with the third injection but still significant (P < 0.001) with baseline [Table 2].
Table 2: Best-corrected visual acuity comparison between baseline, 4 weeks after the three injections and 6 months from baseline (n=50)

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After three intravitreal injections of ranibizumab, the change in CMT was clinically significant with the change in BCVA (P < 0.001). In the current study, there was no improvement from baseline BCVA in four eyes even with decreased CMT [Table 3].
Table 3: Correlation between central macular thickness and best-corrected visual acuity means at all levels

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  Discussion Top

In the current study, it was observed that ranibizumab significantly improved BCVA and CMT after three consecutive monthly intravitreal injections, and this significance was maintained up to 3 months after the last injection. The results of previous studies concerning the relationship between VA or macular thickness and intravitreal ranibizumab confirm these findings [9].

Previous major clinical trials have reported that VA improvements from baseline tended to be associated with reductions in the CMT from baseline [10]. Indeed, there was a significant (P < 0.01) correlation between the mean change in CMT of all study stages and the mean change in BCVA. One month after each injection, BCVA improved significantly, as a result of reduced macular edema and vascular leakage. These findings are in accordance with previous studies' results concerning the relationship between CMT and VA after ranibizumab [7].

At the same time, in four eyes, CMT improved significantly, as observed by OCT, but the BCVA did not; a decrease in macular thickness without improvement in BCVA shows a discrepancy between OCT findings and visual function [11]. Browning et al. [12] mentioned that, although there was a significant correlation between VA and CMT, there was a great change in VA at any given retinal thickness, and OCT measurement solely may not be a nice replacement for VA as the main result in researches of DME. OCT can only record the degree of edema; the duration of edema and the damage to cells cannot be evaluated. Further study with more functional macular tests is warranted to study the relations between VA, macular state, and CMT.

In the current study, the most significant correlation among the three injections was observed between the baseline CMT and at 1 month after the first injection. It was reported that the baseline CMT might predict the structural outcomes in response to intravitreal ranibizumab [13]. The most significant correlation among the three injections, also, was observed between the baseline BCVA and at 1 month. As previously reported, the baseline BCVA might predict the functional outcome after intravitreal ranibizumab therapy [14]. Taken together, the study speculated that measuring the efficacy as early as 1 month after an intravitreal ranibizumab injection in patients with DME might be predictive of the structural and functional effects of the ranibizumab injection in addition to the prediction from the baseline CMT and BCVA.

Given the nature of ranibizumab as an inhibitor of VEGF and VEGF levels proven to reflect the severity of DR [15], the results obtained in this study agree with the theory that the initial response in retinal thickness is dependent on retinopathy status [16]. In the current study, eyes with lower baseline BCVA and higher baseline CMT thickness tended to have a larger increase in BCVA, and decrease in CMT at 1 month, as previously reported [17].

Pro re nata regimens guided by VA have been reported to be effective for treating DME. However, patients might be undertreated on the basis of OCT findings in treat-and-extend protocols [18]. In order to choose adequate injection regimens, the ability to gauge the required treatment intensity might be helpful. The results of the current study indicated that the short-time change could help with this and predict the long-term response.

In addition, a less CMT and BCVA effect was observed at month 2 than at month 1 and at month 3 than at month 2. This implies that retinopathy severity has an effect on the anatomical outcome following intravitreal ranibizumab. This suggests that other inflammatory or angiogenic cytokines further down the cascade at a later stage may contribute to the pharmacodynamics of ranibizumab, which also resembles that of previous landmark studies [7].

Clinically, acknowledging a slower response in mild retinopathy encourages us to be patient with the treatment of such cases, as the response is not rapid and invites further research into alternative and more focused therapies in managing DME related to mild retinopathy. In summary, our findings support the hypothesis that the initial anatomical response in DME treated with intravitreal ranibizumab depends on the severity of baseline DR, with a more significant response in eyes with severe retinopathy.

The current study has some limitations. First, some data such as blood pressure, glycosylated hemoglobin, and duration of DM were not available. Further study using these data about the effect of the preinjection clinical state of the patient on the results may be added in the future. Second, there may be a need to adjust the criteria of upper limit morphological CMT at which the results of injections will be affected, also, the lower limit of thickness, when we decide not to continue the injection or if cases needed more than three injections to reach the normal limit. In addition, other treatments were not totally excluded; only eyes with other treatments administered less than 6 months before injection were excluded. Total exclusion of these eyes might also affect the results.

Because DME can also be treated by photocoagulation [19], local steroid injection [20], and pars plana vitrectomy [21], the advantages of combined therapies should be investigated in the future. The results of the current study may be valuable in designing future clinical studies for optimizing treatment protocols according to patient characteristics. Some patients required bilateral intravitreal ranibizumab, which may have contributed to patient hesitation due to psychological issues. However, they got full psychological support, and consents were given.

The current study had no control group. It could not exclude the influences of the natural disease course or previous treatments on the current results. It was reported that retinal thickness measurements vary over the course of a day [22]. In the current study, it was not possible to evaluate the effect of circadian fluctuation and the reproducibility and variations in the retinal thickness measurements in both healthy participants and patients. Another study including a control group and repeated measurements is needed.

  Conclusion Top

Current treatment options for DME include macular laser photocoagulation, intravitreal corticosteroids, and anti-VEGF agents (i.e. intravitreal aflibercept, ranibizumab, and bevacizumab). The current findings suggested that intravitreal ranibizumab effectively decreased CMT and improved BCVA. The results were maintained up to 3 months after the last dose of ranibizumab.

Structural and functional effects of intravitreal ranibizumab injection might be detectable as early as 1 month after treatment. The current study believes that evaluation of the short-term effects of the intravitreal ranibizumab can predict the therapeutic outcome 1 month after ranibizumab injection for DME. In addition, rapid response to intravitreal ranibizumab injection can be seen in severe cases of DME.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]


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