Efficacy of ranibizumab with laser in the treatment of diabetic retinopathy compare with laser monotherapy: A systematic review and meta-analysis

Abstract

Background

Diabetic retinopathy (DR) is one of the serious complications of diabetes mellitus. Laser therapy is the traditional treatment for DR, and the role of vitreous injection of ranibizumab in DR requires evaluation. This meta-analysis aimed to compare the efficacy of ranibizumab combined with laser versus laser monotherapy in treating diabetic retinopathy.

Method: We searched PubMed, Scopus, Web of Science, Embase, China Biology Medicine Disc (CBM), China National Knowledge Infrastructure (CNKI), and Wanfang databases, from their inception to October 2024. Randomized controlled trials (RCTs) that compared the effectiveness of ranibizumab combined with laser versus laser monotherapy in the treatment of diabetic retinopathy were searched. We used the Cochrane Collaboration tool to evaluate the risk of bias.

Results

Our analysis included 18 studies. The improvement time for retinal edema in the ranibizumab combined with the laser group was significantly shorter than that in the laser monotherapy group (P < 0.05). The time to absorb fundus hemorrhage in the ranibizumab combined with the laser group was significantly shorter than that in the laser monotherapy group (P < 0.05). The absorption time of fundus exudation in the ranibizumab combined with the laser group was significantly lower than that of the laser monotherapy group (P < 0.05). The rate of improvement in vision in the ranibizumab combined with the laser group was significantly higher than that of the laser monotherapy group (P < 0.05). There were no significant differences in the incidence of adverse reactions (P > 0.05) and retinal thickness in the macula (P > 0.05) between ranibizumab combined with the laser group and the laser monotherapy group.

Conclusion

The combination of ranibizumab and laser for diabetic retinopathy is more effective than laser monotherapy.

Keywords

ranibizumab laser therapy diabetic retinopathy

Impact statements

Ranibizumab and laser therapy are used to treat diabetic retinopathy.

The combination of ranibizumab and laser for diabetic retinopathy is more effective than laser monotherapy.

1 Introduction

Diabetic retinopathy (DR) is a common microangiopathy associated with diabetes. The global prevalence of DR among diabetic patients is 22.27%, and it is estimated that the number of patients with DR will increase to 160.50 million by 2025.¹ The leading cause of DR is damage to the retinal microvascular system. The retinal capillaries are damaged after damage to the microvessels due to high blood glucose. Leakage can lead to edema, hemorrhage in the surrounding tissues, and capillary occlusion. This cascade of events results in retinal ischemia, hypoxia, and neovascularization. This gives rise to numerous retinal hemorrhages and substantial intravitreous accumulation of blood. The consequential pulling forces may lead to retinal detachment, posing a risk of varying degrees of vision loss. Without timely interventions, this progression could ultimately culminate in blindness, significantly diminishing the quality of life for individuals affected by diabetes.² Globally, over 161 million people experience visual impairment, and cases of blindness attributed to diabetic retinopathy DR constitute 4.8% of the total global blindness burden.³ The main treatments for DR are vitreous injection of antivascular endothelial growth factor drugs, laser therapy, and vitrectomy.⁴

There are many controversies about the efficacy of vitreoretinal injection of Ranibizumab and laser therapy for DR.⁵ Ranibizumab, a high-affinity anti-vascular endothelial growth factor Fab that neutralizes all subtypes of VEGF-α,⁶ which is a monoclonal antibody after bevacizumab. Ranibizumab binds to vascular endothelial factor to induce macular edema to subside and can allow retinal neovascularization to subside in patients with DR,⁷ thereby preventing pathologic vascular leakage, angiogenesis. Laser monotherapy can reduce neovascularization by destroying the peripheral retinal area but preserving central vision, leading to retinal neovascularization regression and reducing the risk of severe vision loss in diabetic retinopathy.⁸ A meta-analysis has explored the efficacy of Ranibizumab in combination with laser therapy for the treatment of DR and found that the combination improves the treatment effectiveness of DR,⁹ however, we are unsure of whether the combination treatment is superior to laser monotherapy. So this meta-analysis aimed to compare the efficacy of ranibizumab in combination with laser therapy against laser monotherapy for treating DR.

2 Method

This analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA).

2.1 Search strategy

We searched PubMed, Scopus, Web of Science, Embase, CBM, CNKI, and Wanfang databases, from their inception to October 2024. Key search terms included (1) ranibizumab or its synonyms, (2) laser therapy or its synonyms, and (3) diabetic retinopathy or its synonyms. Details can be found in Supplemental Frame 1. Literature retrieval, screening and data extraction were done independently by two researchers(Ju Huang and Xin Liang), and then the information obtained by both of them was cross-checked, and if there was any literature with disagreement, the two of them would first have a discussion to decide whether to include it or not, and if they still couldn't decide whether to include it or not, then a third scholar(Pan Hu) would join the discussion to decide.

2.2 Selection criteria

Inclusion criteria were (1) subjects were individuals with DR, (2) RCTs, and (3) the interventions investigated included ranibizumab combined with laser therapy (experimental group) and laser monotherapy alone (control group). Outcome indicators included four elements: (1) the duration of the improvement of retinal edema, (2) the absorption time of fundus hemorrhage, (3) the absorption time of fundus exudation, and (4) the improvement rate of vision. Studies were excluded if they did not have access to valid outcome data or if they were duplicates.

2.3 Data extraction

We retrieved the following information: author details, study period, study design, diagnostic technique, group categorization, sample size, participant age, treatment modalities, and outcomes. In cases of incomplete data, we contacted the respective authors via email for additional information. The data extraction process involved three researchers, and the results were cross-checked to ensure accuracy.

2.4 Quality assessment

Two reviewers evaluated the quality of included studies using the Cochrane Collaboration's tool for assessing the risk of bias, which includes 6 domains, including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. Each indicator is evaluated using “low bias,” “high bias,” or “uncertain.”

2.5 Statistical analyses

Stata 15.1 was used for data analysis. Dichotomous variables are described using odds ratios (OR), while standardized mean difference (SMD) is used for continuous variables. Heterogeneity was assessed using the chi-square test, considering P < 0.1 and I²> 50% indicative of heterogeneity, prompting a random-effects model. In contrast, a fixed-effects model was applied if P > 0.1 and I²< 50%. Statistical testing of the combined effect sizes was conducted using the Z test. Sensitivity analyses were performed using the one-by-one exclusion method. Publication bias was evaluated using the Egger test.

3 Results

3.1 Literature screening

A total of 1801 articles were screened, with 736 identified as duplicates. Following the abstract review, 893 articles were excluded based on study type. After examination of the full text, 154 articles were excluded, as illustrated in Figure 1. Ultimately, 18 articles^10–27 were included in the meta-analysis (Supplemental Table 1).

Figure 1.

PRISMA flowchart.

3.2 Quality assessment

Regarding random sequence generation, 14 studies^{10–12,14–17,19,21–26} were rated as “low,” while 4 studies^13,18,20,27 were rated as “high.” In terms of allocation concealment, 11 studies^{10–12,15,17,21–26} received a “low” rating, and 7^{13,14,16,18–20,27} were rated “high.” All 18 studies^10–27 received a “low” rating for blinding of participants and personnel and for blinding of outcome assessment. For incomplete outcome data, 16 studies^{10–20,23–27} were rated “low,” and 2^21,22 were rated “high.” In the evaluation of selective reporting, 14 studies^{11,12,14–19,21–24,26,27} were rated “low,” while 4^10,13,20,25 were rated “high.” Two studies^10,18 were rated “high” for other biases, and 16^{11–17,19–27} were deemed “uncertain.” Details are provided in Supplemental Table 2.

3.3 Improvement time of retinal edema

The improvement time of retinal edema was reported in 18 studies.^10–27 The heterogeneity test revealed significant heterogeneity with I²= 83.4%, P < 0.1. Using a random-effects model, the combined SWD was −2.77 (95% CI: −3.10 to −2.45), suggesting that the improvement time for retinal edema in the experimental group was significantly lower than in the control group (z = 16.69, P < 0.01). Figure 2 shows a visual representation of these findings.

Figure 2.

Forest plot and meta-analysis of the improvement time of retinal edema.

3.4 Absorption time of fundus hemorrhage

The absorption time of fundus hemorrhage was reported in 18 studies.^10–27 The heterogeneity test demonstrated significant heterogeneity with I²= 94.0%, P < 0.1. Using a random-effects model, the combined SWD was −2.57 (95% CI: −3.10 to −2.04), suggesting that the absorption time of fundus hemorrhage in the experimental group was significantly lower than in the control group (z = 9.49, P < 0.05). Figure 3 shows a visual representation of these results.

Figure 3.

Forest plot and meta-analysis of absorption time of fundus hemorrhage.

3.5 Absorption time of fundus exudation

The absorption time of fundus exudation was reported in 18 studies.^10–27 The heterogeneity test revealed significant heterogeneity with I²= 89.6%, P < 0.1. Using a random-effects model, the combined SWD was −1.87 (95% CI: −2.21 to −1.52), suggesting that the absorption time of fundus exudation in the experimental group was significantly lower than in the control group (z = 10.50, P < 0.05). Figure 4 shows a visual representation of these results.

Figure 4.

Forest plot and meta-analysis of absorption time of fundus exudation.

3.6 Improvement rate of vision

The improvement rate of vision was reported in 18 studies.^10–27 The heterogeneity test did not indicate significant heterogeneity with I²= 0.2% and P = 0.452. Using a fixed-effect model, the combined OR was 2.37 (95% CI 1.95 to 2.88), suggesting that the improvement rate of vision in the experimental group was significantly higher than in the control group (z = 8.72, P < 0.05). Figure 5 shows a visual representation of these results.

Figure 5.

Forest plot and meta-analysis of the improvement rate of vision.

3.7 Incidence of adverse reactions

The incidence of adverse reactions was reported in 9 studies.^{10,12,14,17,18,23,25,27} The heterogeneity test indicated significant heterogeneity with I²= 75.1% and P < 0.1. Using a random-effects model, the combined OR was 0.40 (95% CI: 0.12 to 1.31), suggesting that the incidence of adverse reactions in the experimental group was lower than in the control group, but the differences were not statistically significant (z = 1.52, P = 0.128). Details are shown in Supplemental Figure 1.

3.8 Retinal thickness in the macula

The retinal thickness in the macula was reported in 11 studies.^{10,13–15,17,18,22,23,25–27} The heterogeneity test indicated significant heterogeneity with I²= 98.4% and P < 0.1. Using a random-effects model, the combined SWD was 0.22 (95% CI: −0.98 to 1.41), suggesting that the retinal thickness in the macula in the experimental group was higher than in the control group, but the differences were not statistically significant (z = 0.36, P = 0.722). Supplemental Figure 2 shows the visual representation of these results.

3.9 Subgroup analysis

The studies were divided into four subgroups based on publication time, sample size, intravitreal (IVT) treatment sequence, and ranibizumab dose. Subgroup analyses for both the improvement time of retinal edema and the absorption time of fundus hemorrhage show that none of the four factors explained the source of heterogeneity (I²> 50%, P < 0.1). Detailed results are shown in Supplemental Table 3A and Table 3B.

3.10 Absorption time of fundus exudation

In the subgroup analysis of the absorption time of fundus exudation, there was no heterogeneity within the second IVT starting group (I²= 0.0, P = 0.439). However, heterogeneity was present within the IVT first treatment group (I²> 50%, P < 0.1). Heterogeneity persisted in the other three subgroups. Additional details can be found in Supplemental Table 3C.

3.11 Incidence of adverse reactions

The subgroup analysis of the incidence of adverse reactions revealed the following results. In the pre-2020 group, there was significant heterogeneity in the incidence of adverse reactions (I²> 50%, P < 0.1), while in the group after 2020, there was no significant heterogeneity (I²= 17.6, P = 0.297). There was no heterogeneity in the incidence of adverse reactions in the group with a sample size of 50–100 (I²= 0.0, P = 0.495). Still, there was heterogeneity in the group with a sample size of ≥100 (I²> 50%, P < 0.1). No heterogeneity was observed in the incidence of adverse reactions in the first IVT treatment group (I²= 0.0, P = 0.857), while there was significant heterogeneity in the second IVT starting group (I²> 50%, P < 0.1). In the ranibizumab dose < 1 mg group, there was no heterogeneity in the incidence of adverse reactions (I²= 0.0, P = 0.990), while significant heterogeneity was observed in the ranibizumab dose ≥ 1 mg group (I²> 50%, P < 0.1). Detailed results are presented in Supplemental Table 3D.

3.12 Retinal thickness in the macula

The subgroup analysis of retinal thickness in the macula revealed no heterogeneity in the group with publication time after 2020 (I²= 0.0, P = 0.736). In contrast, a significant heterogeneity was observed in the group of publication time before 2020 (I²> 50%, P < 0.1). Specifically, heterogeneity persisted within the publication time before the 2020 group (I²> 50%, P < 0.1). Furthermore, heterogeneity was evident in the other three subgroups as well. Details are shown in Supplemental Table 3E.

3.13 Meta-regression

We incorporated publication time, sample size, sequence of IVT treatments, and ranibizumab dosage as four covariates in the meta-regression analysis. Publication time and sample size significantly contribute to explaining the inconsistency in the improvement time of retinal edema (P<0.05). Moreover, the sample size was identified as a factor that may present a part of the inconsistency in the absorption time of fundus exudation (P<0.05). However, these four covariates could not elucidate the sources of heterogeneity in the absorption time of fundus hemorrhage, the incidence of adverse reactions, and the retinal thickness in the macula (P > 0.05). Detailed information can be found in Supplemental Tables 4A-4E.

3.14 Sensitivity analysis

Sensitivity analysis was performed using the one-by-one exclusion method, and the results show that regardless of the literature excluded, there were no effects on the combined results of the six outcome indicators, indicating that the combined results of the meta-analysis were robust and reliable.

3.15 Publication bias

We utilized Egger's test to examine publication bias. There were significant publication bias in the improvement time of retinal edema (t = −2.49, P = 0.024), the absorption time of fundus exudation (t = −3.58, P = 0.003), and the improvement rate of vision (t = 3.88, P = 0.001). In contrast, no publication bias was detected in the absorption time of fundus hemorrhage (t = −0.69, P = 0.500), the incidence of adverse reactions (t = −2.43, P = 0.072), and retinal thickness in the macula (t = 0.30, P = 0.774).

We used the trim and fill method to assess outcome indicators with publication bias. After including four virtual studies in the improvement time of retinal edema, the heterogeneity test results were as follows: Q = 168.95, P < 0.0001. Using a random-effects model, the combined SMD remained unchanged at −2.445 (95% CI: −3.10 to −1.79). Similarly, after incorporating six virtual studies in the improvement rate of vision, the heterogeneity test yielded Q = 32.65, P = 0.087. The combined OR was 2.03 (95% CI: 1.69 to 2.44), in a random-effect model, and the combined results remained consistent.

Regarding the absorption time of fundus exudation, including one virtual study resulted in a heterogeneity test outcome of Q = 205.52, P < 0.0001. Using a random-effects model, the combined SMD remained stable at −1.774 (95% CI: −2.60 to −0.95). These results indicate the robustness of the combined findings for these three indicators, suggesting that they are not significantly influenced by publication bias.

4 Discussion

This analysis revealed that the combination of ranibizumab and laser therapy for DR exhibited greater efficacy compared to laser monotherapy in several aspects, including the improvement time of retinal edema, the absorption time of fundus hemorrhage, the absorption time of fundus exudation, and the improvement rate of vision. However, no significant differences were observed in the incidence of adverse reactions and retinal thickness in the macula.

Previous research has explored the effects of different therapeutic approaches on vision in DR patients. A study compared the efficacy of ranibizumab monotherapy, ranibizumab + laser, and laser monotherapy for DR, and ranibizumab + laser demonstrated superior improvements in visual acuity compared to laser monotherapy.²⁸ Another study involving 345 cases of DR found that ranibizumab + laser improved visual acuity more than laser monotherapy.²⁹ Ranibizumab + laser was more effective than laser monotherapy in treating DR associated with visual impairment.³⁰ Consistent with these findings, our study also observed that the combination of ranibizumab and laser therapy for DR led to an increased improvement rate of vision, further underscoring its superior effectiveness compared to laser monotherapy.

The progression of DR is a multifaceted and variable pathological process that ultimately induces alterations in the anatomy and function of retinal cells. This leads to increased secretion of vascular endothelial growth factor (VEGF) by retinal cells, disrupting the intraretinal barrier.³¹ Consequently, neovascularization and retinal edema ensue, contributing to impaired vision. Ranibizumab, a recombinant human monoclonal anti-VEGF antibody fragment, binds to VEGF-A and quickly targets the focal area. This action reduces VEGF-induced neovascularization and decelerates retinal exudation and hemorrhage, thus restoring visual acuity.³² Laser treatment for DR operates on the principle of the thermal effect of the laser, coagulating proteins through local tissue heating. This process ablates ischemic zones and reduces the oxygen consumption of the retina.³³ The laser facilitates increased oxygen supply to the inner retina from the choroid and capillaries, promoting repair of the retinal structure and function and ultimately improving the patient's visual acuity. Although ranibizumab requires frequent injections to maintain efficacy due to its short half-life, it cannot address issues such as retinal non-perfusion zones, microaneurysms, abnormal capillary dilation, and neovascular glaucoma.

On the other hand, laser treatment can eliminate capillary nonperfusion zones and effectively reduce the risk of blindness.³⁴ The combined use of ranibizumab and laser not only ensures treatment efficacy but also minimizes retinal damage. Consequently, combined ranibizumab therapy with laser therapy has a superior effect on improving visual acuity compared to laser monotherapy.

In addition to increasing the rate of visual acuity improvement, the combination of ranibizumab with laser treatment demonstrated superior efficacy in reducing retinal edema and facilitating the absorption of fundus hemorrhage and exudate compared to laser monotherapy. A potential explanation for this lies in the characteristic thickening of the capillary basement membrane in the retina of patients with DR, predisposing them to the development of capillary hemangiomas. This thickening induces ischemia and hypoxia in the patient's retina, triggering the release of VEGF and ultimately leading to retinal hemorrhage and exudation.³⁵ Unlike laser monotherapy, ranibizumab exerts inhibitory effects on neovascularization, decreases fundus vascular permeability, and regulates the blood-retinal barrier's permeability. This mechanism promotes the regression of retinal edema and accelerates the absorption of fundus exudates and hemorrhages.³⁶ Laser monotherapy, on the other hand, can induce retinal contraction, which can lead to serious complications such as macular edema and vitreous cavity hemorrhage.³⁷ In contrast, ranibizumab effectively treats macular edema and vitreous cavity hemorrhage.³⁸ Consequently, the combination of ranibizumab and laser treatment for diabetic retinopathy synergizes these effects, offering a more comprehensive approach to address the multifaceted aspects of the condition.

We conducted a subgroup analysis to explore factors contributing to heterogeneity in various outcome measures. The order of IVT treatment emerged as a partial explanatory factor for the heterogeneity observed in the absorption time of fundus exudation. Additionally, variables such as publication time, sample size, and order of IVT treatment were identified as partial sources of heterogeneity in the incidence of adverse reactions. Furthermore, publication time was identified as a partial explanatory factor for the heterogeneity in retinal thickness in the macula. However, the sources of heterogeneity in retinal edema's improvement time and fundus hemorrhage's absorption time remained unidentified. A hypothesis suggests that glycemic control might be a potential contributing factor. In cases of poor blood glucose control, the compromised retinal capillary barrier is exacerbated, potentially leading to worsening of retinal edema and increased fundus hemorrhage. Consequently, the time required for improvement may be prolonged under such conditions.³⁹

For outcome indicators with I² > 75%, we performed meta-regression to explore sources of heterogeneity and found that publication time and sample size significantly contribute to explaining the inconsistency in the improvement time of retinal edema, the sample size was identified as a factor that may present a part of the inconsistency in the absorption time of fundus exudation. But publication time, sample size, sequence of IVT treatments, and ranibizumab dosage could not elucidate the sources of heterogeneity in the absorption time of fundus hemorrhage, the incidence of adverse reactions, and the retinal thickness in the macula, so more studies are required for further exploration.

This study has several limitations. First, the overall quality of the included studies is assessed as low, underscoring the need for additional high-quality research focused on the treatment of DR. Second, the study included six outcome indicators, and all literature is from China, so the patient population may be underrepresented. Given favorable conditions, future research could benefit from incorporating additional parameters such as best-corrected visual acuity (BVCA), retreatment rates, and the degree of disease progression to provide a more comprehensive understanding of treatment outcomes in DR.

5 Conclusion

The combination of ranibizumab and laser for DR was more effective than laser monotherapy in accelerating the resolution of retinal edema, absorption of fundus hemorrhage, and removal of fundus exudation while simultaneously enhancing the rate of visual improvement. Healthcare professionals should carefully assess individual patient conditions to determine the optimal approach.

Supplemental Material

sj-zip-1-thc-10.1177_09287329241296696 - Supplemental material for Efficacy of ranibizumab with laser in the treatment of diabetic retinopathy compare with laser monotherapy: A systematic review and meta-analysis

Supplemental material, sj-zip-1-thc-10.1177_09287329241296696 for Efficacy of ranibizumab with laser in the treatment of diabetic retinopathy compare with laser monotherapy: A systematic review and meta-analysis by Ju Huang, Xin Liang, Qiu-fen Liu, Ming-jing Zhou, Pan Hu and Shi-chun Jiang in Technology and Health Care

Footnotes

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental material

Supplemental material for this article is available online.

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