Clinical Outcomes of Anti-VEGF Monotherapy Versus Combination Therapy in Diabetic Macular Edema: A Retrospective Cohort Study

Summary

Here, we present a retrospective study (n=200) comparing anti-VEGF versus combination therapy, which showed faster early gains with combination therapy, but no sustained 6-month benefit and higher risks of elevated intraocular pressure and cataract progression.

Abstract

Diabetic macular edema (DME) is a leading cause of blindness involving vascular endothelial growth factor (VEGF) leakage and inflammation. This retrospective, single-center cohort study evaluated the efficacy and safety of intravitreal anti-VEGF monotherapy versus combination therapy with anti-VEGF plus dexamethasone implant in DME. A total of 200 patients (one eye per patient) treated between January 2021 and December 2024 were included, with 100 receiving anti-VEGF monotherapy and 100 receiving combination therapy. Best-corrected visual acuity (BCVA), central macular thickness (CMT), adverse events, and quality of life (NEI-VFQ-25) were assessed at baseline and at 1, 3, and 6 months. At 1 and 3 months, the combination therapy group showed faster improvement in BCVA (0.53±0.14 vs. 0.61±0.14 at 1 month; 0.46±0.13 vs. 0.53±0.12 at 3 months) and CMT (342±52 µm vs. 380±55 µm at 1 month; 315±48 µm vs. 345±50 µm at 3 months) compared with the monotherapy group (all P < 0.05), along with a higher rapid response rate (68.0% vs. 42.0%, P < 0.001). However, these differences were no longer significant at 6 months. The combination therapy group had higher rates of elevated intraocular pressure (18% vs. 6%, P < 0.05) and cataract progression (12% vs. 3%, P < 0.05). In conclusion, combination therapy was associated with faster early improvement in visual acuity and macular edema resolution within the first 3 months, but this early advantage was not sustained at 6 months and was accompanied by increased risks of elevated intraocular pressure and cataract progression.

Introduction

Diabetic macular edema (DME), as one of the most severe microvascular complications of diabetic retinopathy (DR), has become the leading cause of irreversible vision loss and legal blindness among working-age adults worldwide¹. The persistent rise in global diabetes prevalence has led to an increased burden of DME, posing severe challenges to individual quality of life and public health systems. Epidemiological data confirm that the prevalence of DME reaches 10% among individuals with a 20-year history of diabetes. The risk of this condition is directly correlated with the level of glycemic, blood pressure, and lipid control, making systematic management crucial².

The pathophysiology of DME involves a chronic, low-grade inflammatory process with multiple signaling pathways. Vascular endothelial growth factor (VEGF) plays a central role in the pathogenesis of DME, primarily by inducing a marked increase in vascular permeability and compromising the blood-retinal barrier through the disruption of inter-endothelial tight junctions³. In this, intravitreal injections of anti-VEGF drugs (such as ranibizumab, aflibercept, or bevacizumab) rapidly reduce vascular leakage by specifically neutralizing VEGF. Over the past decade, they have been established as the first-line standard treatment for DME with foveal involvement. Their efficacy in improving visual acuity has been demonstrated in multiple large randomized controlled clinical trials^4,5,6.

However, limitations of anti-VEGF monotherapy have gradually become apparent. First, approximately 30–40% of patients continue to experience persistent or recurrent macular edema despite adequate anti-VEGF treatment, a phenomenon often termed “treatment resistance⁷. This suggests that mechanisms beyond the VEGF pathway, particularly inflammation, contribute to the disease. Elevated levels of inflammatory mediators such as interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1) have been observed in the vitreous and aqueous humor of DME patients, and these factors can compromise blood-retinal barrier function. Therefore, for DME subtypes with a prominent inflammatory component, VEGF inhibition alone may be insufficient. Second, anti-VEGF treatment requires frequent injections and close follow-up, imposing significant time and financial burdens on patients and healthcare systems, which may reduce treatment adherence and affect long-term visual outcomes.

To overcome these challenges, researchers have turned their attention to corticosteroids (CS), which offer broad-spectrum anti-inflammatory effects and help stabilize the blood-retinal barrier⁸. Intravitreal dexamethasone implants provide sustained drug release for up to six months, potentially reducing treatment frequency. Despite their marked efficacy in reducing central macular thickness (CMT) and their inclusion in multiple treatment guidelines for DME, their clinical application remains constrained by two primary adverse effects: secondary intraocular pressure elevation^9,10.

Against this backdrop, the concept of "combination therapy" has emerged as a potential strategy in DME treatment. The theoretical rationale is that anti-VEGF agents target the VEGF pathway to control acute leakage, while corticosteroids provide broader anti-inflammatory effects that may address non-VEGF-dependent pathways^11,12. This approach has been hypothesized to offer faster anatomical resolution and potentially reduce treatment frequency¹³. However, it also introduces well-known corticosteroid-related risks, including elevated intraocular pressure and cataract progression. Given these trade-offs, the clinical value of combination therapy remains under investigation. This retrospective cohort study, therefore, aimed to compare the efficacy and safety of anti-VEGF monotherapy versus combination therapy with anti-VEGF plus dexamethasone implant in patients with DME, with a focus on early versus mid-term outcomes and the trade-off between therapeutic benefit and corticosteroid-related risks.

Protocol

This study was approved by the Institutional Review Board (IRB) of Guangdong Provincial People’s Hospital(Approval No.: GY--20200618). This clinical study complies with relevant ethical regulations, such as the Declaration of Helsinki¹⁴ and international research ethics standards. Informed consent was waived for this retrospective analysis of anonymized clinical data, with all identifiers removed to ensure privacy.

1. Patient selection and preoperative assessment (Figure 1)

Potential patients were screened for a diagnosis of center-involving DME, which was confirmed by optical coherence tomography (OCT) and defined as CMT > 300 µm. The diagnosis of type 2 diabetes mellitus was confirmed, and BCVA was verified to be between 0.05 and 0.5 on the Snellen chart (approximately 1.3 to 0.3 logarithm of the minimum angle of resolution (LogMAR)). For study purposes, BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart and converted to LogMAR units for analysis, with Snellen equivalents provided for clinical reference.

Figure 1: Research flowchart. Please click here to view a larger version of this figure.

The study cohort was established by applying predefined inclusion criteria¹⁵. Only patients with central macular edema (CMT > 300 µm) confirmed by OCT were included. Patients were required to have type 2 diabetes and baseline BCVA between 0.05 and 0.5 on the Snellen chart. Additionally, only patients with complete clinical data and a planned follow-up duration of ≥6 months were included.

Exclusion criteria were applied to ensure patient safety and protocol validity^16,17. Patients with a history of intraocular surgery or laser treatment in the study eye within the past six months were excluded. Patients with co-existing ocular pathologies such as glaucoma, neovascular age-related macular degeneration, or retinal vascular occlusion in the study eye were also excluded. Individuals with known hypersensitivity to any component of ranibizumab, aflibercept, or dexamethasone were excluded, as were pregnant or lactating women.

A post-hoc sample size estimation was performed to assess the statistical adequacy of the retrospective dataset. Statistical software¹⁸ was used for the calculation, which was based on the primary efficacy measure (change in BCVA from baseline to 6 months), with a significance level (α) of 0.05 (two-tailed) and statistical power (1 – β) of 0.8, and assuming a large effect size (d=0.8) based on relevant literature¹⁹. The estimated minimum sample size was 58 patients per group (total 116). To account for a potential dropout rate of approximately 20% and to enable exploratory subgroup analyses, we enrolled 100 patients per group. This sample size provides adequate statistical power for the primary and secondary analyses.

A total of 200 patients were enrolled in this study, with 100 patients assigned to each treatment group. For patients with bilateral DME, only the study eye meeting the inclusion criteria was selected for analysis. If both eyes were eligible, the eye with the worse baseline BCVA was designated as the study eye to avoid within-patient correlation bias.

Follow-up and data completeness. All 200 enrolled patients completed the 6-month follow-up period. No patients were lost to follow-up, and no data were missing for the primary efficacy and safety endpoints. Therefore, no imputation methods were required.

Treatment group assignment
Treatment selection was determined by the attending ophthalmologist based on comprehensive clinical evaluation, including disease severity, inflammatory features (e.g., presence of hard exudates or cystoid edema on OCT), patient preference, and economic considerations. Patients with a history of glaucoma or significant lens opacity were more likely to receive anti-VEGF monotherapy to avoid corticosteroid-related adverse events. All treatment decisions were made prior to and independently of the study design.

Distribution of anti-VEGF agents. Ranibizumab and aflibercept were used in both groups. The distribution of these agents across groups is reported in the Results section (Additional treatment exposure data). The choice of anti-VEGF agent was not controlled in the analysis, and this heterogeneity is acknowledged as a limitation.

Treatment administration
All intravitreal injections were performed in a sterile operating room setting. The procedures were conducted by an experienced ophthalmologist. Preoperative topical anesthesia was administered, and routine antisepsis of the conjunctival sac was performed. Postoperative topical antibiotic eye drops were prescribed to prevent infection.

For patients assigned to the combination therapy group, the initial treatment consisted of same-day administration of both the anti-VEGF agent (ranibizumab 0.5 mg or aflibercept 2 mg) and the dexamethasone intravitreal implant (0.7 mg). The anti-VEGF agent was administered first via intravitreal injection, followed by administration of the dexamethasone implant in a separate quadrant using its dedicated injector system. Patients were classified as receiving combination therapy if they received at least one dexamethasone implant during the 6-month follow-up period. In this study, all patients in the combination group received the implant at baseline, with 32 patients (32.0%) receiving a second implant at month 3 due to recurrent edema. Unlike the monotherapy group, the combination therapy group did not receive a loading phase of three-monthly anti-VEGF injections, as the dexamethasone implant was expected to provide sustained anti-inflammatory coverage during the early treatment period. For subsequent treatments, anti-VEGF re-injection followed either a Treat-and-Extend (T&E) or Pro Re Nata (PRN) regimen (detailed criteria as described below). Re-implantation of the dexamethasone implant was considered based on its duration of efficacy (typically every 4–6 months) and clinical evidence of recurrent edema²⁰.

Regarding the feasibility of this combined regimen, in China, the simultaneous administration of intravitreal anti-VEGF agents and dexamethasone implant on the same day is reimbursed under the national healthcare insurance system for patients meeting specific clinical criteria, including center-involving DME with documented inadequate response to monotherapy or presence of significant inflammatory features.

In the anti-VEGF monotherapy group, only intravitreal anti-VEGF injections (ranibizumab or aflibercept) were administered. Treatment was initiated with a loading phase of three-monthly injections. Thereafter, anti-VEGF re-injection followed the same T&E or PRN criteria as described for the combination therapy group. Specifically, in the T&E regimen, the injection interval was extended by 2-week increments in the absence of disease activity (CMT stable or decreased, no new fluid on OCT, and stable BCVA), up to a maximum of 12 weeks. In the PRN regimen, re-injection was performed upon meeting any of the following: (1) CMT increase ≥50 µm from the lowest recorded value, (2) new or persistent intraretinal or subretinal fluid on OCT, or (3) BCVA decline of ≥5 letters compared to the previous visit²¹.

Observation and measurement procedures
Primary efficacy endpoints were assessed at baseline, 1, 3, and 6 months post-treatment. BCVA was measured using a standard ETDRS chart or equivalent under standardized lighting conditions, and the results were converted to LogMAR units for recording and analysis²². CMT was measured using spectral-domain OCT, with the device's built-in software used to calculate the average retinal thickness within a 1 mm-diameter central subfield centered on the fovea. Treatment response was defined and evaluated as follows: "Rapid Response" was defined as a reduction in CMT of ≥100 µm at the 1-month visit compared to baseline, while "Effective Response" was defined as an improvement in BCVA of ≥5 letters (≈0.1 LogMAR) and a reduction in CMT of ≥20% at the 6-month visit compared to baseline²³. Lens changes were quantified using anterior segment optical coherence tomography (AS-OCT) to measure lens thickness (LT) and lens density (LD) at each follow-up visit²⁴. Cataract outcomes were analyzed only in phakic eyes at baseline (i.e., patients with prior cataract surgery or aphakia were excluded from lens-specific analyses). Baseline lens status was comparable between groups (Table 1), and no adjustment was made for lens status beyond this exclusion.

Safety indicators were monitored at each follow-up visit. Intraocular pressure (IOP) was measured using a calibrated tonometer, and any elevation defined as IOP > 25 mmHg or an increase of >10 mmHg from baseline was recorded²⁵. The lens was assessed using slit-lamp biomicroscopy, and any new onset or progression of cataract was documented and graded according to the Lens Opacities Classification System III (LOCS III)²⁶. All adverse events, including serious adverse reactions such as endophthalmitis, retinal detachment, or infectious keratitis, were documented²⁷. Quality of life was evaluated using the validated Chinese version of the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25)²⁷. The questionnaire was administered by trained research staff at baseline and at each follow-up visit (1, 3, and 6 months) in a standardized manner.

Data management and statistical analysis
Statistical analysis was performed using appropriate software. Quantitative data that were normally distributed were presented as mean ± standard deviation (x̄ ± s). Continuous variables between the two treatment groups at each time point were compared using independent samples t-tests. To evaluate the overall treatment effect over time and assess the interaction between treatment group and time, a two-way repeated-measures analysis of variance (ANOVA) with group (combination therapy vs. monotherapy) as the between-subjects factor and time (baseline, 1 month, 3 months, 6 months) as the within-subjects factor was performed. This model enabled formal testing of the group × time interaction, which is essential for determining whether the treatment effect differs across groups over the follow-up period. Categorical data were presented as counts and percentages (n, %), and comparisons between groups were performed using the Chi-square test or Fisher's exact test, as appropriate.

Results

Baseline characteristics
As shown in Table 1, baseline characteristics for the combination therapy group and the anti-VEGF monotherapy group (n = 100 each) are as follows. The two groups showed no significant differences in any of the demographic and clinical characteristics assessed, including age, gender, diabetes duration, baseline BCVA and CMT, lens status, and NEI-VFQ-25 scores (all P > 0.05). This indicates that the baseline homogeneity of patients in both groups wa...

Discussion

This retrospective analysis of 200 DME patients over 6 months provides real-world evidence for understanding the clinical value of combined anti-VEGF and corticosteroid therapy. The combination therapy strategy was associated with faster early improvement in visual acuity and macular thickness within the first 3 months. However, this early advantage was not sustained at 6 months and was accompanied by higher rates of corticosteroid-related adverse events. These findings highlight a trade-off between short-term efficacy a...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Aflibercept	Regeneron Pharmaceuticals / Bayer	2 mg/0.05 mL	Anti-VEGF agent used in intravitreal injections.
Anterior Segment OCT (AS-OCT)	Zeiss	Visante OCT / Anterion	Used for measuring lens thickness and density.
Dexamethasone Intravitreal Implant (Ozurdex®)	Allergan (AbbVie)	0.7 mg	Biodegradable sustained-release corticosteroid implant.
National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25)	N/A	N/A	Patient-reported quality of life assessment tool.
Non-contact Tonometer	Suzhou Liuliu Vision Technology Co., Ltd.	YZ30	Pneumatic tonometer for intraocular pressure (IOP) monitoring.
Optical Coherence Tomography (OCT)	Shenzhen Moting Medical Technology Co., Ltd.	Colombo IOL series	Used for measuring Central Macular Thickness (CMT).
Povidone-Iodine 5% Ophthalmic Solution	Alcon	5% w/v sterile solution	Gold standard for pre-intravitreal injection antisepsis. Used for conjunctival sac and eyelid skin disinfection. Contact time ≥30 seconds, followed by irrigation with sterile BSS to minimize endophthalmitis risk.
Ranibizumab	Novartis	0.5 mg/0.05 mL	Anti-VEGF agent used in intravitreal injections.
Sample Size Calculation Software	G*Power	Version 3.1	Used for a priori power analysis.
Slit Lamp Microscope	Wuhan Yijiexun’an Trading Co., Ltd. / Shanghai Yimu Medical Equipment Co., Ltd.	YZ5G	For cataract assessment using LOCS III grading.
Statistical Analysis Software	IBM SPSS Statistics	Version 25.0	Used for all data analysis.
Topical Antibiotic Eye Drops	Alcon	0.5% Moxifloxacin	Broad-spectrum fluoroquinolone, common choice for post-operative prophylaxis.Frequently specified in clinical trial protocols, typically used QID for 3-7 days post-injection.
Topical Anesthetic Eye Drops	Akorn	0.5% Proparacaine HCl	Most commonly used topical anesthetic.Rapid onset (~20 seconds). 1-2 drops are instilled pre-injection for adequate corneal and conjunctival anesthesia.
Visual Acuity Chart	Wenzhou Xingkang Medical Technology Co., Ltd.	XK100	Low-vision chart for BCVA testing, converted to LogMAR.