Preliminary Efficacy Analysis of Early Combination Therapy with Intravitreal Aflibercept and Dexamethasone Implant for Diabetic Macular Edema

Preliminary Efficacy Analysis of Early Combination Therapy with Intravitreal Aflibercept and Dexamethasone Implant for Diabetic Macular Edema | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Preliminary Efficacy Analysis of Early Combination Therapy with Intravitreal Aflibercept and Dexamethasone Implant for Diabetic Macular Edema Xiaonan Fu, Yue Chen, Dingxi Liu, Beichen Liu, Yongxia Zhao, Sheng Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7500444/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Purpose To evaluate the differences in preliminary clinical efficacy and safety between intravitreal aflibercept monotherapy and early combination therapy with aflibercept and dexamethasone implant (DEX-I) for diabetic macular edema (DME). Methods Prospective study. Fifty-nine patients (59 eyes) diagnosed with DME at the Ophthalmology Department of Dalian Third People's Hospital between March 2024 and December 2024 were enrolled. Patients were divided into an aflibercept monotherapy group (30 patients, 30 eyes) and an aflibercept combined with DEX implant group (29 patients, 29 eyes). The monotherapy group received intravitreal injections of aflibercept (2mg/0.05ml) every 4 weeks for 4 doses, followed by a pro re nata (PRN) regimen until week 24. The combination group received an initial intravitreal injection of aflibercept (2mg/0.05ml) combined with DEX-I (0.7mg) in the same session. From week 4 to week 12, they received monthly aflibercept injections (2mg/0.05ml), followed by a PRN regimen until week 24. Before treatment, all patients underwent best-corrected visual acuity (BCVA) assessment using the ETDRS chart (letters recorded), slit-lamp examination, intraocular pressure (IOP) measurement, indirect ophthalmoscopy, spectral-domain optical coherence tomography (SD-OCT), and optical coherence tomography angiography (OCTA). After treatment, patients in both groups were assessed every 4 weeks ± 7 days until week 24. Results Compared to the monotherapy group, the combination group showed a significantly greater mean increase in BCVA from baseline to week 12 (P < 0.05). The mean BCVA increase from baseline to week 24 was also greater in the combination group (P = 0.094). The proportion of eyes gaining ≥ 15 letters from baseline at week 12 was 58.62% in the combination group versus 30% in the monotherapy group (P < 0.05). Compared to baseline, both groups showed statistically significant reductions in central retinal thickness (CRT) at all follow-up time points (P < 0.001 for all). The difference in CRT reduction between the monotherapy and combination groups was statistically significant at 20 weeks post-injection (P < 0.05). Conclusions Compared to aflibercept monotherapy, early combination therapy with aflibercept and DEX-I resulted in faster visual acuity improvement, greater reduction in central macular thickness, and reduced edema fluctuation in the early treatment phase for DME. Diabetic Macular Edema Aflibercept Injection Dexamethasone Intraocular Implant Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Diabetic retinopathy (DR) remains the leading cause of blindness among individuals of working age, with diabetic macular edema (DME) being the primary contributor to vision loss in these patients [ 1 ] . DME manifests as the accumulation of fluid within the retinal layers, and occasionally beneath the retina, resulting in thickening of the macular region [ 2 ] . This pathological change may lead to symptoms such as blurred vision, distorted images, reduced color sensitivity, and, if left untreated, permanent retinal damage causing irreversible visual impairment. The underlying mechanisms of DME are intricate and involve both vascular and inflammatory pathways [ 3 , 4 ] . Key contributors include vascular endothelial growth factor (VEGF) and various inflammatory cytokines [ 5 ] .Although anti-VEGF therapy is widely accepted as the first-line approach for DME [ 6 ] , a significant proportion of patients-estimated at 30–50% exhibit suboptimal responses [ 7 ] .Corticosteroids by inhibiting phospholipase A2 and the arachidonic acid cascade, help suppress VEGF production and reduce inflammatory cytokine activity. These actions contribute to the stabilization of the blood-retinal barrier, reduction of leukocyte adhesion, enhancement of tight junction integrity in retinal capillaries, improved retinal oxygenation, and protection against endothelial cell damage and apoptosis [ 8 , 9 ] . As a result, intravitreal corticosteroids have gained traction as either alternative or supplementary treatments. Nevertheless, even long-acting steroid formulations often necessitate repeated injections to maintain therapeutic efficacy. Therefore, minimizing injection frequency while achieving optimal outcomes is a shared objective for both clinicians and patients. Given the multifaceted nature of DME pathogenesis, involving diverse signaling pathways, combining anti-VEGF agents with anti-inflammatory treatments has emerged as a practical strategy. In clinical settings, combination therapy is implemented in various ways some practitioners prefer sequential administration, while others opt for simultaneous use. However, there is limited clinical evidence and research regarding the early initiation of simultaneous combination therapy.This study seeks to evaluate the preliminary effectiveness of such an approach, aiming to enrich clinical experience and provide new perspectives on DME management. The initial findings are presented below. 1. Materials and Methods 1.1 Materials Fifty-nine patients (59 eyes) clinically diagnosed with DME at the Ophthalmology Department of Dalian Third People's Hospital between March 2024 and March 2025 were enrolled. There were 22 males (22 eyes) and 37 females (37 eyes), aged 33–80 years (mean age 60.51 ± 10.28 years). Inclusion criteria: (1) Age ≥ 18 years with type 2 diabetes mellitus and glycated hemoglobin (HbA1c) ≤ 12.0%; (2) Study eye baseline BCVA ≥ 34 and ≤ 68 ETDRS letters, with vision loss primarily attributed to DME involving the fovea as determined by the investigator; (3) SD-OCT showing central retinal thickness (CRT) ≥ 300 µm within the macular region, with the presence of intraretinal cysts within 1000 µm of the fovea. Exclusion criteria: (1) Concurrent macular pathologies such as epiretinal membrane, macular hole, vitreomacular interface abnormalities, or macular edema due to other causes (e.g., uveitis, retinal vein occlusion); (2) Retinal laser photocoagulation in the study eye within 90 days prior to treatment; (3) Previous systemic or ocular treatment with anti-VEGF agents or steroids; (4) History of vitreoretinal surgery; (5) History of glaucoma or ocular hypertension; (6) Cerebrovascular accident and/or myocardial infarction within 180 days prior to enrollment; (7) Other conditions deemed by the investigator as requiring exclusion. This study was approved by the Ethics Committee of the Third People's Hospital of Dalian (Approval No.: 2024-047-002). All patients and their families provided informed consent after being fully informed about the study content and protocol. 1.2 Methods 1.2.1 Basic Protocol and Treatment Methods The monotherapy group consisted of 12 males (12 eyes) and 18 females (18 eyes), aged 33–78 years (mean age 60.23 ± 10.91 years). The combination group consisted of 10 males (10 eyes) and 19 females (19 eyes), aged 42–80 years (mean age 60.79 ± 9.73 years). There were no statistically significant differences in preoperative baseline characteristics (gender, age, BCVA, IOP) between the two groups (P > 0.05), as shown in Table 1 . Before treatment, all patients underwent BCVA (ETDRS letters), slit-lamp examination, IOP measurement, indirect ophthalmoscopy, SD-OCT, and OCTA. Table 1 Baseline Characteristics of Patients in Combination and Monotherapy Groups Characteristic Combination Group (n = 29) Monotherapy (n = 30) t/χ² P Age, Mean ± SD 60.79 ± 9.73 60.23 ± 10.91 t = 0.21 0.84 BCVA, Mean ± SD 49.90 ± 11.82 46.50 ± 11.49 t = 1.12 0.27 IOP, Mean ± SD 14.86 ± 3.13 16.17 ± 3.09 t=-1.61 0.11 Gender, n(%) χ²=0.19 0.66 Male 10 (34.48) 12 (40.00) Female 19 (65.52) 18 (60.00) Monotherapy Group: Received intravitreal aflibercept injections (2mg/0.05ml) every 4 weeks for the first 12 weeks (4 injections), followed by a PRN regimen (injection triggered by BCVA loss > 5 letters or CRT > 300µm) until week 24. Combination Group: Received initial intravitreal injection of aflibercept (2mg/0.05ml) combined with DEX-I (0.7mg) in the same surgical session. From week 4 to week 12, they received monthly aflibercept injections (2mg/0.05ml), followed by a PRN regimen (same criteria) until week 24. The treatment and follow-up schedule is shown in Fig. 1. Treatment Procedure: Patients were instructed to use gatifloxacin eye drops (both eyes) four times daily for 3 days preoperatively. Both groups received preoperative mydriasis with compound tropicamide eye drops and topical anesthesia with proparacaine eye drops. After standard disinfection and draping, the conjunctival sac was irrigated with 5% povidone-iodine for 1 minute and then rinsed. An intravitreal injection was administered slowly through the pars plana 4mm posterior to the limbus in the inferotemporal quadrant: The monotherapy group received aflibercept 2mg/0.05ml (Eylea, Bayer, Germany). The combination group received DEX implant 0.7mg (OZURDEX, Allergan, Ireland) in the inferotemporal quadrant and aflibercept 2mg/0.05ml in a different quadrant, both during the same surgical session. At the end of the procedure, IOP was checked digitally and light perception confirmed.Postoperatively, gatifloxacin eye drops were instilled into the study eye four times daily for 5 days. 1.2.2 Observation Indicators Patients in both groups were assessed every 4 weeks ± 7 days until week 24. Each follow-up included BCVA, slit-lamp examination, IOP measurement, indirect ophthalmoscopy, SD-OCT, and safety assessment. The primary outcomes were: Mean change in BCVA (ETDRS letters) from baseline at 12 and 24 weeks; Mean change in CRT from baseline at 12 and 24 weeks; Proportion of patients gaining ≥ 15 letters from baseline at 12 and 24 weeks. 1.3 Statistical Methods Statistical analysis was performed using SPSS 22.0 software. Categorical data were compared between groups using the Chi-square test. Continuous data are expressed as mean ± standard deviation (SD). Intergroup comparisons of continuous data were performed using independent samples t-tests or repeated-measures analysis of variance (ANOVA). Intragroup comparisons for the same indicator were performed using one-way ANOVA. A P-value < 0.05 was considered statistically significant. 2. Results 2.1 Visual Acuity Outcomes Figure 2 illustrates the mean number of ETDRS letters gained monthly in both treatment groups. Compared to baseline, BCVA scores improved significantly at every follow-up visit in both groups and remained stable until the final visit (P < 0.001 at all time points). The mean improvement in BCVA from baseline at week 12 was significantly greater in the combination group (15.69 ± 8.58 letters) than in the monotherapy group (11.43 ± 7.24 letters) (P < 0.05). At week 24, the mean improvement was 16.34 ± 9.63 letters in the combination group versus 12.20 ± 9.04 letters in the monotherapy group (P = 0.094). A significantly higher proportion of patients in the combination group gained ≥ 15 letters from baseline at week 12 (58.62% vs. 30%, P = 0.027, Fig. 3 ). At week 24, the proportions were 58.62% and 40%, respectively (P = 0.153; Fig. 4 ). Visual acuity improvement was statistically significantly greater in the combination group compared to the monotherapy group at 4, 8, and 12 weeks post-injection (P < 0.05). 2.2 Anatomical Outcomes Figure 5 shows the mean change in CRT relative to baseline at monthly follow-ups for both groups. Compared to baseline, CRT reduction was statistically significant at all follow-up visits in both groups (P < 0.001 at all time points). The difference in CRT reduction between the monotherapy and combination groups was statistically significant at 20 weeks post-injection (P < 0.05). Subgroup Analysis: A subgroup was defined including patients with SD-OCT features: CRT ≥ 300µm, presence of intraretinal cysts within 1000µm of the fovea, hyperreflective foci (HRF) within 500µm of the fovea, and subretinal neuroretinal detachment (SND). This subgroup included 6 males (6 eyes) and 11 females (11 eyes), mean age 62.41 ± 8.40 years in the monotherapy group (n = 17), and 6 males (6 eyes) and 12 females (12 eyes), mean age 60.50 ± 11.63 years in the combination group (n = 18). There were no statistically significant differences in preoperative baseline characteristics (gender, age, BCVA, IOP) between these subgroups (P > 0.05). In this subgroup, the mean BCVA improvement from baseline at week 12 was significantly greater in the combination group (16.78 ± 7.63 letters) than in the monotherapy group (12.82 ± 6.66 letters) (P < 0.05). At week 24, the improvements were 17.67 ± 8.91 letters and 13.18 ± 10.21 letters, respectively (P = 0.174). The proportion gaining ≥ 15 letters at week 12 was 61.11% in the combination group versus 41.18% in the monotherapy group (P = 0.315). At week 24, the proportions were 61.11% and 47.06%, respectively (P = 0.503). Visual acuity improvement was significantly greater in the combination group at 4 weeks post-injection compared to monotherapy (P = 0.015). CRT reduction was statistically significant from baseline at all follow-ups in both subgroups (P 0.05). Table 2 shows differences in morphological findings between the study groups within this subgroup. The baseline number of cysts within 1000µm of the fovea (≥ 300µm diameter) was significantly reduced at 24 weeks in the combination group (from 3.56 ± 2.31 to 0.33 ± 0.84, P < 0.001) and in the monotherapy group (from 5.76 ± 2.25 to 3.06 ± 1.60, P < 0.001), with a statistically significant difference in the reduction between groups (P < 0.001). At 24 weeks, SND had completely resolved in 88.89% of patients in the combination group versus 70.59% in the monotherapy group; Fisher's exact test showed no statistically significant difference in resolution rates (p > 0.05), although the absolute difference of 18.3 percentage points favoring the combination group might warrant validation in a larger sample. At 24 weeks, the mean number of intraretinal HRF (within 500µm) showed a statistically significant reduction in both the monotherapy and combination groups (P < 0.001 and P = 0.038, respectively). Table 2: Differences in Morphological Outcomes from Baseline to 24 Weeks in Subgroup (Combination n=18, Monotherapy n=17) Combination Group (n = 18) Monotherapy Group (n = 17) t P Cyst Count （ 0w ） , Mean ± SD 3.56 ± 2.31 5.76 ± 2.25 t=-2.87 0.007 SND （ 0w ） 18 17 HRF （ 0w ） 5.06 ± 2.90 3.76 ± 3.17 1.26 0.217 Cyst Count （ 24w ） , Mean ± SD 0.33 ± 0.84 3.06 ± 1.60 t=-6.26 < 0 .001 SND （ 24w ） 2 （ 11.1% ） 5 （ 29.4% ） 2.3 Injection Frequency By week 24, the mean number of injections was significantly lower in the combination group (4.17 ± 0.38) compared to the monotherapy group (5.50 ± 1.04) (t = -6.53, P < 0.001). 2.4 Ocular Adverse Events Cataract progression and elevated IOP were the observed ocular adverse events. No treatment-related cases of retinal detachment or endophthalmitis were identified. Intraocular Pressure (IOP): During follow-up, IOP increased by ≥ 5 mmHg from baseline in 24.14% (7/29) of eyes treated with DEX implant and 13.33% (4/30) of eyes treated with aflibercept alone; the difference between groups was not statistically significant (P > 0.05). Furthermore, IOP exceeded 25 mmHg at least once in one eye during the study. This occurred in an eye that received the DEX implant. Elevated IOP was effectively managed with observation or topical anti-glaucoma medication. Cataract The percentage of pseudophakic eyes at baseline was 11.86%. Lens opacity density did not show a significant increase from baseline in phakic eyes of either group, possibly related to the short observation period. 2.5 Systemic Adverse Events Both DEX implant and intravitreal aflibercept were well tolerated. No systemic serious adverse events were observed during any follow-up visit. 3. Discussion This clinical study demonstrates that both intravitreal aflibercept monotherapy and its combination with DEX-I yield significant beneficial outcomes for visual acuity and anatomy in DME. The combination group showed superior results in early visual acuity improvement metrics compared to the monotherapy group. Although the monotherapy group also showed increased vision at the primary efficacy endpoint, the improvement was more rapid in the combination group. The results indicate that simultaneous intravitreal injection of aflibercept and DEX-I early in the treatment course is superior to aflibercept monotherapy for achieving significant visual acuity gains. Besides the primary efficacy outcome, CRT reduction was statistically significant compared to baseline at all follow-ups in both groups, with a statistically significant difference favoring the combination group at 20 weeks post-injection. Analysis suggests this difference arose because, per our study design (4 loading doses + PRN), some patients in the monotherapy group experienced significant CRT fluctuations after discontinuation of the loading phase around week 20. This finding suggests greater stability in CRT reduction with combination therapy. Regarding injection frequency, the mean number was significantly lower in the combination group (4.17 ± 0.38) compared to the monotherapy group (5.50 ± 1.04) (P < 0.001). This indicates that combination therapy achieved visual and anatomical benefits earlier with fewer injections. VEGF inhibitors are widely used as first-line therapy for DME [ 6 , 10 ] , yet 30–50% of patients show limited response [ 11 , 12 ] . Adding a DEX-I may help manage residual edema [ 13 ] . Inflammation plays a key role in DME pathogenesis [ 14 ] , with elevated levels of angiogenic factors, cytokines, chemokines, complement proteins, and oxidative stress markers found in the vitreous and aqueous humor of DR patients [ 15 , 16 ] . Intravitreal corticosteroids, with anti-inflammatory and anti-edematous properties, effectively target these pathways and offer a strong therapeutic option. In addition, some of these biomarkers are considered to correlate with intraocular inflammation levels and responsiveness to anti-VEGF and steroid therapy,such as intraretinal cystoid spaces, increased number of hyperreflective foci (HRF) in the outer retina near the fovea, presence of foveal exudation, and subretinal neuroretinal detachment (SND) [ 17 ] .Whether patients with any of these inflammatory biomarkers on SD-OCT achieve better functional and anatomical outcomes with simultaneous DEX-I combined with anti-VEGF therapy compared to anti-VEGF monotherapy was a key question. In our study, we administered a single dose of dexamethasone combined with the first aflibercept injection, followed by monthly aflibercept until week 12, and then a PRN regimen. The 24-week results show that the combination group achieved faster visual improvement and more stable CRT reduction with less edema fluctuation early on compared to the monotherapy group. Furthermore, subgroup analysis of patients with SD-OCT features suggestive of active inflammation (CRT ≥ 300µm, intraretinal cysts within 1000µm of fovea, HRF within 500µm, SND) showed that visual acuity improved more rapidly in the combination group at week 4. At week 24, the reduction in cyst count was significantly greater in the combination group. We propose that SND, HRF, and foveal cystoid spaces serve as biomarkers predicting better early visual outcomes and more stable maintenance with combination therapy in DME eyes. Studies on DEX-I combined with anti-VEGF for DME are limited. Totan et al [ 18 ] assessed the therapeutic effect of DEX-I in 30 eyes with chronic DME unresponsive to at least three bevacizumab injections. Notable enhancements in BCVA and CRT were observed at 1 and 3 months; however, these benefits were not maintained long-term and showed a decline between the third and sixth months post-injection. Koc et al [ 19 ] reported no meaningful differences in BCVA or CMT among 94 eyes with DME resistant to ranibizumab or aflibercept, regardless of whether treatment continued with anti-VEGF or switched to DEX. Busch et al [ 20 ] demonstrated that eyes failing to respond during the anti-VEGF loading phase experienced superior visual and anatomical outcomes over 24 months when transitioned early to DEX-I, compared to those maintained on anti-VEGF monotherapy. Eyes that remained on anti-VEGF alone showed minimal vision gains and no significant CFT reduction at 12 or 24 months. Those converted to steroid therapy in the second year also exhibited substantial functional and structural improvements.Ferhat et al [ 21 ] highlighted the therapeutic advantages of DEX in managing inadequately controlled DME. Following DEX administration, patients experienced a marked decrease in CST, reflecting better disease control and functional stabilization. Their findings emphasized the benefit of reduced treatment frequency made possible by incorporating DEX into the regimen. Kaya et al [ 22 ] randomized DME patients to ranibizumab monotherapy or simultaneous ranibizumab + DEX treatment. The combination group showed significantly greater BCVA gains at 6 and 12 months (P = 0.002, P < 0.001) and superior CRT reduction starting at 2 months and continuing throughout, indicating faster and more pronounced improvements. Inflammatory OCT biomarkers also improved more in the combination group at 12 and 24 months. Overall, simultaneous dual therapy proved to be an effective first-line option for DME with inflammatory features or reduced vision. In our study, the combination group achieved earlier visual gains and greater macular thickness reduction. Intensive anti-VEGF therapy combined with DEX-I resulted in better functional and anatomical outcomes than monotherapy. Early combination therapy for diabetic macular edema (DME) offers rapid onset by targeting both VEGF-driven leakage and inflammation, significantly reducing CRT within a month. In contrast, sequential treatment-adding DEX only after poor anti-VEGF response-delays edema control and risks irreversible retinal damage. Patients receiving early combination show greater BCVA gains and faster anatomical recovery, lowering the risk of photoreceptor apoptosis. DEX, sustained-release profile also reduces injection frequency, improving compliance. Sequential regimens often require more injections and raise costs. Overall, early combination therapy provides superior outcomes, faster recovery, reduced treatment burden, and better cost-effectiveness, making it a more efficient strategy for managing DME. Regarding safety, this study primarily evaluated adverse events postoperatively. During follow-up, IOP exceeded 25 mmHg at least once in one eye in the combination group (at 8 weeks post-injection), which was effectively managed with topical anti-glaucoma medication, allowing discontinuation 3 months post-injection. Regarding cataracts, lens opacity density did not show a significant increase from baseline in phakic eyes of either group, possibly due to the short observation period. No other serious complications, such as retinal detachment or endophthalmitis, occurred in either group. Based on the observed adverse events, close monitoring of IOP during treatment is essential, but overall, the regimen demonstrated a favorable safety profile. However, limitations include a relatively small sample size, short follow-up duration, and insufficient patient numbers. Future studies with larger samples and longer follow-up periods are needed to investigate the long-term impact of combination therapy on DME. 4. Conclusions Intravitreal aflibercept monotherapy significantly improves visual acuity and anatomical outcomes in DME patients. Furthermore, combining DEX-I with the first intravitreal aflibercept injection leads to more favorable early visual outcomes and superior early anatomical results compared to aflibercept monotherapy, regardless of the presence of inflammatory biomarkers on SD-OCT. Declarations Funding: This study received no specific financial support. Author Contribution The authors thank Dr. Sheng L, Miss. Yue C, Ms. Dingxi L, Miss. Beichen L, Ms. Yongxia Z and all clinical investigators for their contribution to the collection of data. The authors also thank Dr. Sheng L for assistance with writing and editing of the manuscript. Acknowledgments The authors thank Dr. Sheng Li, Miss. Yue Chen, Ms. Dingxi Liu, Miss. Beichen Liu, Ms. Yongxia Zhao and all clinical investigators for their contribution to the collection of data. The authors also thank Dr. Sheng Li for assistance with writing and editing of the manuscript. Ethics declarations : This study was approved by the Ethics Committee of the Third People's Hospital of Dalian (Approval No.: 2024-047-002). Consent for publication : Not applicable. Conflicts of Interest : The authors declare no conflicts of interest. Data Availability Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available due to privacy or ethical restrictions. References Schmidt-Erfurth U, Garcia-Arumi J, Bandello F, et al. Guidelines for the management ofdiabetic macular edema by the european society of retina specialists (euretina). Ophthalmologica. 2017;237:185–222. 10.1159/000458539 . Zhang J, Zhang J, Zhang C et al. Diabetic Macular Edema: current Understanding, Molecular Mechanisms and Therapeutic Implications. Cells.2022;11(21). 10.3390/CELLS11213362 Arimura N, Otsuka H, Yamakiri K, et al. Vitreous mediators after intravitreal bevacizumab or triamcinolone acetonide in eyes with proliferative diabetic retinopathy. Ophthalmology. 2009;116:921–6. 10.1016/j.ophtha.2008.12.024 . Ho AC, Scott IU, Kim SJ, et al. Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: a report by the American Academy of Ophthalmology. Ophthalmology. 2012;119:2179–88. 10.1016/j.ophtha.2012.07.058 . Romero-Aroca P, Baget-Bernaldiz M, Pareja-Rios A et al. Diabetic Macular Edema Pathophysiology: Vasogenic versus Inflammatory. J. Diabetes Res. 2016, 2016, 2156273. 10.1155/2016/2156273 Schmidt-Erfurth U, Garcia-Arumi J, Bandello F, Berg K, Chakravarthy U, Gerendas BS, Loewenstein A. Guidelines for the Management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA). Ophthalmologica. 2017;237:185–222. Shah AR, Yonekawa Y, Todorich B, et al. Prediction of Anti-VEGF Response in Diabetic Macular Edema After 1 Injection. J Vitreoretin Dis. 2017;1:169–74. 10.1177/2474126416682569 . Bucolo C, Gozzo L, Longo L, Mansueto S, Vitale DC, Drago F. Long-term efficacy and safety profile of multiple injections of intravitreal dexamethasone implant to manage diabetic macular edema: a systematic review of real-world studies. J Pharmacol Sci. 2018;138(4):219–32. 10.1016/J.JPHS.2018.11.001 . Urbančič M, Topčić IG. Dexamethasone implant in the management of diabetic macular edema from clinician’s perspective. Clin Ophthalmol. 2019;13:821–8. 10.2147/OPTH.S206769 . Virgili G, Parravano M, Evans JR, Gordon I, Lucenteforte E. (2018) Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis. Cochrane Database Syst Rev. 2018;10(10):CD007419. doi: org/ 10.1002/14651 858.CD007 419 . pub6. Duh EJ, Sun JK, Stitt AW. (2017) Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight.2017;2(14):e93751. 10.1172/jci.insight.93751 Shah AR, Yonekawa Y, Todorich B, et al. Prediction of anti-VEGF response in diabetic macular edema after 1 injection. J Vitreoretin Dis. 2017;1(3):169–74. 10.1177/2474126416682569 . Lee H, Kang KE, Chung H, Kim HC. Prognostic factors for functional and anatomic outcomes in patients with diabetic macular edema treated with dexamethasone implant. Korean J Ophthalmol. 2018;32:116–25. 10.3341/kjo.2017.0041 . Whitcup SM, Cidlowski JA, Csaky KG, Ambati J. Pharmacology of Corticosteroids for Diabetic Macular Edema. Invest Ophthalmol Vis Sci. 2018;59(1):1–12. 10.1167/IOVS.17-22259 . Loukovaara S, Nurkkala H, Tamene F, et al. Quantitative Proteomics Analysis of Vitreous Humor from Diabetic Retinopathy Patients. J Proteome Res. 2015;14(12):5131–43. 10.1021/ACS.JPROTEOME.5B00900 . Vujosevic S, Simó R. Local and Systemic Inflammatory Biomarkers of Diabetic Retinopathy: an Integrative Approach. Invest Ophthalmol Vis Sci. 2017;58(6):BIO68–75. 10.1167/IOVS.17-21769 . Vujosevic S, Toma C, Villani E, et al. Diabetic macular edema with neuroretinal detachment: OCT and OCT-angiography biomarkers of treatment response to anti-VEGF and steroids. Acta Diabetol. 2020;57(3):287–96. 10.1007/S00592-019-01424-4 . Totan Y, Güler E, Güraʇaç FB. Dexamethasone Intravitreal Implant for Chronic Diabetic Macular Edema Resistant to Intravitreal Bevacizumab Treatment. Curr Eye Res. 2016;41(1):107–13. 10.3109/02713683.2014.1002048 . Koc H, Alpay A, Ugurbas SH. Comparison of the efficacy of intravitreal Anti-VEGF versus intravitreal dexamethasone implant in treatment resistant diabetic Macular Edema. BMC Ophthalmol. 2023;23(1):1–7. 10.1186/S12886-023-02831-6/TABLES/4 . Busch C, Fraser-Bell S, Iglicki M, Lupidi M, Couturier A, Chaikitmongkol V, .International Retina Group. Real-world outcomes of non-responding diabetic macular edema treated with continued anti-VEGF therapy versus early switch to dexamethasone implant: 2-year results. Acta Diabetol. 2019;56:1341–50. 10.1007/s00592-019-01416-4 . Ferhat T, Gábor M, Christoph T, et al. Intravitreal Dexamethasone Implant in Anti-Vascular Endothelial Growth Factor Pretreated Diabetic Macular Edema—A Swiss Cohort Study. Pharmaceuticals (Basel). 2024;17(9):1235. 10.3390/ph17091235 . Kaya M, Kocak N,Ozturk T et al. Intravitreal ranibizumab and dexamethasone implant injections as primary treatment of diabetic macular edema:simultaneously double protocol[J]. Eye (Lond) 2021,35(3):777–85. 10.1038/s41433-020-0949-2 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 23 Oct, 2025 Reviewers agreed at journal 16 Oct, 2025 Reviewers invited by journal 06 Oct, 2025 Editor invited by journal 03 Sep, 2025 Editor assigned by journal 02 Sep, 2025 Submission checks completed at journal 02 Sep, 2025 First submitted to journal 31 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7500444","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":530577182,"identity":"2c6d9c6a-d920-4b08-9666-28270499b098","order_by":0,"name":"Xiaonan Fu","email":"","orcid":"","institution":"The Third People's Hospital of Dalian","correspondingAuthor":false,"prefix":"","firstName":"Xiaonan","middleName":"","lastName":"Fu","suffix":""},{"id":530577183,"identity":"cf0000a5-f02d-4eda-acbf-e67fbb8228ea","order_by":1,"name":"Yue Chen","email":"","orcid":"","institution":"The Third People's Hospital of 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12:26:08","extension":"html","order_by":29,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":90911,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7500444/v1/6c3433c8b623197098599624.html"},{"id":93774773,"identity":"25cf12da-7090-4720-a41c-b46c88b26092","added_by":"auto","created_at":"2025-10-17 12:26:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":24997,"visible":true,"origin":"","legend":"\u003cp\u003eTreatment and Follow-up Schedule for Combination and Monotherapy Groups\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7500444/v1/83d6c4d35a5a01495289cf88.png"},{"id":93775940,"identity":"9de903a5-db16-4ba1-8c0f-ce7fbb919f5f","added_by":"auto","created_at":"2025-10-17 12:34:08","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":75943,"visible":true,"origin":"","legend":"\u003cp\u003eMean change in letters gained from baseline at each 4-week interval up to 24 weeks.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7500444/v1/68a864340457de10fa27c347.png"},{"id":93774774,"identity":"2bb1ebb3-3b8f-4bd3-9606-67108f5bceb4","added_by":"auto","created_at":"2025-10-17 12:26:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":113792,"visible":true,"origin":"","legend":"\u003cp\u003eProportion of eyes gaining ≥15 letters from baseline to week 12.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7500444/v1/1eaefbf0cb909a0c0c0ed15e.png"},{"id":93774778,"identity":"dbbc5c71-71ab-4b7c-88df-847036c8809f","added_by":"auto","created_at":"2025-10-17 12:26:08","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":79822,"visible":true,"origin":"","legend":"\u003cp\u003eProportion of eyes gaining ≥15 letters from baseline to week 24.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7500444/v1/05c4b8054fc3f0f326b82a16.png"},{"id":93775947,"identity":"362a5499-cf77-4f2a-8311-cef1b8c6c6db","added_by":"auto","created_at":"2025-10-17 12:34:08","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":63517,"visible":true,"origin":"","legend":"\u003cp\u003eMean change in CRT reduction from baseline at each 4-week interval for both groups up to 24 weeks.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7500444/v1/15776a0435a59a2a1871c7c2.png"},{"id":93780063,"identity":"9fb5a37a-9fc0-4b35-97d9-6d136d80dce6","added_by":"auto","created_at":"2025-10-17 12:58:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":931476,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7500444/v1/4c99c548-2c38-4478-8496-f3cddf2dc3f5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Preliminary Efficacy Analysis of Early Combination Therapy with Intravitreal Aflibercept and Dexamethasone Implant for Diabetic Macular Edema","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDiabetic retinopathy (DR) remains the leading cause of blindness among individuals of working age, with diabetic macular edema (DME) being the primary contributor to vision loss in these patients\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. DME manifests as the accumulation of fluid within the retinal layers, and occasionally beneath the retina, resulting in thickening of the macular region \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. This pathological change may lead to symptoms such as blurred vision, distorted images, reduced color sensitivity, and, if left untreated, permanent retinal damage causing irreversible visual impairment.\u003c/p\u003e\u003cp\u003eThe underlying mechanisms of DME are intricate and involve both vascular and inflammatory pathways \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Key contributors include vascular endothelial growth factor (VEGF) and various inflammatory cytokines \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.Although anti-VEGF therapy is widely accepted as the first-line approach for DME \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e, a significant proportion of patients-estimated at 30\u0026ndash;50% exhibit suboptimal responses\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e.Corticosteroids by inhibiting phospholipase A2 and the arachidonic acid cascade, help suppress VEGF production and reduce inflammatory cytokine activity. These actions contribute to the stabilization of the blood-retinal barrier, reduction of leukocyte adhesion, enhancement of tight junction integrity in retinal capillaries, improved retinal oxygenation, and protection against endothelial cell damage and apoptosis\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. As a result, intravitreal corticosteroids have gained traction as either alternative or supplementary treatments. Nevertheless, even long-acting steroid formulations often necessitate repeated injections to maintain therapeutic efficacy. Therefore, minimizing injection frequency while achieving optimal outcomes is a shared objective for both clinicians and patients.\u003c/p\u003e\u003cp\u003eGiven the multifaceted nature of DME pathogenesis, involving diverse signaling pathways, combining anti-VEGF agents with anti-inflammatory treatments has emerged as a practical strategy. In clinical settings, combination therapy is implemented in various ways some practitioners prefer sequential administration, while others opt for simultaneous use. However, there is limited clinical evidence and research regarding the early initiation of simultaneous combination therapy.This study seeks to evaluate the preliminary effectiveness of such an approach, aiming to enrich clinical experience and provide new perspectives on DME management. The initial findings are presented below.\u003c/p\u003e"},{"header":"1. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e1.1 Materials\u003c/h2\u003e\u003cp\u003eFifty-nine patients (59 eyes) clinically diagnosed with DME at the Ophthalmology Department of Dalian Third People's Hospital between March 2024 and March 2025 were enrolled. There were 22 males (22 eyes) and 37 females (37 eyes), aged 33\u0026ndash;80 years (mean age 60.51\u0026thinsp;\u0026plusmn;\u0026thinsp;10.28 years). Inclusion criteria: (1) Age\u0026thinsp;\u0026ge;\u0026thinsp;18 years with type 2 diabetes mellitus and glycated hemoglobin (HbA1c)\u0026thinsp;\u0026le;\u0026thinsp;12.0%; (2) Study eye baseline BCVA\u0026thinsp;\u0026ge;\u0026thinsp;34 and \u0026le;\u0026thinsp;68 ETDRS letters, with vision loss primarily attributed to DME involving the fovea as determined by the investigator; (3) SD-OCT showing central retinal thickness (CRT)\u0026thinsp;\u0026ge;\u0026thinsp;300 \u0026micro;m within the macular region, with the presence of intraretinal cysts within 1000 \u0026micro;m of the fovea. Exclusion criteria: (1) Concurrent macular pathologies such as epiretinal membrane, macular hole, vitreomacular interface abnormalities, or macular edema due to other causes (e.g., uveitis, retinal vein occlusion); (2) Retinal laser photocoagulation in the study eye within 90 days prior to treatment; (3) Previous systemic or ocular treatment with anti-VEGF agents or steroids; (4) History of vitreoretinal surgery; (5) History of glaucoma or ocular hypertension; (6) Cerebrovascular accident and/or myocardial infarction within 180 days prior to enrollment; (7) Other conditions deemed by the investigator as requiring exclusion. This study was approved by the Ethics Committee of the Third People's Hospital of Dalian (Approval No.: 2024-047-002). All patients and their families provided informed consent after being fully informed about the study content and protocol.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e1.2 Methods\u003c/h2\u003e\u003cdiv id=\"Sec5\" class=\"Section3\"\u003e\u003ch2\u003e1.2.1 Basic Protocol and Treatment Methods\u003c/h2\u003e\u003cp\u003eThe monotherapy group consisted of 12 males (12 eyes) and 18 females (18 eyes), aged 33\u0026ndash;78 years (mean age 60.23\u0026thinsp;\u0026plusmn;\u0026thinsp;10.91 years). The combination group consisted of 10 males (10 eyes) and 19 females (19 eyes), aged 42\u0026ndash;80 years (mean age 60.79\u0026thinsp;\u0026plusmn;\u0026thinsp;9.73 years). There were no statistically significant differences in preoperative baseline characteristics (gender, age, BCVA, IOP) between the two groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05), as shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Before treatment, all patients underwent BCVA (ETDRS letters), slit-lamp examination, IOP measurement, indirect ophthalmoscopy, SD-OCT, and OCTA.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline Characteristics of Patients in Combination and Monotherapy Groups\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCombination Group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;29)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMonotherapy (n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003et/χ\u0026sup2;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60.79\u0026thinsp;\u0026plusmn;\u0026thinsp;9.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e60.23\u0026thinsp;\u0026plusmn;\u0026thinsp;10.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003et\u0026thinsp;=\u0026thinsp;0.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.84\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBCVA, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e49.90\u0026thinsp;\u0026plusmn;\u0026thinsp;11.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e46.50\u0026thinsp;\u0026plusmn;\u0026thinsp;11.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003et\u0026thinsp;=\u0026thinsp;1.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.27\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIOP, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14.86\u0026thinsp;\u0026plusmn;\u0026thinsp;3.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16.17\u0026thinsp;\u0026plusmn;\u0026thinsp;3.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003et=-1.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.11\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eχ\u0026sup2;=0.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.66\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (34.48)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 (40.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19 (65.52)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (60.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eMonotherapy Group: Received intravitreal aflibercept injections (2mg/0.05ml) every 4 weeks for the first 12 weeks (4 injections), followed by a PRN regimen (injection triggered by BCVA loss\u0026thinsp;\u0026gt;\u0026thinsp;5 letters or CRT\u0026thinsp;\u0026gt;\u0026thinsp;300\u0026micro;m) until week 24.\u003c/p\u003e\u003cp\u003eCombination Group: Received initial intravitreal injection of aflibercept (2mg/0.05ml) combined with DEX-I (0.7mg) in the same surgical session. From week 4 to week 12, they received monthly aflibercept injections (2mg/0.05ml), followed by a PRN regimen (same criteria) until week 24. The treatment and follow-up schedule is shown in Fig.\u0026nbsp;1.\u003c/p\u003e\u003cp\u003eTreatment Procedure: Patients were instructed to use gatifloxacin eye drops (both eyes) four times daily for 3 days preoperatively. Both groups received preoperative mydriasis with compound tropicamide eye drops and topical anesthesia with proparacaine eye drops. After standard disinfection and draping, the conjunctival sac was irrigated with 5% povidone-iodine for 1 minute and then rinsed. An intravitreal injection was administered slowly through the pars plana 4mm posterior to the limbus in the inferotemporal quadrant: The monotherapy group received aflibercept 2mg/0.05ml (Eylea, Bayer, Germany). The combination group received DEX implant 0.7mg (OZURDEX, Allergan, Ireland) in the inferotemporal quadrant and aflibercept 2mg/0.05ml in a different quadrant, both during the same surgical session. At the end of the procedure, IOP was checked digitally and light perception confirmed.Postoperatively, gatifloxacin eye drops were instilled into the study eye four times daily for 5 days.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\u003ch2\u003e1.2.2 Observation Indicators\u003c/h2\u003e\u003cp\u003ePatients in both groups were assessed every 4 weeks\u0026thinsp;\u0026plusmn;\u0026thinsp;7 days until week 24. Each follow-up included BCVA, slit-lamp examination, IOP measurement, indirect ophthalmoscopy, SD-OCT, and safety assessment. The primary outcomes were: Mean change in BCVA (ETDRS letters) from baseline at 12 and 24 weeks; Mean change in CRT from baseline at 12 and 24 weeks; Proportion of patients gaining\u0026thinsp;\u0026ge;\u0026thinsp;15 letters from baseline at 12 and 24 weeks.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e1.3 Statistical Methods\u003c/h2\u003e\u003cp\u003eStatistical analysis was performed using SPSS 22.0 software. Categorical data were compared between groups using the Chi-square test. Continuous data are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). Intergroup comparisons of continuous data were performed using independent samples t-tests or repeated-measures analysis of variance (ANOVA). Intragroup comparisons for the same indicator were performed using one-way ANOVA. A P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"2. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Visual Acuity Outcomes\u003c/h2\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates the mean number of ETDRS letters gained monthly in both treatment groups. Compared to baseline, BCVA scores improved significantly at every follow-up visit in both groups and remained stable until the final visit (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 at all time points). The mean improvement in BCVA from baseline at week 12 was significantly greater in the combination group (15.69\u0026thinsp;\u0026plusmn;\u0026thinsp;8.58 letters) than in the monotherapy group (11.43\u0026thinsp;\u0026plusmn;\u0026thinsp;7.24 letters) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). At week 24, the mean improvement was 16.34\u0026thinsp;\u0026plusmn;\u0026thinsp;9.63 letters in the combination group versus 12.20\u0026thinsp;\u0026plusmn;\u0026thinsp;9.04 letters in the monotherapy group (P\u0026thinsp;=\u0026thinsp;0.094). A significantly higher proportion of patients in the combination group gained\u0026thinsp;\u0026ge;\u0026thinsp;15 letters from baseline at week 12 (58.62% vs. 30%, P\u0026thinsp;=\u0026thinsp;0.027, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e). At week 24, the proportions were 58.62% and 40%, respectively (P\u0026thinsp;=\u0026thinsp;0.153; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Visual acuity improvement was statistically significantly greater in the combination group compared to the monotherapy group at 4, 8, and 12 weeks post-injection (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Anatomical Outcomes\u003c/h2\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e shows the mean change in CRT relative to baseline at monthly follow-ups for both groups. Compared to baseline, CRT reduction was statistically significant at all follow-up visits in both groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 at all time points). The difference in CRT reduction between the monotherapy and combination groups was statistically significant at 20 weeks post-injection (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eSubgroup Analysis: A subgroup was defined including patients with SD-OCT features: CRT\u0026thinsp;\u0026ge;\u0026thinsp;300\u0026micro;m, presence of intraretinal cysts within 1000\u0026micro;m of the fovea, hyperreflective foci (HRF) within 500\u0026micro;m of the fovea, and subretinal neuroretinal detachment (SND). This subgroup included 6 males (6 eyes) and 11 females (11 eyes), mean age 62.41\u0026thinsp;\u0026plusmn;\u0026thinsp;8.40 years in the monotherapy group (n\u0026thinsp;=\u0026thinsp;17), and 6 males (6 eyes) and 12 females (12 eyes), mean age 60.50\u0026thinsp;\u0026plusmn;\u0026thinsp;11.63 years in the combination group (n\u0026thinsp;=\u0026thinsp;18). There were no statistically significant differences in preoperative baseline characteristics (gender, age, BCVA, IOP) between these subgroups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003eIn this subgroup, the mean BCVA improvement from baseline at week 12 was significantly greater in the combination group (16.78\u0026thinsp;\u0026plusmn;\u0026thinsp;7.63 letters) than in the monotherapy group (12.82\u0026thinsp;\u0026plusmn;\u0026thinsp;6.66 letters) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). At week 24, the improvements were 17.67\u0026thinsp;\u0026plusmn;\u0026thinsp;8.91 letters and 13.18\u0026thinsp;\u0026plusmn;\u0026thinsp;10.21 letters, respectively (P\u0026thinsp;=\u0026thinsp;0.174). The proportion gaining\u0026thinsp;\u0026ge;\u0026thinsp;15 letters at week 12 was 61.11% in the combination group versus 41.18% in the monotherapy group (P\u0026thinsp;=\u0026thinsp;0.315). At week 24, the proportions were 61.11% and 47.06%, respectively (P\u0026thinsp;=\u0026thinsp;0.503). Visual acuity improvement was significantly greater in the combination group at 4 weeks post-injection compared to monotherapy (P\u0026thinsp;=\u0026thinsp;0.015). CRT reduction was statistically significant from baseline at all follow-ups in both subgroups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), but the difference between groups was not statistically significant (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows differences in morphological findings between the study groups within this subgroup. The baseline number of cysts within 1000\u0026micro;m of the fovea (\u0026ge;\u0026thinsp;300\u0026micro;m diameter) was significantly reduced at 24 weeks in the combination group (from 3.56\u0026thinsp;\u0026plusmn;\u0026thinsp;2.31 to 0.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.84, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and in the monotherapy group (from 5.76\u0026thinsp;\u0026plusmn;\u0026thinsp;2.25 to 3.06\u0026thinsp;\u0026plusmn;\u0026thinsp;1.60, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with a statistically significant difference in the reduction between groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). At 24 weeks, SND had completely resolved in 88.89% of patients in the combination group versus 70.59% in the monotherapy group; Fisher's exact test showed no statistically significant difference in resolution rates (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), although the absolute difference of 18.3 percentage points favoring the combination group might warrant validation in a larger sample. At 24 weeks, the mean number of intraretinal HRF (within 500\u0026micro;m) showed a statistically significant reduction in both the monotherapy and combination groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and P\u0026thinsp;=\u0026thinsp;0.038, respectively).\u003c/p\u003e\n\u003cp style='margin:0cm;text-align:center;font-size:14px;font-family:\"Arial Unicode MS\",serif;color:black;line-height:150%;'\u003e\u003cspan style='font-family:\"Calibri\",sans-serif;background:white;'\u003eTable 2: Differences in Morphological Outcomes from Baseline to 24 Weeks in Subgroup (Combination n=18, Monotherapy n=17)\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0cm;text-align:left;font-size:14px;font-family:\"Arial Unicode MS\",serif;color:black;text-indent:24.0pt;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Calibri\",sans-serif;background:white;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"margin-left: 10.8pt;background: rgb(79, 129, 189);border-collapse: collapse;border: none;width: 675px;\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:151.7pt;border-top:solid black 1.0pt;border-left: none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:4.0pt 4.0pt 4.0pt 4.0pt;height:29.55pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;'\u003e\u003cspan style='font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:119.95pt;border-top:solid black 1.0pt;border-left: none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:4.0pt 6.0pt 4.0pt 6.0pt;height:29.55pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003eCombination Group\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;(n = 18)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:91.65pt;border-top:solid black 1.0pt;border-left: none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:4.0pt 6.0pt 4.0pt 6.0pt;height:29.55pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003eMonotherapy Group (n = 17)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.55pt;border-top:solid black 1.0pt;border-left: none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:4.0pt 6.0pt 4.0pt 6.0pt;height:29.55pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003et\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:75.75pt;border-top:solid black 1.0pt;border-left: none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:4.0pt 6.0pt 4.0pt 6.0pt;height:29.55pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cem\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003eP\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:151.7pt;border:none;background:white;padding:4.0pt 4.0pt 4.0pt 4.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;'\u003e\u003cspan style='font-size:14px;font-family: \"Calibri\",sans-serif;'\u003eCyst Count\u003c/span\u003e\u003cspan style=\"font-size:14px;font-family:Calibri;\"\u003e（\u003c/span\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e0w\u003c/span\u003e\u003cspan style=\"font-size:14px;font-family:Calibri;\"\u003e）\u003c/span\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e, Mean \u0026plusmn; SD\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:119.95pt;border:none;background:white;padding:4.0pt 6.0pt 4.0pt 6.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e3.56 \u0026plusmn; 2.31\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:91.65pt;border:none;background:white;padding:4.0pt 6.0pt 4.0pt 6.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e5.76 \u0026plusmn; 2.25\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.55pt;border:none;background:white;padding:4.0pt 6.0pt 4.0pt 6.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003et=-2.87\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:75.75pt;border:none;background:white;padding:4.0pt 6.0pt 4.0pt 6.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;color:red;'\u003e0.007\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:151.7pt;border:none;background:white;padding: 4.0pt 4.0pt 4.0pt 4.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;'\u003e\u003cspan style='font-size:14px;font-family: \"Calibri\",sans-serif;'\u003eSND\u003c/span\u003e\u003cspan style=\"font-size:14px;font-family: Calibri;\"\u003e（\u003c/span\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e0w\u003c/span\u003e\u003cspan style=\"font-size:14px;font-family:Calibri;\"\u003e）\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:119.95pt;border:none;background:white;padding: 4.0pt 6.0pt 4.0pt 6.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e18\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:91.65pt;border:none;background:white;padding: 4.0pt 6.0pt 4.0pt 6.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e17\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.55pt;border:none;background:white;padding:4.0pt 4.0pt 4.0pt 4.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;'\u003e\u003cspan style='font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:75.75pt;border:none;background:white;padding: 4.0pt 4.0pt 4.0pt 4.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;'\u003e\u003cspan style='font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:151.7pt;border:none;background:white;padding: 4.0pt 4.0pt 4.0pt 4.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;'\u003e\u003cspan style='font-size:14px;font-family: \"Calibri\",sans-serif;'\u003eHRF\u003c/span\u003e\u003cspan style=\"font-size:14px;font-family: Calibri;\"\u003e（\u003c/span\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e0w\u003c/span\u003e\u003cspan style=\"font-size:14px;font-family:Calibri;\"\u003e）\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:119.95pt;border:none;background:white;padding: 4.0pt 6.0pt 4.0pt 6.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e5.06 \u0026plusmn; 2.90\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:91.65pt;border:none;background:white;padding: 4.0pt 6.0pt 4.0pt 6.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e3.76 \u0026plusmn; 3.17\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.55pt;border:none;background:white;padding:4.0pt 6.0pt 4.0pt 6.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e1.26\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:75.75pt;border:none;background:white;padding: 4.0pt 6.0pt 4.0pt 6.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e0.217\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:151.7pt;border:none;background:white;padding:4.0pt 4.0pt 4.0pt 4.0pt;height:16.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003eCyst Count\u003c/span\u003e\u003cspan style=\"font-size:14px;font-family:Calibri;\"\u003e（\u003c/span\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e24w\u003c/span\u003e\u003cspan style=\"font-size:14px;font-family:Calibri;\"\u003e）\u003c/span\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e, Mean \u0026plusmn; SD\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:119.95pt;border:none;background:white;padding: 4.0pt 6.0pt 4.0pt 6.0pt;height:16.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e0.33 \u0026plusmn; 0.84\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:91.65pt;border:none;background:white;padding:4.0pt 6.0pt 4.0pt 6.0pt;height:16.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e3.06 \u0026plusmn; 1.60\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.55pt;border:none;background:white;padding:4.0pt 6.0pt 4.0pt 6.0pt;height:16.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003et=-6.26\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:75.75pt;border:none;background:white;padding:4.0pt 6.0pt 4.0pt 6.0pt;height:16.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;color:red;'\u003e\u0026lt;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;color:red;'\u003e0\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;color:red;'\u003e.001\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:151.7pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:4.0pt 4.0pt 4.0pt 4.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003eSND\u003c/span\u003e\u003cspan style=\"font-size:14px;font-family:Calibri;\"\u003e（\u003c/span\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e24w\u003c/span\u003e\u003cspan style=\"font-size:14px;font-family:Calibri;\"\u003e）\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:119.95pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:4.0pt 6.0pt 4.0pt 6.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e2\u003c/span\u003e\u003cspan style=\"font-size:14px;font-family:Calibri;\"\u003e（\u003c/span\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e11.1%\u003c/span\u003e\u003cspan style=\"font-size:14px;font-family:Calibri;\"\u003e）\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:91.65pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:4.0pt 6.0pt 4.0pt 6.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:2.0pt;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;text-align:center;'\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e5\u003c/span\u003e\u003cspan style=\"font-size:14px;font-family:Calibri;\"\u003e（\u003c/span\u003e\u003cspan style='font-size:14px;font-family:\"Calibri\",sans-serif;'\u003e29.4%\u003c/span\u003e\u003cspan style=\"font-size:14px;font-family:Calibri;\"\u003e）\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.55pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:4.0pt 4.0pt 4.0pt 4.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;'\u003e\u003cspan style='font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:75.75pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:4.0pt 4.0pt 4.0pt 4.0pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Arial Unicode MS\",serif;color:black;'\u003e\u003cspan style='font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin:0cm;text-align:left;font-size:14px;font-family:\"Arial Unicode MS\",serif;color:black;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Calibri\",sans-serif;background:white;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Injection Frequency\u003c/h2\u003e\u003cp\u003eBy week 24, the mean number of injections was significantly lower in the combination group (4.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.38) compared to the monotherapy group (5.50\u0026thinsp;\u0026plusmn;\u0026thinsp;1.04) (t = -6.53, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Ocular Adverse Events\u003c/h2\u003e\u003cp\u003eCataract progression and elevated IOP were the observed ocular adverse events. No treatment-related cases of retinal detachment or endophthalmitis were identified.\u003c/p\u003e\u003cp\u003eIntraocular Pressure (IOP): During follow-up, IOP increased by \u0026ge;\u0026thinsp;5 mmHg from baseline in 24.14% (7/29) of eyes treated with DEX implant and 13.33% (4/30) of eyes treated with aflibercept alone; the difference between groups was not statistically significant (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Furthermore, IOP exceeded 25 mmHg at least once in one eye during the study. This occurred in an eye that received the DEX implant. Elevated IOP was effectively managed with observation or topical anti-glaucoma medication.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCataract\u003c/strong\u003e\u003cp\u003eThe percentage of pseudophakic eyes at baseline was 11.86%. Lens opacity density did not show a significant increase from baseline in phakic eyes of either group, possibly related to the short observation period.\u003c/p\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Systemic Adverse Events\u003c/h2\u003e\u003cp\u003eBoth DEX implant and intravitreal aflibercept were well tolerated. No systemic serious adverse events were observed during any follow-up visit.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eThis clinical study demonstrates that both intravitreal aflibercept monotherapy and its combination with DEX-I yield significant beneficial outcomes for visual acuity and anatomy in DME. The combination group showed superior results in early visual acuity improvement metrics compared to the monotherapy group. Although the monotherapy group also showed increased vision at the primary efficacy endpoint, the improvement was more rapid in the combination group. The results indicate that simultaneous intravitreal injection of aflibercept and DEX-I early in the treatment course is superior to aflibercept monotherapy for achieving significant visual acuity gains. Besides the primary efficacy outcome, CRT reduction was statistically significant compared to baseline at all follow-ups in both groups, with a statistically significant difference favoring the combination group at 20 weeks post-injection. Analysis suggests this difference arose because, per our study design (4 loading doses\u0026thinsp;+\u0026thinsp;PRN), some patients in the monotherapy group experienced significant CRT fluctuations after discontinuation of the loading phase around week 20. This finding suggests greater stability in CRT reduction with combination therapy. Regarding injection frequency, the mean number was significantly lower in the combination group (4.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.38) compared to the monotherapy group (5.50\u0026thinsp;\u0026plusmn;\u0026thinsp;1.04) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This indicates that combination therapy achieved visual and anatomical benefits earlier with fewer injections.\u003c/p\u003e\u003cp\u003eVEGF inhibitors are widely used as first-line therapy for DME \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e, yet 30\u0026ndash;50% of patients show limited response \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Adding a DEX-I may help manage residual edema \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Inflammation plays a key role in DME pathogenesis \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e, with elevated levels of angiogenic factors, cytokines, chemokines, complement proteins, and oxidative stress markers found in the vitreous and aqueous humor of DR patients \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Intravitreal corticosteroids, with anti-inflammatory and anti-edematous properties, effectively target these pathways and offer a strong therapeutic option.\u003c/p\u003e\u003cp\u003eIn addition, some of these biomarkers are considered to correlate with intraocular inflammation levels and responsiveness to anti-VEGF and steroid therapy,such as intraretinal cystoid spaces, increased number of hyperreflective foci (HRF) in the outer retina near the fovea, presence of foveal exudation, and subretinal neuroretinal detachment (SND) \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.Whether patients with any of these inflammatory biomarkers on SD-OCT achieve better functional and anatomical outcomes with simultaneous DEX-I combined with anti-VEGF therapy compared to anti-VEGF monotherapy was a key question.\u003c/p\u003e\u003cp\u003eIn our study, we administered a single dose of dexamethasone combined with the first aflibercept injection, followed by monthly aflibercept until week 12, and then a PRN regimen. The 24-week results show that the combination group achieved faster visual improvement and more stable CRT reduction with less edema fluctuation early on compared to the monotherapy group. Furthermore, subgroup analysis of patients with SD-OCT features suggestive of active inflammation (CRT\u0026thinsp;\u0026ge;\u0026thinsp;300\u0026micro;m, intraretinal cysts within 1000\u0026micro;m of fovea, HRF within 500\u0026micro;m, SND) showed that visual acuity improved more rapidly in the combination group at week 4. At week 24, the reduction in cyst count was significantly greater in the combination group. We propose that SND, HRF, and foveal cystoid spaces serve as biomarkers predicting better early visual outcomes and more stable maintenance with combination therapy in DME eyes.\u003c/p\u003e\u003cp\u003eStudies on DEX-I combined with anti-VEGF for DME are limited. Totan et al\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e assessed the therapeutic effect of DEX-I in 30 eyes with chronic DME unresponsive to at least three bevacizumab injections. Notable enhancements in BCVA and CRT were observed at 1 and 3 months; however, these benefits were not maintained long-term and showed a decline between the third and sixth months post-injection. Koc et al\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e reported no meaningful differences in BCVA or CMT among 94 eyes with DME resistant to ranibizumab or aflibercept, regardless of whether treatment continued with anti-VEGF or switched to DEX. Busch et al\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e demonstrated that eyes failing to respond during the anti-VEGF loading phase experienced superior visual and anatomical outcomes over 24 months when transitioned early to DEX-I, compared to those maintained on anti-VEGF monotherapy. Eyes that remained on anti-VEGF alone showed minimal vision gains and no significant CFT reduction at 12 or 24 months. Those converted to steroid therapy in the second year also exhibited substantial functional and structural improvements.Ferhat et al\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e highlighted the therapeutic advantages of DEX in managing inadequately controlled DME. Following DEX administration, patients experienced a marked decrease in CST, reflecting better disease control and functional stabilization. Their findings emphasized the benefit of reduced treatment frequency made possible by incorporating DEX into the regimen. Kaya et al \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e randomized DME patients to ranibizumab monotherapy or simultaneous ranibizumab\u0026thinsp;+\u0026thinsp;DEX treatment. The combination group showed significantly greater BCVA gains at 6 and 12 months (P\u0026thinsp;=\u0026thinsp;0.002, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and superior CRT reduction starting at 2 months and continuing throughout, indicating faster and more pronounced improvements. Inflammatory OCT biomarkers also improved more in the combination group at 12 and 24 months. Overall, simultaneous dual therapy proved to be an effective first-line option for DME with inflammatory features or reduced vision. In our study, the combination group achieved earlier visual gains and greater macular thickness reduction. Intensive anti-VEGF therapy combined with DEX-I resulted in better functional and anatomical outcomes than monotherapy.\u003c/p\u003e\u003cp\u003eEarly combination therapy for diabetic macular edema (DME) offers rapid onset by targeting both VEGF-driven leakage and inflammation, significantly reducing CRT within a month. In contrast, sequential treatment-adding DEX only after poor anti-VEGF response-delays edema control and risks irreversible retinal damage. Patients receiving early combination show greater BCVA gains and faster anatomical recovery, lowering the risk of photoreceptor apoptosis. DEX, sustained-release profile also reduces injection frequency, improving compliance. Sequential regimens often require more injections and raise costs. Overall, early combination therapy provides superior outcomes, faster recovery, reduced treatment burden, and better cost-effectiveness, making it a more efficient strategy for managing DME.\u003c/p\u003e\u003cp\u003eRegarding safety, this study primarily evaluated adverse events postoperatively. During follow-up, IOP exceeded 25 mmHg at least once in one eye in the combination group (at 8 weeks post-injection), which was effectively managed with topical anti-glaucoma medication, allowing discontinuation 3 months post-injection. Regarding cataracts, lens opacity density did not show a significant increase from baseline in phakic eyes of either group, possibly due to the short observation period. No other serious complications, such as retinal detachment or endophthalmitis, occurred in either group. Based on the observed adverse events, close monitoring of IOP during treatment is essential, but overall, the regimen demonstrated a favorable safety profile. However, limitations include a relatively small sample size, short follow-up duration, and insufficient patient numbers. Future studies with larger samples and longer follow-up periods are needed to investigate the long-term impact of combination therapy on DME.\u003c/p\u003e"},{"header":"4. Conclusions","content":"\u003cp\u003eIntravitreal aflibercept monotherapy significantly improves visual acuity and anatomical outcomes in DME patients. Furthermore, combining DEX-I with the first intravitreal aflibercept injection leads to more favorable early visual outcomes and superior early anatomical results compared to aflibercept monotherapy, regardless of the presence of inflammatory biomarkers on SD-OCT.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eThis study received no specific financial support.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eThe authors thank Dr. Sheng L, Miss. Yue C, Ms. Dingxi L, Miss. Beichen L, Ms. Yongxia Z and all clinical investigators for their contribution to the collection of data. The authors also thank Dr. Sheng L for assistance with writing and editing of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e\u003cp\u003eThe authors thank Dr. Sheng Li, Miss. Yue Chen, Ms. Dingxi Liu, Miss. Beichen Liu, Ms. Yongxia Zhao and all clinical investigators for their contribution to the collection of data. The authors also thank Dr. Sheng Li for assistance with writing and editing of the manuscript.\u003c/p\u003e\u003cp\u003e\u003cb\u003eEthics declarations\u003c/b\u003e: This study was approved by the Ethics Committee of the Third People's Hospital of Dalian (Approval No.: 2024-047-002).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConsent for publication\u003c/b\u003e: Not applicable.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConflicts of Interest\u003c/b\u003e: The authors declare no conflicts of interest.\u003c/p\u003e\u003ch2\u003eData Availability Statement:\u003c/h2\u003e\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available due to privacy or ethical restrictions.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSchmidt-Erfurth U, Garcia-Arumi J, Bandello F, et al. Guidelines for the management ofdiabetic macular edema by the european society of retina specialists (euretina). Ophthalmologica. 2017;237:185\u0026ndash;222. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1159/000458539\u003c/span\u003e\u003cspan address=\"10.1159/000458539\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang J, Zhang J, Zhang C et al. Diabetic Macular Edema: current Understanding, Molecular Mechanisms and Therapeutic Implications. Cells.2022;11(21). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/CELLS11213362\u003c/span\u003e\u003cspan address=\"10.3390/CELLS11213362\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArimura N, Otsuka H, Yamakiri K, et al. Vitreous mediators after intravitreal bevacizumab or triamcinolone acetonide in eyes with proliferative diabetic retinopathy. Ophthalmology. 2009;116:921\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ophtha.2008.12.024\u003c/span\u003e\u003cspan address=\"10.1016/j.ophtha.2008.12.024\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHo AC, Scott IU, Kim SJ, et al. Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: a report by the American Academy of Ophthalmology. Ophthalmology. 2012;119:2179\u0026ndash;88. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ophtha.2012.07.058\u003c/span\u003e\u003cspan address=\"10.1016/j.ophtha.2012.07.058\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRomero-Aroca P, Baget-Bernaldiz M, Pareja-Rios A et al. Diabetic Macular Edema Pathophysiology: Vasogenic versus Inflammatory. J. Diabetes Res. 2016, 2016, 2156273. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1155/2016/2156273\u003c/span\u003e\u003cspan address=\"10.1155/2016/2156273\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchmidt-Erfurth U, Garcia-Arumi J, Bandello F, Berg K, Chakravarthy U, Gerendas BS, Loewenstein A. Guidelines for the Management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA). Ophthalmologica. 2017;237:185\u0026ndash;222.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShah AR, Yonekawa Y, Todorich B, et al. Prediction of Anti-VEGF Response in Diabetic Macular Edema After 1 Injection. J Vitreoretin Dis. 2017;1:169\u0026ndash;74. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/2474126416682569\u003c/span\u003e\u003cspan address=\"10.1177/2474126416682569\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBucolo C, Gozzo L, Longo L, Mansueto S, Vitale DC, Drago F. Long-term efficacy and safety profile of multiple injections of intravitreal dexamethasone implant to manage diabetic macular edema: a systematic review of real-world studies. J Pharmacol Sci. 2018;138(4):219\u0026ndash;32. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/J.JPHS.2018.11.001\u003c/span\u003e\u003cspan address=\"10.1016/J.JPHS.2018.11.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUrbančič M, Topčić IG. Dexamethasone implant in the management of diabetic macular edema from clinician\u0026rsquo;s perspective. Clin Ophthalmol. 2019;13:821\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/OPTH.S206769\u003c/span\u003e\u003cspan address=\"10.2147/OPTH.S206769\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVirgili G, Parravano M, Evans JR, Gordon I, Lucenteforte E. (2018) Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis. Cochrane Database Syst Rev. 2018;10(10):CD007419. doi: org/ \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/14651 858.CD007 419\u003c/span\u003e\u003cspan address=\"10.1002/14651 858.CD007 419\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. pub6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDuh EJ, Sun JK, Stitt AW. (2017) Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight.2017;2(14):e93751. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1172/jci.insight.93751\u003c/span\u003e\u003cspan address=\"10.1172/jci.insight.93751\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShah AR, Yonekawa Y, Todorich B, et al. Prediction of anti-VEGF response in diabetic macular edema after 1 injection. J Vitreoretin Dis. 2017;1(3):169\u0026ndash;74. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/2474126416682569\u003c/span\u003e\u003cspan address=\"10.1177/2474126416682569\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLee H, Kang KE, Chung H, Kim HC. Prognostic factors for functional and anatomic outcomes in patients with diabetic macular edema treated with dexamethasone implant. Korean J Ophthalmol. 2018;32:116\u0026ndash;25. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3341/kjo.2017.0041\u003c/span\u003e\u003cspan address=\"10.3341/kjo.2017.0041\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWhitcup SM, Cidlowski JA, Csaky KG, Ambati J. Pharmacology of Corticosteroids for Diabetic Macular Edema. Invest Ophthalmol Vis Sci. 2018;59(1):1\u0026ndash;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1167/IOVS.17-22259\u003c/span\u003e\u003cspan address=\"10.1167/IOVS.17-22259\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLoukovaara S, Nurkkala H, Tamene F, et al. Quantitative Proteomics Analysis of Vitreous Humor from Diabetic Retinopathy Patients. J Proteome Res. 2015;14(12):5131\u0026ndash;43. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1021/ACS.JPROTEOME.5B00900\u003c/span\u003e\u003cspan address=\"10.1021/ACS.JPROTEOME.5B00900\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVujosevic S, Sim\u0026oacute; R. Local and Systemic Inflammatory Biomarkers of Diabetic Retinopathy: an Integrative Approach. Invest Ophthalmol Vis Sci. 2017;58(6):BIO68\u0026ndash;75. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1167/IOVS.17-21769\u003c/span\u003e\u003cspan address=\"10.1167/IOVS.17-21769\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVujosevic S, Toma C, Villani E, et al. Diabetic macular edema with neuroretinal detachment: OCT and OCT-angiography biomarkers of treatment response to anti-VEGF and steroids. Acta Diabetol. 2020;57(3):287\u0026ndash;96. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/S00592-019-01424-4\u003c/span\u003e\u003cspan address=\"10.1007/S00592-019-01424-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTotan Y, G\u0026uuml;ler E, G\u0026uuml;raʇa\u0026ccedil; FB. Dexamethasone Intravitreal Implant for Chronic Diabetic Macular Edema Resistant to Intravitreal Bevacizumab Treatment. Curr Eye Res. 2016;41(1):107\u0026ndash;13. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3109/02713683.2014.1002048\u003c/span\u003e\u003cspan address=\"10.3109/02713683.2014.1002048\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKoc H, Alpay A, Ugurbas SH. Comparison of the efficacy of intravitreal Anti-VEGF versus intravitreal dexamethasone implant in treatment resistant diabetic Macular Edema. BMC Ophthalmol. 2023;23(1):1\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/S12886-023-02831-6/TABLES/4\u003c/span\u003e\u003cspan address=\"10.1186/S12886-023-02831-6/TABLES/4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBusch C, Fraser-Bell S, Iglicki M, Lupidi M, Couturier A, Chaikitmongkol V, .International Retina Group. Real-world outcomes of non-responding diabetic macular edema treated with continued anti-VEGF therapy versus early switch to dexamethasone implant: 2-year results. Acta Diabetol. 2019;56:1341\u0026ndash;50. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00592-019-01416-4\u003c/span\u003e\u003cspan address=\"10.1007/s00592-019-01416-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFerhat T, G\u0026aacute;bor M, Christoph T, et al. Intravitreal Dexamethasone Implant in Anti-Vascular Endothelial Growth Factor Pretreated Diabetic Macular Edema\u0026mdash;A Swiss Cohort Study. Pharmaceuticals (Basel). 2024;17(9):1235. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/ph17091235\u003c/span\u003e\u003cspan address=\"10.3390/ph17091235\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKaya M, Kocak N,Ozturk T et al. Intravitreal ranibizumab and dexamethasone implant injections as primary treatment of diabetic macular edema:simultaneously double protocol[J]. Eye (Lond) 2021,35(3):777\u0026ndash;85. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41433-020-0949-2\u003c/span\u003e\u003cspan address=\"10.1038/s41433-020-0949-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Diabetic Macular Edema, Aflibercept Injection, Dexamethasone Intraocular Implant","lastPublishedDoi":"10.21203/rs.3.rs-7500444/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7500444/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eTo evaluate the differences in preliminary clinical efficacy and safety between intravitreal aflibercept monotherapy and early combination therapy with aflibercept and dexamethasone implant (DEX-I) for diabetic macular edema (DME).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eProspective study. Fifty-nine patients (59 eyes) diagnosed with DME at the Ophthalmology Department of Dalian Third People's Hospital between March 2024 and December 2024 were enrolled. Patients were divided into an aflibercept monotherapy group (30 patients, 30 eyes) and an aflibercept combined with DEX implant group (29 patients, 29 eyes). The monotherapy group received intravitreal injections of aflibercept (2mg/0.05ml) every 4 weeks for 4 doses, followed by a pro re nata (PRN) regimen until week 24. The combination group received an initial intravitreal injection of aflibercept (2mg/0.05ml) combined with DEX-I (0.7mg) in the same session. From week 4 to week 12, they received monthly aflibercept injections (2mg/0.05ml), followed by a PRN regimen until week 24. Before treatment, all patients underwent best-corrected visual acuity (BCVA) assessment using the ETDRS chart (letters recorded), slit-lamp examination, intraocular pressure (IOP) measurement, indirect ophthalmoscopy, spectral-domain optical coherence tomography (SD-OCT), and optical coherence tomography angiography (OCTA). After treatment, patients in both groups were assessed every 4 weeks\u0026thinsp;\u0026plusmn;\u0026thinsp;7 days until week 24.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eCompared to the monotherapy group, the combination group showed a significantly greater mean increase in BCVA from baseline to week 12 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The mean BCVA increase from baseline to week 24 was also greater in the combination group (P\u0026thinsp;=\u0026thinsp;0.094). The proportion of eyes gaining\u0026thinsp;\u0026ge;\u0026thinsp;15 letters from baseline at week 12 was 58.62% in the combination group versus 30% in the monotherapy group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Compared to baseline, both groups showed statistically significant reductions in central retinal thickness (CRT) at all follow-up time points (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all). The difference in CRT reduction between the monotherapy and combination groups was statistically significant at 20 weeks post-injection (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eCompared to aflibercept monotherapy, early combination therapy with aflibercept and DEX-I resulted in faster visual acuity improvement, greater reduction in central macular thickness, and reduced edema fluctuation in the early treatment phase for DME.\u003c/p\u003e","manuscriptTitle":"Preliminary Efficacy Analysis of Early Combination Therapy with Intravitreal Aflibercept and Dexamethasone Implant for Diabetic Macular Edema","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-17 12:26:03","doi":"10.21203/rs.3.rs-7500444/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-10-24T03:26:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"65781651704965081789252201902845854025","date":"2025-10-17T03:01:17+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-06T10:35:43+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-03T06:05:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-02T06:47:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-02T06:45:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2025-08-31T12:02:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f4dfee00-a9a5-417c-ac28-2489a3bf7f34","owner":[],"postedDate":"October 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-10-17T12:26:03+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-17 12:26:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7500444","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7500444","identity":"rs-7500444","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}