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An Updated and Comprehensive Meta-Analysis of Association between VEGA -634G > C, -460T > C, +405G > C and +936C > T Polymorphisms and Retinopathy of Prematurity Risk.
Gohari, M, Bahrami, R, Dastgheib, SA, Lookzadeh, MH, Noorishadkam, M, Mirjalili, SR, Zare-Shehneh, M, Neamatzadeh, H
Fetal and pediatric pathology. 2021;(3):233-249
Abstract
Previous studies have suggested an association between VEGF-A polymorphisms and retinopathy of prematurity (ROP) risk. But the conclusions are still controversial. The aim of this meta-analysis was to evaluate the association between the VEGF-A polymorphisms and susceptibility of ROP. Methods: We searched PubMed, Scopus, WanFang and CNKI databases for all eligible case-control studies published before September 30, 2019. Results: A total of 27 case-control studies with 5,748 ROP cases and 6,146 controls were selected. The results suggested that there was an association between VEGF-A -460T > C polymorphism and increased risk of ROP under the allele model (C vs. T: OR= 0.879, 95% CI 0.776-0.994, p = 0.040). However, VEGF-A -634G > C, +405G > C and +936C > T polymorphisms were not significantly associated with risk of ROP. The subgroup analysis demonstrated that VEGF-A +405G > C polymorphism was associated with ROP risk in Caucasians. Conclusions: This meta-analysis indicates that VEGF-A -460T > C polymorphism may contribute to the susceptibility for ROP.
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Associations between Vascular Endothelial Growth Factor Gene Polymorphisms and Different Types of Diabetic Retinopathy Susceptibility: A Systematic Review and Meta-Analysis.
Hu, L, Gong, C, Chen, X, Zhou, H, Yan, J, Hong, W
Journal of diabetes research. 2021;:7059139
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) gene polymorphisms have been shown to be associated with the risk of diabetic retinopathy (DR), but the results were inconsistent. The aim of this study was to systematically assess the associations between VEGF gene polymorphisms and different types of DR (nonproliferative DR and proliferative DR). METHODS Electronic databases PubMed, Embase, Web of Science, CNKI, and WANFANG DATA were searched for articles on the associations between VEGF gene polymorphisms and different types of DR up to November 6, 2019. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and subgroup analyses were conducted by ethnicity. Sensitivity analysis was conducted to assess the stability of the results. Publication bias was assessed by using the Egger regression asymmetry test and visualization of funnel plots. A systematic review was conducted for polymorphisms with a high degree of heterogeneity (I 2 > 75%) or studied in only one study. RESULTS A total of 13 and 18 studies analyzed the associations between VEGF SNPs and nonproliferative DR (NPDR) as well as proliferative DR (PDR), respectively. There were significant associations between rs2010963 and NPDR in Asian (dominant model: OR = 1.29, 95%CI = 1.04 - 1.60); and rs2010963 is associated with PDR in total population (dominant model: OR = 1.20, 95%CI = 1.03 - 1.41), either Asian (recessive model: OR = 1.57, 95%CI = 1.04 - 2.35) or Caucasian (recessive model: OR = 1.83, 95%CI = 1.28 - 2.63). Rs833061 is associated with PDR in Asian (recessive model: OR = 1.58, 95%CI = 1.11 - 2.26). Rs699947 is associated with NPDR in the total population (dominant model: OR = 2.04, 95%CI = 1.30 - 3.21) and associated with PDR in Asian (dominant model: OR = 1.72, 95%CI = 1.05 - 2.84). CONCLUSIONS Rs2010963, rs833061, and rs699947 are associated with NPDR or PDR, which may be involved in the occurrence and development of DR.
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Intravitreal conbercept improves outcome in patients undergoing vitrectomy for proliferative diabetic retinopathy: A systematic review and meta-analysis.
Pranata, R, Vania, A
Journal of evidence-based medicine. 2020;(2):116-124
Abstract
OBJECTIVES To evaluate the latest evidence concerning the efficacy of conbercept on vitrectomy for proliferative diabetic retinopathy (PDR) and its efficacy compared to control and other antivascular endothelial growth factor. METHODS We performed a systematic literature search on topics that assess the role of conbercept in patients undergoing vitrectomy for PDR from inception to November 2019, using PubMed, EuropePMC, Cochrane Central Database, ProQuest, ScienceDirect, and Clinicaltrials.gov. Two researchers independently searched literature, extracted data, and evaluated the risk of bias. RevMan 5.3 and StataMP 16 software were used to perform data analysis. RESULTS There were 699 cases (eyes) from eight studies. Baseline best-corrected visual acuity (BCVA) was better in the control group compared to conbercept group (mean difference [MD] = 0.13, I2 = 0%). A greater BCVA improvement was observed in the conbercept group after 1-month (MD = -0.27, I2 = 1%), 3-month (MD = -0.28, I2 = 0%), and 6-month (MD = -0.20, I2 = 78%) follow-up. The need for endodiathermy (odds ratio [OR] = 0.20, I2 = 0%) and silicone oil tamponade use (OR = 0.59, I2 = 72%) and intraoperative bleeding (OR = 0.11, I2 = 33%) was lower in conbercept group. Postoperative early (OR = 0.22, I2 = 0%) and late (OR = 0.47, I2 = 0%) vitreous hemorrhage was lower in conbercept group. There was no significant difference in BCVA improvement and intraoperative outcome between conbercept and ranibizumab. CONCLUSIONS Intravitreal conbercept was associated with a more significant BCVA improvement, better intraoperative outcome, and less postoperative vitreous hemorrhage compared to no conbercept.
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Association of VEGF Gene Polymorphisms with Susceptibility to Diabetic Retinopathy: A Systematic Review and Meta-Analysis.
Yang, Q, Zhang, Y, Zhang, X, Li, X, Liu, J
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2020;(5):264-279
Abstract
The associations between vascular endothelial growth factor (VEGF) gene polymorphisms and risk of type 2 diabetic retinopathy (DR) - proliferative diabetic retinopathy (PDR), and nonproliferative diabetic retinopathy (NPDR) - remain unclear. A systematic search and meta-analysis using odds ratio (OR) with 95% confidence interval (CI) was performed to evaluate the association. Our study concluded 26 studies containing 10 single nucleotide polymorphisms (SNPs). In Asian populations, rs3025039 polymorphism was associated with DR risk, while in overall populations and Caucasians, the DR risk was increased by association with rs2010963. There was a significant association between rs25648 and rs833061 and DR risk in Caucasians. DR risks were found to be significantly associated between rs3025021, rs13207351, and rs2146323 in either overall populations, Caucasians or Asians. Besides, in overall and Asian populations, rs699947 and rs3025039 were associated with PDR risk. rs1570360, rs3025039, and rs833061 played a key role in PDR etiology in Caucasians. rs2010963 was associated with increased risk of PDR in overall populations. A significant association between rs699947, rs3025039, and rs833061 and NPDR risk in overall populations and Asians was found. A significant association was observed between rs2010963 and increased NPDR risk in overall and Caucasian populations. This study provides a new insight into the parthenogenesis of diabetic retinopathy. Targeting VEGF SNPs may be a potential of therapeutic approach for the treatment of DR, PDR, and NPDR.
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Anti-vascular endothelial growth factor for macular oedema secondary to branch retinal vein occlusion.
Shalchi, Z, Mahroo, O, Bunce, C, Mitry, D
The Cochrane database of systematic reviews. 2020;(7):CD009510
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Abstract
BACKGROUND Branch retinal vein occlusion (BRVO) is one of the most commonly occurring retinal vascular abnormalities. The most common cause of visual loss in people with BRVO is macular oedema (MO). Grid or focal laser photocoagulation has been shown to reduce the risk of visual loss. Limitations to this treatment exist, however, and newer modalities may have equal or improved efficacy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) has recently been used successfully to treat MO resulting from a variety of causes. OBJECTIVES To investigate the efficacy and gather evidence from randomised controlled trials (RCTs) on the potential harms of anti-vascular endothelial growth factor (VEGF) agents for the treatment of macular oedema (MO) secondary to branch retinal vein occlusion (BRVO). SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2019, Issue 6); MEDLINE Ovid; Embase Ovid; the ISRCTN registry; ClinicalTrials.gov; and the WHO ICTRP. The date of the last search was 12 June 2019. SELECTION CRITERIA We included randomised controlled trials (RCTs) investigating BRVO. Eligible trials had to have at least six months' follow-up where anti-VEGF treatment was compared with another treatment, no treatment, or placebo. We excluded trials where combination treatments (anti-VEGF plus other treatments) were used; and trials that investigated the dose and duration of treatment without a comparison group (other treatment/no treatment/sham). DATA COLLECTION AND ANALYSIS Two review authors independently extracted the data using standard methodological procedures expected by Cochrane. The primary outcome was the proportion of participants with an improvement from baseline in best-corrected visual acuity of greater than or equal to 15 letters (3 lines) on the Early Treatment in Diabetic Retinopathy Study (ETDRS) Chart at six months and 12 months of follow-up. The secondary outcomes were the proportion of participants who lost greater than or equal to 15 ETDRS letters (3 lines) and the mean visual acuity (VA) change at six and 12 months, as well as the change in central retinal thickness (CRT) on optical coherence tomography from baseline at six and 12 months. We also collected data on adverse events and quality of life (QoL). MAIN RESULTS We found eight RCTs of 1631 participants that met the inclusion criteria after independent and duplicate review of the search results. These studies took place in Europe, North America, Eastern Mediterranean region and East Asia. Included participants were adults aged 18 or over with VA of 20/40 or worse. Studies varied by duration of disease but permitted previously treated eyes as long as there was sufficient treatment-free interval. All anti-VEGF agents (bevacizumab, ranibizumab and aflibercept) and steroids (triamcinolone and dexamethasone) were included. Overall, we judged the studies to be at moderate or unclear risk of bias. Four of the eight studies did not mask participants or outcome assessors, or both. One trial compared anti-VEGF to sham. At six months, eyes receiving anti-VEGF were significantly more likely to have a gain of 15 or more ETDRS letters (risk ratio (RR) 1.72, 95% confidence interval (CI) 1.19 to 2.49; 283 participants; moderate-certainty evidence). Mean VA was better in the anti-VEGF group at six months compared with control (mean difference (MD) 7.50 letters, 95% CI 5.29 to 9.71; 282 participants; moderate-certainty evidence). Anti-VEGF also proved more effective at reducing CRT at six months (MD -57.50 microns, 95% CI -108.63 to -6.37; 281 participants; lower CRT is better; moderate-certainty evidence). There was only very low-certainty evidence on adverse effects. There were no reports of endophthalmitis. Mean change in QoL (measured using the National Eye Institute Visual Functioning Questionnaire VFQ-25) was better in people treated with anti-VEGF compared with people treated with sham (MD 7.6 higher score, 95% CI 4.3 to 10.9; 281 participants; moderate-certainty evidence). Three RCTs compared anti-VEGF with macular laser (total participants = 473). The proportion of eyes gaining 15 or more letters was greater in the anti-VEGF group at six months (RR 2.09, 95% CI 1.44 to 3.05; 2 studies, 201 participants; moderate-certainty evidence). Mean VA in the anti-VEGF groups was better than the laser groups at six months (MD 9.63 letters, 95% CI 7.23 to 12.03; 3 studies, 473 participants; moderate-certainty evidence). There was a greater reduction in CRT in the anti-VEGF group compared with the laser group at six months (MD -147.47 microns, 95% CI -200.19 to -94.75; 2 studies, 201 participants; moderate-certainty evidence). There was only very low-certainty evidence on adverse events. There were no reports of endophthalmitis. QoL outcomes were not reported. Four studies compared anti-VEGF with intravitreal steroid (875 participants). The proportion of eyes gaining 15 or more ETDRS letters was greater in the anti-VEGF group at six months (RR 1.67, 95% CI 1.33 to 2.10; 2 studies, 330 participants; high-certainty evidence) and 12 months (RR 1.76, 95% CI 1.36 to 2.28; 1 study, 307 participants; high-certainty evidence). Mean VA was better in the anti-VEGF group at six months (MD 8.22 letters, 95% CI 5.69 to 10.76; 2 studies, 330 participants; high-certainty evidence) and 12 months (MD 9.15 letters, 95% CI 6.32 to 11.97; 2 studies, 343 participants; high-certainty evidence). Mean CRT also showed a greater reduction in the anti-VEGF arm at 12 months compared with intravitreal steroid (MD -26.92 microns, 95% CI -65.88 to 12.04; 2 studies, 343 participants; moderate-certainty evidence). People receiving anti-VEGF showed a greater improvement in QoL at 12 months compared to those receiving steroid (MD 3.10, 95% CI 0.22 to 5.98; 1 study, 307 participants; moderate-certainty evidence). Moderate-certainty evidence suggested increased risk of cataract and raised IOP with steroids. There was only very low-certainty evidence on APTC events. No cases of endophthalmitis were observed. AUTHORS' CONCLUSIONS The available RCT evidence suggests that treatment of MO secondary to BRVO with anti-VEGF improves visual and anatomical outcomes at six and 12 months.
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Serum Vascular Endothelial Growth Factor Levels Correlate with Severity of Retinopathy in Diabetic Patients: A Systematic Review and Meta-Analysis.
Zhou, Z, Ju, H, Sun, M, Chen, H
Disease markers. 2019;:9401628
Abstract
BACKGROUND Investigations regarding serum and plasma vascular endothelial growth factor (VEGF) levels in patients with diabetic retinopathy (DR) are conflicting. This meta-analysis is aimed at determining whether serum and plasma VEGF levels are associated with DR and its severity in diabetic patients. METHODS PubMed and EMBASE were used to search for published studies, and serum and plasma VEGF levels were compared among DR, nonproliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), and nondiabetic retinopathy (NDR) patients. Standardized mean differences (SMD) and 95% confidence interval (CI) were pooled using a random effects model. RESULTS A total of 29 studies comprising 1805 DR (or NPDR or PDR) patients and 1699 NDR patients were included. ELISA was used to evaluate serum or plasma VEGF levels in all except for two studies included in this meta-analysis. Overall, serum VEGF levels were significantly higher in DR patients (SMD: 0.74, 95% CI: 0.44-1.03) than those in NDR patients, while plasma VEGF levels were not in the comparison (SMD: 0.40, 95% CI: -0.13-0.92). Similarly, NPDR (SMD: 0.51, 95% CI: 0.22-0.80) and PDR (SMD: 1.32, 95% CI: 0.79-1.85) patients had higher serum VEGF levels compared with NDR patients, but the difference was not significant in plasma samples (SMD: 0.24, 95% CI: -0.47-0.95; SMD: 0.37, 95% CI: -0.30-1.05). In addition, serum VEGF levels were higher in PDR patients than those in NPDR patients (SMD: 0.87, 95% CI: 0.41-1.33), but plasma VEGF levels were not (SMD: -0.00, 95% CI: -0.31-0.31). The subgroup and metaregression analysis revealed that the study location, study design, and publication year of a study have certain influence on heterogeneity between studies in serum or plasma samples. CONCLUSIONS VEGF levels in the serum instead of those in the plasma correlate to the presence and severity of DR in diabetic patients. Further large-scale studies are required to confirm these findings.
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Anti-vascular endothelial growth factor treatment for retinal conditions: a systematic review and meta-analysis.
Pham, B, Thomas, SM, Lillie, E, Lee, T, Hamid, J, Richter, T, Janoudi, G, Agarwal, A, Sharpe, JP, Scott, A, et al
BMJ open. 2019;(5):e022031
Abstract
OBJECTIVES To evaluate the comparative effectiveness and safety of intravitreal bevacizumab, ranibizumab and aflibercept for patients with choroidal neovascular age-related macular degeneration (cn-AMD), diabetic macular oedema (DMO), macular oedema due to retinal vein occlusion (RVO-MO) and myopic choroidal neovascularisation (m-CNV). DESIGN Systematic review and random-effects meta-analysis. METHODS Multiple databases were searched from inception to 17 August 2017. Eligible head-to-head randomised controlled trials (RCTs) comparing the (anti-VEGF) drugs in adult patients aged ≥18 years with the retinal conditions of interest. Two reviewers independently screened studies, extracted data and assessed risk of bias. RESULTS 19 RCTs involving 7459 patients with cn-AMD (n=12), DMO (n=3), RVO-MO (n=2) and m-CNV (n=2) were included. Vision gain was not significantly different in patients with cn-AMD, DMO, RVO-MO and m-CNV treated with bevacizumab versus ranibizumab. Similarly, vision gain was not significantly different between cn-AMD patients treated with aflibercept versus ranibizumab. Patients with DMO treated with aflibercept experienced significantly higher vision gain at 12 months than patients receiving ranibizumab or bevacizumab; however, this difference was not significant at 24 months. Rates of systemic serious harms were similar across anti-VEGF agents. Posthoc analyses revealed that an as-needed treatment regimen (6-9 injections per year) was associated with a mortality increase of 1.8% (risk ratio: 2.0 [1.2 to 3.5], 2 RCTs, 1795 patients) compared with monthly treatment in cn-AMD patients. CONCLUSIONS Intravitreal bevacizumab was a reasonable alternative to ranibizumab and aflibercept in patients with cn-AMD, DMO, RVO-MO and m-CNV. The only exception was for patients with DME and low visual acuity (<69 early treatment diabetic retinopathy study [ETDRS] letters), where treatment with aflibercept was associated with significantly higher vision gain (≥15 ETDRS letters) than bevacizumab or ranibizumab at 12 months; but the significant effects were not maintained at 24 months. The choice of anti-VEGF drugs may depend on the specific retinal condition, baseline visual acuity and treatment regimen. PROSPERO REGISTRATION NUMBER CRD42015022041.
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Clinicohistopathological implications of MMP/VEGF expression in retinoblastoma: a combined meta-analysis and bioinformatics analysis.
Zhu, J, Zhang, X, Ai, L, Yuan, R, Ye, J
Journal of translational medicine. 2019;(1):226
Abstract
BACKGROUND No in-depth systematic evidence is available for assessing retinoblastoma malignancy and eligibility for subsequent treatment. METHODS The Cochrane Library, EMBASE, PubMed, Web of Science, and China Biology Medicine databases were searched, and 16 studies comprising 718 retinoblastoma patients were included. Pooled odds ratios (ORs) and summary correlation coefficients (r) with 95% confidence intervals (CIs) in random-effects, fixed-effects or quality-effects models were calculated using Review Manager 5.3 and MetaXL. GO functional annotation and KEGG pathway analysis were performed using the GO and STRING databases. RESULTS We observed significant associations between high levels of MMP-1 (OR, 4.21; 95% CI 1.86-9.54), MMP-2 (OR, 11.18; 95% CI 4.26-29.30), MMP-9 (OR, 10.41, 95% CI 4.26-25.47), and VEGF (OR, 8.09; 95% CI 4.03-16.20) with tumor invasion; high levels of MMP-1 (OR, 3.58; 95% CI 1.48-8.71), MMP-2 (OR, 2.96; 95% CI 1.32-6.64), MMP-9 (OR, 5.49; 95% CI 3.55-8.48) and VEGF (OR, 5.30; 95% CI 2.93-9.60) with poor differentiation; and overexpression of MMP-9 (OR, 5.17; 95% CI 2.85-9.38) with advanced clinical stages. Moreover, MMP-9 and VEGF expression were positively correlated (r, 0.61; 95% CI 0.38-0.77). Multiple GO terms were enriched associated with MMP-1, MMP-2, MMP-9 and VEGF, and they are closely associated with pathways, proteoglycans and microRNAs related to cancer. CONCLUSIONS MMP-1, MMP-2, MMP-9 and VEGF play important roles in the development and progression of retinoblastoma. High levels of MMP-1, MMP-2, MMP-9 and VEGF are credible implications for increased malignancy, thus the need for more aggressive treatments.
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Subthreshold diode micropulse laser versus conventional laser photocoagulation monotherapy or combined with anti-VEGF therapy for diabetic macular edema: A Bayesian network meta-analysis.
Wu, Y, Ai, P, Ai, Z, Xu, G
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2018;:293-299
Abstract
AIMS: To assess the effects of laser photocoagulation as monotherapy or adjuvant therapy for the treatment of DME. METHODS A search of the Cochrane Library, Pubmed, Embase, and the clinicaltrial.gov registry for randomized clinical trials comparing any two treatments of interest (SDMLP monotherapy, CLP monotherapy, CLP plus anti-VEGF therapy) was performed. Data were collected and pooled by Bayesian network meta-analyses which accounts for both direct and indirect comparisons. The primary outcome was the mean change in best-corrected visual acuity measured by the logarithm of the minimal angle of resolution units. The secondary outcome was the mean change in central macular thickness from baseline to month 12. RESULTS Ranibizumab therapy combined with CLP was more effective than SDMLP alone (MD, -0.396; 95% CrI, -0.746 to -0.062) and CLP alone (MD, -0.621; 95% CrI, -0.823 to -0.431). There was no apparent difference of efficacy between SDMLP alone and CLP alone (MD, -0.225; 95% CrI, -0.501 to 0.058). There was no apparent difference of efficacy between SDMLP alone and Bevacizumab therapy combined with CLP (MD, -0.003, 95% CrI, -0.815 to 0.805). CONCLUSION There was no apparent difference on improving vision between SDMLP monotherapy and CLP monotherapy. The most effective treatment in the network was ranibizumab therapy combined with CLP followed by SDMLP monotherapy, Bevacizumab therapy combined with CLP, and CLP monotherapy in rank order.
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Anti-vascular endothelial growth factor combined with intravitreal steroids for diabetic macular oedema.
Mehta, H, Hennings, C, Gillies, MC, Nguyen, V, Campain, A, Fraser-Bell, S
The Cochrane database of systematic reviews. 2018;(4):CD011599
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BACKGROUND The combination of steroid and anti-vascular endothelial growth factor (VEGF) intravitreal therapeutic agents could potentially have synergistic effects for treating diabetic macular oedema (DMO). On the one hand, if combined treatment is more effective than monotherapy, there would be significant implications for improving patient outcomes. Conversely, if there is no added benefit of combination therapy, then people could be potentially exposed to unnecessary local or systemic side effects. OBJECTIVES To assess the effects of intravitreal agents that block vascular endothelial growth factor activity (anti-VEGF agents) plus intravitreal steroids versus monotherapy with macular laser, intravitreal steroids or intravitreal anti-VEGF agents for managing DMO. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 1); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and the ICTRP. The date of the search was 21 February 2018. SELECTION CRITERIA We included randomised controlled trials (RCTs) of intravitreal anti-VEGF combined with intravitreal steroids versus intravitreal anti-VEGF alone, intravitreal steroids alone or macular laser alone for managing DMO. We included people with DMO of all ages and both sexes. We also included trials where both eyes from one participant received different treatments. DATA COLLECTION AND ANALYSIS We used standard methodological procedures recommended by Cochrane.Two authors independently reviewed all the titles and abstracts identified from the electronic and manual searches against the inclusion criteria. Our primary outcome was change in best corrected visual acuity (BCVA) between baseline and one year. Secondary outcomes included change in central macular thickness (CMT), economic data and quality of life. We considered adverse effects including intraocular inflammation, raised intraocular pressure (IOP) and development of cataract. MAIN RESULTS There were eight RCTs (703 participants, 817 eyes) that met our inclusion criteria with only three studies reporting outcomes at one year. The studies took place in Iran (3), USA (2), Brazil (1), Czech Republic (1) and South Korea (1). Seven studies used the unlicensed anti-VEGF agent bevacizumab and one study used licensed ranibizumab. The study that used licensed ranibizumab had a unique design compared with the other studies in that included eyes had persisting DMO after anti-VEGF monotherapy and received three monthly doses of ranibizumab prior to allocation. The anti-VEGF agent was combined with intravitreal triamcinolone in six studies and with an intravitreal dexamethasone implant in two studies. The comparator group was anti-VEGF alone in all studies; two studies had an additional steroid monotherapy arm, another study had an additional macular laser photocoagulation arm. Whilst we judged these studies to be at low risk of bias for most domains, at least one domain was at unclear risk in all studies.When comparing anti-VEGF/steroid with anti-VEGF monotherapy as primary therapy for DMO, we found no meaningful clinical difference in change in BCVA (mean difference (MD) -2.29 visual acuity (VA) letters, 95% confidence interval (CI) -6.03 to 1.45; 3 RCTs; 188 eyes; low-certainty evidence) or change in CMT (MD 0.20 μm, 95% CI -37.14 to 37.53; 3 RCTs; 188 eyes; low-certainty evidence) at one year. There was very low-certainty evidence on intraocular inflammation from 8 studies, with one event in the anti-VEGF/steroid group (313 eyes) and two events in the anti-VEGF group (322 eyes). There was a greater risk of raised IOP (Peto odds ratio (OR) 8.13, 95% CI 4.67 to 14.16; 635 eyes; 8 RCTs; moderate-certainty evidence) and development of cataract (Peto OR 7.49, 95% CI 2.87 to 19.60; 635 eyes; 8 RCTs; moderate-certainty evidence) in eyes receiving anti-VEGF/steroid compared with anti-VEGF monotherapy. There was low-certainty evidence from one study of an increased risk of systemic adverse events in the anti-VEGF/steroid group compared with the anti-VEGF alone group (Peto OR 1.32, 95% CI 0.61 to 2.86; 103 eyes).One study compared anti-VEGF/steroid versus macular laser therapy. At one year investigators did not report a meaningful difference between the groups in change in BCVA (MD 4.00 VA letters 95% CI -2.70 to 10.70; 80 eyes; low-certainty evidence) or change in CMT (MD -16.00 μm, 95% CI -68.93 to 36.93; 80 eyes; low-certainty evidence). There was very low-certainty evidence suggesting an increased risk of cataract in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 4.58, 95% 0.99 to 21.10, 100 eyes) and an increased risk of elevated IOP in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 9.49, 95% CI 2.86 to 31.51; 100 eyes).One study provided very low-certainty evidence comparing anti-VEGF/steroid versus steroid monotherapy at one year. There was no evidence of a meaningful difference in BCVA between treatments at one year (MD 0 VA letters, 95% CI -6.1 to 6.1, low-certainty evidence). Likewise, there was no meaningful difference in the mean CMT at one year (MD - 9 μm, 95% CI -39.87μm to 21.87μm between the anti-VEGF/steroid group and the steroid group. There was very low-certainty evidence on raised IOP at one year comparing the anti-VEGF/steroid versus steroid groups (Peto OR 0.75, 95% CI 0.16 to 3.55).No included study reported impact of treatment on patients' quality of life or economic data. None of the studies reported any cases of endophthalmitis. AUTHORS' CONCLUSIONS Combination of intravitreal anti-VEGF plus intravitreal steroids does not appear to offer additional visual benefit compared with monotherapy for DMO; at present the evidence for this is of low-certainty. There was an increased rate of cataract development and raised intraocular pressure in eyes treated with anti-VEGF plus steroid versus anti-VEGF alone. Patients were exposed to potential side effects of both these agents without reported additional benefit. The majority of the evidence comes from studies of bevacizumab and triamcinolone used as primary therapy for DMO. There is limited evidence from studies using licensed intravitreal anti-VEGF agents plus licensed intravitreal steroid implants with at least one year follow-up. It is not known whether treatment response is different in eyes that are phakic and pseudophakic at baseline.