Safety of intravitreal anti VEGF injections in diabetic macular edema

Safety of intravitreal anti VEGF injections in 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 Safety of intravitreal anti VEGF injections in diabetic macular edema Mohamed ELShafie This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2172497/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective Diabetic macular edema (DME) is the most common cause of visual impairment in patients with diabetes mellitus. The pathogenesis of DME is complex and multifactorial. DME can be diagnosed using noncontact stereoscopic biomicroscopy, contact lens biomicroscopy, Fundus fluorescein angiography (FFA), and Optical Coherence Tomography (OCT). Intravitreal anti-vascular endothelial growth factor (VEGF) agents have been investigated in the treatment of DME. This study aims to investigate safety of intravitreal anti VEGF during six-month follow up. Methods Sixty patients with type I or II diabetes mellitus complaining from central involved DME were recruited for this longitudinal study. All patients were subjected to full history taking, complete ophthalmological examination, systemic evaluation, FFA and OCT imaging. Patients were subdivided into three groups, 20 patients each: Ranibizumab group, Bevacizumab group and Aflibercept group. Results After 6-month follow-up, the ranibizumab group showed slightly higher systemic cardiovascular and cerebrovascular accidents rates, while the Bevacizumab group showed insignificant higher risk of ocular inflammation and endophthalmitis, aflibercept has the least incidence of ocular adverse effects. Conclusion Anti VEGF intravitreal injections are relatively safe for treatment of DME. Aflibercept showed the least incidence of ocular side effects. The current study suggested that intravitreal anti-VEGF could be administered safely to diabetic patients with decreased glomerular filtration rate (GFR). Ophthalmology aflibercept ranibizumab bevacizumab Diabetic Macular Edema Muller cells vascular endothelial growth factor (VEGF) Introduction About a third of diabetic people have diabetic retinopathy (DR), and about tenth are affected by Diabetic Macular Edema (DME). The incidence of DME increases with diabetes duration, hemoglobin A1C, and blood pressure levels, it is higher in people with type 1 compared with type 2 diabetes ( 1 ). Macular edema is defined as accumulation of excess fluid in the extracellular space of the neurosensory retina causing abnormal thickening of the macula. Intracellular fluid involving Muller cells can be observed in some histopathological cases ( 2 ). Diabetic Macular Edema results from retinal microvascular changes. Thickening of the basement membrane and reduction in the number of pericytes are believed to increase permeability and incompetence of the retinal vasculature. Leakage of plasma constituents to the surrounding retina, with subsequent retinal edema due to compromised blood retinal barrier (BRB). Hypoxia produced by this mechanism can also stimulate the production of vascular endothelial growth factor (VEGF). There is evidence that VEGF is up regulated in DME and proliferative diabetic retinopathy ( 3 ). A great variety of morphological patterns became apparent, even though all patients had the same underlying disease ( 4 ). So, a combination of Optical Coherence Tomography (OCT) with Fundus Fluorescein Angiography (FFA) is considered more advantageous for the classification of DR. Morphological biomarkers - recognized on OCT or FFA - can define patients with recalcitrant disease; and thus, help to guide and predict the prognosis of individual treatment regiments ( 5 ). Although the standard treatment of DME is focal laser photocoagulation, it can only slow progression with low ability to reverse vision loss ( 6 ). Antiangiogenic therapy has largely replaced laser photocoagulation as it was proven to be more effective ( 7 ). Anti-VEGF agents, interrupting a critical stimulus for the development of BRB breakdown, have been studied in the treatment of DME, as Pegaptanib sodium (Macugen, Eyetech Pfizer), Ranibizumab (Lucentis, Genentech Inc., San Francisco, CA), Bevacizumab (Avastin, Genentech, and South San Francisco, CA) and aflibercept (Eylea, Regeneron, NY, USA). Although bevacizumab is currently approved by FDA (Food and Drug Administration) for the treatment of metastatic colorectal cancer, it is widely off-label used in treatment for neovascular age-related macular degeneration (ARMD) and retinal vascular disorders including retinal vein occlusion and DME due to its low cost ( 8 ). Diabetic retinopathy clinical research network trial (DRCR.net) evaluated the short-term value of intravitreal bevacizumab in diabetic patients demonstrating a beneficial effect in center involved DME ( 9 ). Treatment effectiveness indicators include duration of diabetes, number of injections, and response to previous treatments in conjunction with visual acuity, central macular thickness (CMT) and residual macular edema presenting within or under the retina. Compared to intravenous anti VEGFs, used for cancer treatment, the much lower dose of intravitreal anti VEGFs had less systemic adverse effects. These adverse effects, however, increase in high-risk patients with intense anti VEGF treatment for two years ( 10 ). Although intravitreal route is associated with less systemic adverse effects, it is associated with ocular adverse effects: including infectious endophthalmitis, post-injection inflammation, and post- injection increase in intra ocular pressure ( 11 ). This study aims to evaluate systemic and ocular adverse effects of intravitreal anti VEGF during six-month follow up. Patients And Methods This prospective interventional randomized study was held on 60 eyes of 60 patients at the Retina Clinic of Mansoura University ophthalmology center from October 2018 to October 2019.The study was pre-approved by the ethical committee at Mansoura University in 2017. Approval code: MD/17.01.41 The study included patients above age of 18 diagnosed with type 1 or 2 DM who had center involved DME with the following criteria:1- Clear media enough to document macular edema by OCT. 2- Definite retinal thickening due to DME involving center of macula > 300 µm by OCT, assessed to be the main cause of visual loss. 3- Best corrected visual acuity less than .2 log MAR. Exclusion Criteria: 1- Associated vitreoretinal changes: subretinal fibrosis, significant vitreoretinal traction on OCT indicating vitrectomy or poor prognostic factors for injection like distorted inner retinal layers, disrupted ellipsoid zone or macular ischemia. 2- Patients treated with laser or intravitreal injection in last six months. 3- Associated ocular diseases such as: glaucoma, glaucoma suspect, ocular hypertension, or significant cataract which affects vision. 4- Systemic diseases that interfere with Anti VEGF injections such as: Recent stroke or transient ischemic attack. 5- Ocular surgery: like glaucoma related procedure. The patients were classified randomly into three groups: Group A (20 patients): received Lucentis (Ranibizumab .5mg) 3 injections, a month apart. Group B (20 patients): received Avastin (Bevacizumab 1.25 mg) 3 injections, a month apart. Group C (20 patients): received Eylea (Aflibercept 2 mg) 3 injections, a month apart. A simple random sample was done using randomly picked, concealed numbers; each number corresponding to one treatment group. All patients provided an informed written consent before baseline assessment. Statistical analysis was done using IBM’s SPSS statistics (Statistical Package for the Social Sciences) for windows (version 25, 2017). The normality of data distribution was checked using Shapiro-Wilk test. All tests were conducted with 95% confidence interval. Statistical significance was considered if ( P < .05). Results Sixty eyes of sixty patients with type 1 or 2 diabetes were involved in this study. The mean age of the patients was 61.62 with SD 8.33 (range 18-75years), there were 37 male (61.7%) and 23 female (38.3%) subjects. Patients were randomized to three groups, 20 eyes (20 patients) were treated with intravitreal Bevacizumab 1.25 mg (IVB group), 20 eyes (20 patients) received intravitreal Ranibizumab .5mg (IVR group) and 20 eyes (20 patients) treated with intravitreal Aflibercept 2 mg (IVA group). Among the Bevacizumab group, 10 patients were males, 10 patients were females with mean age 59.05 years. The duration of diabetes was an average of 12.55 years. Among the Ranibizumab group, there were 12 male patients and 8 female patients, the mean age was 62 years. The duration of diabetes was an average of 11.90 years, while in the Aflibercept group there were 15 males and 5 females with average age of 63.8 years and disease duration of 12.10 years. HbA1c % (7.30, 7.70, 7.45), IOP mmHg (17.8, 17.55, 17.62), Phakic eyes % (80, 90, 70), Pseudophakic eyes % ( 20 , 10 , 30 ) in three groups (Table 1 ). Table 1 Baseline demographic analysis between the treatment groups Bevacizumab Ranibizumab Aflibercept P Age 59.05 ± 10.49 62.00 ± 6.52 63.80 ± 7.18 .192 Gender Male 50.0% (10) 60.0% (12) 75.0% (15) .262 Female 50.0% (10) 40.0% (8) 25.0% (5) Duration of DM 12.55 ± 3.03 11.90 ± 3.09 12.10 ± 4.46 .842 HbA1c 7.30 ± 0.92 7.70 ± 1.17 7.45 ± 1.19 .515 IOP 17.87 ± 0.746 17.55 ± 0.726 17.62 ± 0.57 .307 Lens state Phakic 80.0% (16) 90.0% (18) 70.0% (14) .346 PCIOL 20.0% (4) 10.0% (2) 30.0% (6) Data is expressed as mean and standard deviation or percentage and frequency. P is significant when ( P ˂ .05). IOP: Intraocular pressure, PCIOL: Posterior chamber intraocular lens. Injection-related infectious endophthalmitis occurred in two bevacizumab -treated eye and no ranibizumab -treated or aflibercept-treated eyes. Ocular inflammation other than endophthalmitis was reported in one ranibizumab-treated eye, three bevacizumab-treated eyes and two aflibercept-treated eyes. Ocular adverse events are detailed in Table 2 . Table 2 Ocular adverse effects during the follow up period in the studied groups Bevacizumab Ranibizumab Aflibercept P Endophthalmitis 10% (2) 0% (0) 0% (0) .322 Inflammation 15% (3) 5% (1) 10% (2) .863 Retinal detachment 0% (0) 0% (0) 0% (0) - Vitreous hemorrhage 5% (1) 5% (1) 0% (0) 1 Cataract 5% (1) 0% (0) 0% (0) 1 Data is expressed as percentage and frequency. P is significant when ( P ˂ .05). Mean IOP values changed from 17.69 ± 0.69 at baseline; to be 21.96 ± 1.53 after one hour, 19.62 ± 1.53 after one week, and 18.5 ± 1.41 after one month. No significant differences were found in IOP elevations between the three groups depending on the anti VEGF agent used (bevacizumab, ranibizumab or aflibercept) as shown in Table 3 , although bevacizumab group seemed to induce a slightly higher IOP level than other two groups. Table 3 Basal and follow up mean IOP values in the studied groups IOP IVB IVR IVA P Basal 17.88 ± 0.75 17.56 ± 0.77 17.63 ± 0.57 .307 One hour 21.91 ± 1.5 21.41 ± 1.84 21.75 ± 1.24 .580 One week 19.83 ± 1.54 19.37 ± 1.8 19.64 ± 1.23 .640 One month 18.68 ± 1.33 18.30 ± 1.72 18.52 ± 1.17 .708 Data is expressed as mean and standard deviation. P is significant when ( P ˂ .05) IOP: intraocular pressure, IVB: Intravitreal bevacizumab. IVA: Intravitreal aflibercept. IVR: Intravitreal ranibizumab. The rate of systemic adverse events was mostly similar in the three treatment groups. The present rate of cardiovascular and cerebrovascular events was more evident in the ranibizumab group than the other two groups, with non-significant P value. The current study tried to detect the effect of intravitreal anti-VEGFs injection in DME on the renal functions, by measurement of estimated GFR before and after intravitreal injections. Overall, no significant changes in estimated GFR were observed after the three injections in three groups (86 ± 15, 83 ± 12, and 85 ± 17 respectively; ( P = .768), when compared with before the injections (91 ± 16, 88 ± 12, and 90 ± 16 respectively; ( P = .784). Systemic adverse events are detailed in Table 4 . Table 4 Systemic adverse effects during the follow-up period in the studied groups Bevacizumab Ranibizumab Aflibercept P cardio & cerebrovascular events 5% (1) 15% (3) 10% (2) .56 Estimated GFR Pre-injection 91.68 ± 16.48 88.40 ± 12.16 90.77 ± 16.88 .784 Post-injection 86.68 ± 15.99 83.07 ± 12.98 85.10 ± 17.89 .768 Data is expressed as percentage and frequency. P is significant when ˂ 0.05. GFR: glomerular filtration rate. Discussion Diabetic Macular Edema is a chronic disease with variable responses and clinical manifestations during the whole life of the affected patients. Therefore, a single treatment may not be enough for the entire course of the disease ( 12 ). A comprehensive approach should include the complex pathogenetic mechanism underlying DME and match with any specific manifestation. ( 13 ). Therefore, there is no a 100% successful treatment for DME, and recurrence is the rule in the majority of cases treated with one or more of the currently available treatment modalities ( 14 , 15 ). The commonest Anti VEGF agents used in DME are aflibercept, bevacizumab, or ranibizumab. The three agents differ in structure, growth factor specificity, and VEGF-binding affinity, but the ways in which these differences between them may relate to efficacy is not fully known ( 16 ). Bevacizumab is by far the most used anti VEGF agent globally, it is important to inform clinicians, patients, and funders that bevacizumab and ranibizumab are similar for treating DME based on published trials comparing the 2 drugs in age related macular degeneration ( 17 ) Recurrence of macular edema with bevacizumab injection was observed within a few weeks after the treatment, and so repetition of Bevacizumab was considered by many surgeons ( 18 , 19 ). Many studies evaluated the treatment response behaviour of aflibercept in DME like DA VINCI study, which differs in design from the more recent VIVID-DME and VISTA-DME studies in many aspects, including loading phase (DA VINCI included three initial loading doses in some arms compared with five in VIVID-DME and VISTA-DME). This current study tried to highlight safety of intravitreal bevacizumab, ranibizumab or aflibercept injection in treating central involved DME. To know the difference of study design, VISTA and VIVID trials demonstrated substantial improvements in BCVA and CST among eyes treated with aflibercept regardless of whether the eyes had previously been treated with anti-VEGF 3 or more months prior to study enrolment. In this current study we excluded cases of previous treatment. This current study evaluated ocular and systemic adverse event outcomes of intravitreal aflibercept, ranibizumab and bevacizumab in patients with DME. This study showed no significant differences between drugs in rates of ocular adverse events. As regard to endophthalmitis incidence, no significant difference was observed among the three groups in intraocular inflammation ( P = .322 between groups), suggesting that there was adequate adherence to the aseptic injection procedure. This agreed with DRCR.net Protocol T which reported that endophthalmitis only occurred in a single patient during the 24-month trial (0.5% of bevacizumab group; P = .66 between groups). Although preoperative prophylactic topical antibiotic eye drops were used to lower endophthalmitis rates after IVI procedures, two cases in bevacizumab group showed postoperative endophthalmitis. Torres-Costa S et al., 2020 reported no effect of antibiotic prophylaxis on the incidence of endophthalmitis ( 20 ). As regard to the results for bevacizumab group, we referred it to repackaging the agent into single-use vials that underwent independent testing for sterility, purity, and potency before use. This standard may not always be feasible in clinical practice. The present study removed all individuals previously diagnosed with glaucoma, glaucoma suspect, or ocular hypertension - as well as those who have taken glaucoma medication or underwent a glaucoma related procedure. Despite the removal of these high-risk patients, we still found an elevated risk of increased IOP in patients receiving anti- VEGF injections one hour after procedure. IOP values varied from 1 hour, 1 week, and 1 month after treatment. The type of injected drug (bevacizumab, ranibizumab or aflibercept) did not have a statistically remarkable influence on the difference in IOP, but a slightly higher IOP was found in eyes receiving bevacizumab. Mean IOP values reached 21,69 mm Hg 1 hour after injection in three groups, after one-week mean IOP decreased to 19.62 mm Hg, however only four cases showed maintenance of IOP at levels higher than 21 mm Hg and needed for topical medication to be controlled. Lemos V et al., 2015 reported that 89% of patients receiving intravitreal ranibizumab experienced an IOP rise of more than 30 mm Hg at 5 second after injection procedure and approximately one third after the first 5 min ( 21 ). The reason for the sustained increase in IOP is not completely understood and seems to be multifactorial. Yannuzzi NA et al., 2014 speculated that using higher injection volumes as well as a rapid injection technique may both lead to sustained IOP elevation ( 22 ). Kiddee W et al., 2015 suggested that Anti-VEGF agents may directly damage the trabecular meshwork ( 23 ). Reis GM et al., 2017 referred the cause of sustained elevation of IOP to the passage of high molecular weight molecules through the anterior hyaloid or zonule, and consequent obstruction or damage of the trabecular mesh with repeated applications ( 24 ). Meta-analyses of clinical trials involving ranibizumab for DME that focused mostly on safety issues, showed that ranibizumab use for the treatment of DME had minor risk for thromboembolic events compared with laser, triamcinolone acetate or sham injection ( 25 ). This current study showed that systemic cardiovascular and cerebrovascular accidents rates were slightly higher in the ranibizumab group than other two groups, but with insignificant P value. DRCR.net, 2015 reported that the arm treated with intravitreal ranibizumab had significantly higher rates of arterial thrombotic events (5.4% aflibercept vs 7.8% bevacizumab vs 11.9% ranibizumab); a post hoc analysis explained that the statistical relation between ranibizumab and cardiovascular events might be due to chance. This study show that the incidence of arterial thrombotic events was 10% aflibercept vs 5% bevacizumab vs 15% ranibizumab ( 26 ). Wells JA, 2016 demonstrated that the rate of arterial thromboembolic events (ATE) in aflibercept, bevacizumab, and ranibizumab groups was 3%, 4%, and 5% respectively, this present study showed that the rate of cardiovascular and cerebrovascular events was 10%, 5%, and 15% respectively ( 27 ). Analysis of previous studies involving persons with ARMD showed that aflibercept might be associated with a greater risk of stroke than ranibizumab among old persons (85 years or above). On the other hand, meta-analysis of the RISE, RIDE, VISTA, and VIVID trials reported an association between monthly ranibizumab and aflibercept over 2 years with an increased risk of cerebrovascular accidents, vascular deaths, but did not find a difference between ranibizumab and aflibercept ( 28 ). Zarbin MA et al., 2017 found no meaningful differences between patients treated with 0.3 mg or 0.5 mg intravitreal ranibizumab versus control regarding the risk of stroke or TIA ( 29 ). In this current study, it is suggested that no association between monthly ranibizumab and aflibercept or bevacizumab with a significant increased risk of cardiovascular and cerebrovascular events over 6 months. Several studies evaluating the safety and efficacy of anti-VEGF in diabetic patients had reported renal adverse effects, although the mechanisms are still debated ( 30 ). A study was conducted on 121 patients to measure the effect of intravitreal bevacizumab on DME; and noticed that only three cases had a worsened kidney function ( 31 ). Jamrozy-Witkowska A et al., 2011 reported 1 diabetic patient with renal insufficiency after intravitreal Anti-VEGF (Bevacizumab) administration ( 32 ). On the other side Kameda Y et al., 2018 evaluated renal safety following acute anti-VEGF exposure showing no significant change in mean estimated GFR and no episodes of acute kidney injury, following a single intravitreal anti-VEGF injection of ranibizumab, aflibercept or bevacizumab ( 33 ). After three intravitreal injections, there was no significant difference between the pre and post injection values of estimated GFR in the study groups (ranibizumab, aflibercept or bevacizumab). This suggests that intravitreal anti VEGF do not affect renal function, even in patients with diabetes and pre-existing reduced GFR - at least in short term follow up. The DRCR.net Protocol T trial reported that kidney dysfunction was high, but no differences were detected between groups after intravitreal injection of anti VEGF. limitations of this study 1- The moderate sample size of 60 eyes that limits the strength of the analysis. 2- Firm conclusion on the systemic safety of intravitreal anti-VEGF is limited as we measured GFR within just 30 days after administration. Therefore, we did not follow any longitudinal changes in renal dysfunction. 3- Patients with recent stroke or transient ischemic attack were excluded from this study. Thus, the safety results of this study should be interpreted relative to this exclusion. 4- The 6-month follow up is not enough to assess recurrence. Conclusion Intravitreal aflibercept, bevacizumab, and ranibizumab were relatively safe treatments for DME causing vision impairment. The safety profile of ranibizumab, aflibercept and bevacizumab observed in this study was consistent with the well-established safety profile. The results of the present study show that aflibercept has lower incidence of ocular adverse effects through 6-months follow-up period. Declarations Conflict of interest: None to declare. Funding disclosure: None to declare. References Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes care. 2012;35(3):556–64. Augustin AJ. Upcoming therapeutic advances in diabetic macular edema: an intravitreal dexamethasone drug delivery system. Expert opinion on drug delivery. 2011;8(2):271–9. Nguyen Q, Brown D, Marcus D, Boyer D, Patel S, Feiner L, et al. Other treatment & diagnosis. Arch Ophthalmol. 2012;130(2):190–4. 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Jamrozy-Witkowska A, Kowalska K, Jankowska-Lech I, Terelak-Borys B, Nowosielska A, Grabska-Liberek I. Complications of intravitreal injections–own experience. Klinika oczna. 2011;113(4–6):127–31. Kameda Y, Babazono T, Uchigata Y, Kitano S. Renal function after intravitreal administration of vascular endothelial growth factor inhibitors in patients with diabetes and chronic kidney disease. J Diabetes Investig. 2018;9(4):937–9. Cite Share Download PDF Status: Posted Version 1 posted 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-2172497","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":144629924,"identity":"904a09b7-6467-401c-b1fc-fa445f580dd2","order_by":0,"name":"Mohamed ELShafie","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-1527-2282","institution":"kafrelsheikh university","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Mohamed","middleName":"","lastName":"ELShafie","suffix":""}],"badges":[],"createdAt":"2022-10-16 20:36:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2172497/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2172497/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":27889188,"identity":"641bc280-dd63-42be-8694-5258248a9fab","added_by":"auto","created_at":"2022-10-17 19:54:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":213335,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2172497/v1/5511c9a4-ebc5-4b91-8459-8d46e16e052b.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003e\u003cstrong\u003eSafety of intravitreal anti VEGF injections in diabetic macular edema\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAbout a third of diabetic people have diabetic retinopathy (DR), and about tenth are affected by Diabetic Macular Edema (DME). The incidence of DME increases with diabetes duration, hemoglobin A1C, and blood pressure levels, it is higher in people with type 1 compared with type 2 diabetes (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMacular edema is defined as accumulation of excess fluid in the extracellular space of the neurosensory retina causing abnormal thickening of the macula. Intracellular fluid involving Muller cells can be observed in some histopathological cases (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDiabetic Macular Edema results from retinal microvascular changes. Thickening of the basement membrane and reduction in the number of pericytes are believed to increase permeability and incompetence of the retinal vasculature. Leakage of plasma constituents to the surrounding retina, with subsequent retinal edema due to compromised blood retinal barrier (BRB). Hypoxia produced by this mechanism can also stimulate the production of vascular endothelial growth factor (VEGF). There is evidence that VEGF is up regulated in DME and proliferative diabetic retinopathy (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA great variety of morphological patterns became apparent, even though all patients had the same underlying disease (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). So, a combination of Optical Coherence Tomography (OCT) with Fundus Fluorescein Angiography (FFA) is considered more advantageous for the classification of DR.\u003c/p\u003e \u003cp\u003eMorphological biomarkers - recognized on OCT or FFA - can define patients with recalcitrant disease; and thus, help to guide and predict the prognosis of individual treatment regiments (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough the standard treatment of DME is focal laser photocoagulation, it can only slow progression with low ability to reverse vision loss (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Antiangiogenic therapy has largely replaced laser photocoagulation as it was proven to be more effective (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAnti-VEGF agents, interrupting a critical stimulus for the development of BRB breakdown, have been studied in the treatment of DME, as Pegaptanib sodium (Macugen, Eyetech Pfizer), Ranibizumab (Lucentis, Genentech Inc., San Francisco, CA), Bevacizumab (Avastin, Genentech, and South San Francisco, CA) and aflibercept (Eylea, Regeneron, NY, USA).\u003c/p\u003e \u003cp\u003eAlthough bevacizumab is currently approved by FDA (Food and Drug Administration) for the treatment of metastatic colorectal cancer, it is widely off-label used in treatment for neovascular age-related macular degeneration (ARMD) and retinal vascular disorders including retinal vein occlusion and DME due to its low cost (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDiabetic retinopathy clinical research network trial (DRCR.net) evaluated the short-term value of intravitreal bevacizumab in diabetic patients demonstrating a beneficial effect in center involved DME (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTreatment effectiveness indicators include duration of diabetes, number of injections, and response to previous treatments in conjunction with visual acuity, central macular thickness (CMT) and residual macular edema presenting within or under the retina.\u003c/p\u003e \u003cp\u003eCompared to intravenous anti VEGFs, used for cancer treatment, the much lower dose of intravitreal anti VEGFs had less systemic adverse effects. These adverse effects, however, increase in high-risk patients with intense anti VEGF treatment for two years (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Although intravitreal route is associated with less systemic adverse effects, it is associated with ocular adverse effects: including infectious endophthalmitis, post-injection inflammation, and post- injection increase in intra ocular pressure (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study aims to evaluate systemic and ocular adverse effects of intravitreal anti VEGF during six-month follow up.\u003c/p\u003e"},{"header":"Patients And Methods","content":"\u003cp\u003eThis prospective interventional randomized study was held on 60 eyes of 60 patients at the Retina Clinic of Mansoura University ophthalmology center from October 2018 to October 2019.The study was pre-approved by the ethical committee at Mansoura University in 2017. Approval code: MD/17.01.41\u003c/p\u003e\n\u003cp\u003eThe study included patients above age of 18 diagnosed with type 1 or 2 DM who had center involved DME with the following criteria:1- Clear media enough to document macular edema by OCT. 2- Definite retinal thickening due to DME involving center of macula\u0026thinsp;\u0026gt;\u0026thinsp;300 \u0026micro;m by OCT, assessed to be the main cause of visual loss. 3- Best corrected visual acuity less than .2 log MAR.\u003c/p\u003e\n\u003cp\u003eExclusion Criteria: 1- Associated vitreoretinal changes: subretinal fibrosis, significant vitreoretinal traction on OCT indicating vitrectomy or poor prognostic factors for injection like distorted inner retinal layers, disrupted ellipsoid zone or macular ischemia. 2- Patients treated with laser or intravitreal injection in last six months. 3- Associated ocular diseases such as: glaucoma, glaucoma suspect, ocular hypertension, or significant cataract which affects vision. 4- Systemic diseases that interfere with Anti VEGF injections such as: Recent stroke or transient ischemic attack. 5- Ocular surgery: like glaucoma related procedure.\u003c/p\u003e\n\u003cp\u003eThe patients were classified randomly into three groups: Group A (20 patients): received Lucentis (Ranibizumab .5mg) 3 injections, a month apart. Group B (20 patients): received Avastin (Bevacizumab 1.25 mg) 3 injections, a month apart. Group C (20 patients): received Eylea (Aflibercept 2 mg) 3 injections, a month apart. A simple random sample was done using randomly picked, concealed numbers; each number corresponding to one treatment group. All patients provided an informed written consent before baseline assessment.\u003c/p\u003e\n\u003cp\u003eStatistical analysis was done using IBM\u0026rsquo;s SPSS statistics (Statistical Package for the Social Sciences) for windows (version 25, 2017). The normality of data distribution was checked using Shapiro-Wilk test. All tests were conducted with 95% confidence interval. Statistical significance was considered if (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.05).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eSixty eyes of sixty patients with type 1 or 2 diabetes were involved in this study. The mean age of the patients was 61.62 with SD 8.33 (range 18-75years), there were 37 male (61.7%) and 23 female (38.3%) subjects. Patients were randomized to three groups, 20 eyes (20 patients) were treated with intravitreal Bevacizumab 1.25 mg (IVB group), 20 eyes (20 patients) received intravitreal Ranibizumab .5mg (IVR group) and 20 eyes (20 patients) treated with intravitreal Aflibercept 2 mg (IVA group).\u003c/p\u003e\n\u003cp\u003eAmong the Bevacizumab group, 10 patients were males, 10 patients were females with mean age 59.05 years. The duration of diabetes was an average of 12.55 years. Among the Ranibizumab group, there were 12 male patients and 8 female patients, the mean age was 62 years. The duration of diabetes was an average of 11.90 years, while in the Aflibercept group there were 15 males and 5 females with average age of 63.8 years and disease duration of 12.10 years. HbA1c % (7.30, 7.70, 7.45), IOP mmHg (17.8, 17.55, 17.62), Phakic eyes % (80, 90, 70), Pseudophakic eyes % (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e) in three groups (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline demographic analysis between the treatment groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBevacizumab\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRanibizumab\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAflibercept\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59.05\u0026nbsp;\u0026plusmn;\u0026nbsp;10.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e62.00\u0026nbsp;\u0026plusmn;\u0026nbsp;6.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63.80\u0026nbsp;\u0026plusmn;\u0026nbsp;7.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.192\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50.0%\u0026nbsp;(10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60.0%\u0026nbsp;(12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75.0%\u0026nbsp;(15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e.262\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50.0%\u0026nbsp;(10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40.0%\u0026nbsp;(8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.0%\u0026nbsp;(5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDuration of DM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.55\u0026nbsp;\u0026plusmn;\u0026nbsp;3.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.90\u0026nbsp;\u0026plusmn;\u0026nbsp;3.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.10\u0026nbsp;\u0026plusmn;\u0026nbsp;4.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.842\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eHbA1c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.30\u0026nbsp;\u0026plusmn;\u0026nbsp;0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.70\u0026nbsp;\u0026plusmn;\u0026nbsp;1.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.45\u0026nbsp;\u0026plusmn;\u0026nbsp;1.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.515\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eIOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17.87\u0026nbsp;\u0026plusmn;\u0026nbsp;0.746\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17.55\u0026nbsp;\u0026plusmn;\u0026nbsp;0.726\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17.62\u0026nbsp;\u0026plusmn;\u0026nbsp;0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.307\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eLens state\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePhakic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e80.0%\u0026nbsp;(16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90.0%\u0026nbsp;(18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70.0%\u0026nbsp;(14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e.346\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePCIOL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.0%\u0026nbsp;(4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.0%\u0026nbsp;(2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.0%\u0026nbsp;(6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"6\"\u003e\n \u003cp\u003eData is expressed as mean and standard deviation or percentage and frequency. P is significant when (\u003cem\u003eP\u003c/em\u003e ˂ .05).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eIOP: Intraocular pressure, PCIOL: Posterior chamber intraocular lens.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eInjection-related infectious endophthalmitis occurred in two bevacizumab -treated eye and no ranibizumab -treated or aflibercept-treated eyes.\u003c/p\u003e\n\u003cp\u003eOcular inflammation other than endophthalmitis was reported in one ranibizumab-treated eye, three bevacizumab-treated eyes and two aflibercept-treated eyes. Ocular adverse events are detailed in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eOcular adverse effects during the follow up period in the studied groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBevacizumab\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRanibizumab\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAflibercept\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEndophthalmitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10%\u0026nbsp;(2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u0026nbsp;(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u0026nbsp;(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.322\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInflammation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15%\u0026nbsp;(3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5%\u0026nbsp;(1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10%\u0026nbsp;(2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.863\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRetinal detachment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u0026nbsp;(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u0026nbsp;(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u0026nbsp;(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVitreous hemorrhage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5%\u0026nbsp;(1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5%\u0026nbsp;(1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u0026nbsp;(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCataract\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5%\u0026nbsp;(1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u0026nbsp;(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u0026nbsp;(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003eData is expressed as percentage and frequency. P is significant when (\u003cem\u003eP\u003c/em\u003e ˂ .05).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eMean IOP values changed from 17.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.69 at baseline; to be 21.96\u0026thinsp;\u0026plusmn;\u0026thinsp;1.53 after one hour, 19.62\u0026thinsp;\u0026plusmn;\u0026thinsp;1.53 after one week, and 18.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.41 after one month.\u003c/p\u003e\n\u003cp\u003eNo significant differences were found in IOP elevations between the three groups depending on the anti VEGF agent used (bevacizumab, ranibizumab or aflibercept) as shown in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, although bevacizumab group seemed to induce a slightly higher IOP level than other two groups.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab3\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBasal and follow up mean IOP values in the studied groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIOP\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIVB\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIVR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIVA\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBasal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17.88\u0026nbsp;\u0026plusmn;\u0026nbsp;0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17.56\u0026nbsp;\u0026plusmn;\u0026nbsp;0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17.63\u0026nbsp;\u0026plusmn;\u0026nbsp;0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.307\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOne hour\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.91\u0026nbsp;\u0026plusmn;\u0026nbsp;1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.41\u0026nbsp;\u0026plusmn;\u0026nbsp;1.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.75\u0026nbsp;\u0026plusmn;\u0026nbsp;1.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.580\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOne week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19.83\u0026nbsp;\u0026plusmn;\u0026nbsp;1.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19.37\u0026nbsp;\u0026plusmn;\u0026nbsp;1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19.64\u0026nbsp;\u0026plusmn;\u0026nbsp;1.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.640\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOne month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.68\u0026nbsp;\u0026plusmn;\u0026nbsp;1.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.30\u0026nbsp;\u0026plusmn;\u0026nbsp;1.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.52\u0026nbsp;\u0026plusmn;\u0026nbsp;1.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.708\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003eData is expressed as mean and standard deviation. P is significant when (\u003cem\u003eP\u003c/em\u003e ˂ .05)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eIOP: intraocular pressure, IVB: Intravitreal bevacizumab. IVA: Intravitreal aflibercept. IVR: Intravitreal ranibizumab.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eThe rate of systemic adverse events was mostly similar in the three treatment groups. The present rate of cardiovascular and cerebrovascular events was more evident in the ranibizumab group than the other two groups, with non-significant P value. The current study tried to detect the effect of intravitreal anti-VEGFs injection in DME on the renal functions, by measurement of estimated GFR before and after intravitreal injections. Overall, no significant changes in estimated GFR were observed after the three injections in three groups (86\u0026thinsp;\u0026plusmn;\u0026thinsp;15, 83\u0026thinsp;\u0026plusmn;\u0026thinsp;12, and 85\u0026thinsp;\u0026plusmn;\u0026thinsp;17 respectively; (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.768), when compared with before the injections (91\u0026thinsp;\u0026plusmn;\u0026thinsp;16, 88\u0026thinsp;\u0026plusmn;\u0026thinsp;12, and 90\u0026thinsp;\u0026plusmn;\u0026thinsp;16 respectively; (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.784). Systemic adverse events are detailed in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab4\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSystemic adverse effects during the follow-up period in the studied groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003cth align=\"left\" colspan=\"2\" style=\"height: 35px;\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003eBevacizumab\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003eRanibizumab\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003eAflibercept\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd align=\"left\" colspan=\"2\" style=\"height: 35px;\"\u003e\n \u003cp\u003ecardio \u0026amp; cerebrovascular events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003e5% (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003e15% (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003e10% (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003e.56\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd align=\"left\" rowspan=\"2\" style=\"height: 70px;\"\u003e\n \u003cp\u003eEstimated GFR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003ePre-injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003e91.68\u0026nbsp;\u0026plusmn;\u0026nbsp;16.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003e88.40\u0026nbsp;\u0026plusmn;\u0026nbsp;12.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003e90.77\u0026nbsp;\u0026plusmn;\u0026nbsp;16.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003e.784\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003ePost-injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003e86.68\u0026nbsp;\u0026plusmn;\u0026nbsp;15.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003e83.07\u0026nbsp;\u0026plusmn;\u0026nbsp;12.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003e85.10\u0026nbsp;\u0026plusmn;\u0026nbsp;17.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"height: 35px;\"\u003e\n \u003cp\u003e.768\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd align=\"left\" colspan=\"6\" style=\"height: 35px;\"\u003e\n \u003cp\u003eData is expressed as percentage and frequency. P is significant when ˂ 0.05.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr style=\"height: 13px;\"\u003e\n \u003ctd colspan=\"6\" style=\"height: 13px;\"\u003eGFR: glomerular filtration rate.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eDiabetic Macular Edema is a chronic disease with variable responses and clinical manifestations during the whole life of the affected patients. Therefore, a single treatment may not be enough for the entire course of the disease (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA comprehensive approach should include the complex pathogenetic mechanism underlying DME and match with any specific manifestation. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTherefore, there is no a 100% successful treatment for DME, and recurrence is the rule in the majority of cases treated with one or more of the currently available treatment modalities (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe commonest Anti VEGF agents used in DME are aflibercept, bevacizumab, or ranibizumab. The three agents differ in structure, growth factor specificity, and VEGF-binding affinity, but the ways in which these differences between them may relate to efficacy is not fully known (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBevacizumab is by far the most used anti VEGF agent globally, it is important to inform clinicians, patients, and funders that bevacizumab and ranibizumab are similar for treating DME based on published trials comparing the 2 drugs in age related macular degeneration (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eRecurrence of macular edema with bevacizumab injection was observed within a few weeks after the treatment, and so repetition of Bevacizumab was considered by many surgeons (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMany studies evaluated the treatment response behaviour of aflibercept in DME like DA VINCI study, which differs in design from the more recent VIVID-DME and VISTA-DME studies in many aspects, including loading phase (DA VINCI included three initial loading doses in some arms compared with five in VIVID-DME and VISTA-DME).\u003c/p\u003e \u003cp\u003eThis current study tried to highlight safety of intravitreal bevacizumab, ranibizumab or aflibercept injection in treating central involved DME.\u003c/p\u003e \u003cp\u003eTo know the difference of study design, VISTA and VIVID trials demonstrated substantial improvements in BCVA and CST among eyes treated with aflibercept regardless of whether the eyes had previously been treated with anti-VEGF 3 or more months prior to study enrolment. In this current study we excluded cases of previous treatment.\u003c/p\u003e \u003cp\u003eThis current study evaluated ocular and systemic adverse event outcomes of intravitreal aflibercept, ranibizumab and bevacizumab in patients with DME. This study showed no significant differences between drugs in rates of ocular adverse events.\u003c/p\u003e \u003cp\u003eAs regard to endophthalmitis incidence, no significant difference was observed among the three groups in intraocular inflammation (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.322 between groups), suggesting that there was adequate adherence to the aseptic injection procedure.\u003c/p\u003e \u003cp\u003eThis agreed with DRCR.net Protocol T which reported that endophthalmitis only occurred in a single patient during the 24-month trial (0.5% of bevacizumab group; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.66 between groups).\u003c/p\u003e \u003cp\u003eAlthough preoperative prophylactic topical antibiotic eye drops were used to lower endophthalmitis rates after IVI procedures, two cases in bevacizumab group showed postoperative endophthalmitis. Torres-Costa S et al., 2020 reported no effect of antibiotic prophylaxis on the incidence of endophthalmitis (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAs regard to the results for bevacizumab group, we referred it to repackaging the agent into single-use vials that underwent independent testing for sterility, purity, and potency before use. This standard may not always be feasible in clinical practice.\u003c/p\u003e \u003cp\u003eThe present study removed all individuals previously diagnosed with glaucoma, glaucoma suspect, or ocular hypertension - as well as those who have taken glaucoma medication or underwent a glaucoma related procedure.\u003c/p\u003e \u003cp\u003eDespite the removal of these high-risk patients, we still found an elevated risk of increased IOP in patients receiving anti- VEGF injections one hour after procedure. IOP values varied from 1 hour, 1 week, and 1 month after treatment.\u003c/p\u003e \u003cp\u003eThe type of injected drug (bevacizumab, ranibizumab or aflibercept) did not have a statistically remarkable influence on the difference in IOP, but a slightly higher IOP was found in eyes receiving bevacizumab.\u003c/p\u003e \u003cp\u003eMean IOP values reached 21,69 mm Hg 1 hour after injection in three groups, after one-week mean IOP decreased to 19.62 mm Hg, however only four cases showed maintenance of IOP at levels higher than 21 mm Hg and needed for topical medication to be controlled.\u003c/p\u003e \u003cp\u003eLemos V et al., 2015 reported that 89% of patients receiving intravitreal ranibizumab experienced an IOP rise of more than 30 mm Hg at 5 second after injection procedure and approximately one third after the first 5 min (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe reason for the sustained increase in IOP is not completely understood and seems to be multifactorial. Yannuzzi NA et al., 2014 speculated that using higher injection volumes as well as a rapid injection technique may both lead to sustained IOP elevation (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Kiddee W et al., 2015 suggested that Anti-VEGF agents may directly damage the trabecular meshwork (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eReis GM et al., 2017 referred the cause of sustained elevation of IOP to the passage of high molecular weight molecules through the anterior hyaloid or zonule, and consequent obstruction or damage of the trabecular mesh with repeated applications (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMeta-analyses of clinical trials involving ranibizumab for DME that focused mostly on safety issues, showed that ranibizumab use for the treatment of DME had minor risk for thromboembolic events compared with laser, triamcinolone acetate or sham injection (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis current study showed that systemic cardiovascular and cerebrovascular accidents rates were slightly higher in the ranibizumab group than other two groups, but with insignificant P value.\u003c/p\u003e \u003cp\u003eDRCR.net, 2015 reported that the arm treated with intravitreal ranibizumab had significantly higher rates of arterial thrombotic events (5.4% aflibercept vs 7.8% bevacizumab vs 11.9% ranibizumab); a post hoc analysis explained that the statistical relation between ranibizumab and cardiovascular events might be due to chance. This study show that the incidence of arterial thrombotic events was 10% aflibercept vs 5% bevacizumab vs 15% ranibizumab (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWells JA, 2016 demonstrated that the rate of arterial thromboembolic events (ATE) in aflibercept, bevacizumab, and ranibizumab groups was 3%, 4%, and 5% respectively, this present study showed that the rate of cardiovascular and cerebrovascular events was 10%, 5%, and 15% respectively (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAnalysis of previous studies involving persons with ARMD showed that aflibercept might be associated with a greater risk of stroke than ranibizumab among old persons (85 years or above).\u003c/p\u003e \u003cp\u003eOn the other hand, meta-analysis of the RISE, RIDE, VISTA, and VIVID trials reported an association between monthly ranibizumab and aflibercept over 2 years with an increased risk of cerebrovascular accidents, vascular deaths, but did not find a difference between ranibizumab and aflibercept (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eZarbin MA et al., 2017 found no meaningful differences between patients treated with 0.3 mg or 0.5 mg intravitreal ranibizumab versus control regarding the risk of stroke or TIA (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this current study, it is suggested that no association between monthly ranibizumab and aflibercept or bevacizumab with a significant increased risk of cardiovascular and cerebrovascular events over 6 months.\u003c/p\u003e \u003cp\u003eSeveral studies evaluating the safety and efficacy of anti-VEGF in diabetic patients had reported renal adverse effects, although the mechanisms are still debated (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). A study was conducted on 121 patients to measure the effect of intravitreal bevacizumab on DME; and noticed that only three cases had a worsened kidney function (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eJamrozy-Witkowska A et al., 2011 reported 1 diabetic patient with renal insufficiency after intravitreal Anti-VEGF (Bevacizumab) administration (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOn the other side Kameda Y et al., 2018 evaluated renal safety following acute anti-VEGF exposure showing no significant change in mean estimated GFR and no episodes of acute kidney injury, following a single intravitreal anti-VEGF injection of ranibizumab, aflibercept or bevacizumab (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAfter three intravitreal injections, there was no significant difference between the pre and post injection values of estimated GFR in the study groups (ranibizumab, aflibercept or bevacizumab). This suggests that intravitreal anti VEGF do not affect renal function, even in patients with diabetes and pre-existing reduced GFR - at least in short term follow up. The DRCR.net Protocol T trial reported that kidney dysfunction was high, but no differences were detected between groups after intravitreal injection of anti VEGF.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003elimitations of this study\u003c/strong\u003e \u003cp\u003e1- The moderate sample size of 60 eyes that limits the strength of the analysis. 2- Firm conclusion on the systemic safety of intravitreal anti-VEGF is limited as we measured GFR within just 30 days after administration. Therefore, we did not follow any longitudinal changes in renal dysfunction. 3- Patients with recent stroke or transient ischemic attack were excluded from this study. Thus, the safety results of this study should be interpreted relative to this exclusion. 4- The 6-month follow up is not enough to assess recurrence.\u003c/p\u003e \u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIntravitreal aflibercept, bevacizumab, and ranibizumab were relatively safe treatments for DME causing vision impairment. The safety profile of ranibizumab, aflibercept and bevacizumab observed in this study was consistent with the well-established safety profile. The results of the present study show that aflibercept has lower incidence of ocular adverse effects through 6-months follow-up period.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest:\u003c/strong\u003e None to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding disclosure:\u003c/strong\u003e None to declare.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes care. 2012;35(3):556\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAugustin AJ. Upcoming therapeutic advances in diabetic macular edema: an intravitreal dexamethasone drug delivery system. Expert opinion on drug delivery. 2011;8(2):271\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNguyen Q, Brown D, Marcus D, Boyer D, Patel S, Feiner L, et al. Other treatment \u0026amp; diagnosis. Arch Ophthalmol. 2012;130(2):190\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBolz M, Lammer J, Deak G, Pollreisz A, Mitsch C, Scholda C, et al. SAVE: a grading protocol for clinically significant diabetic macular oedema based on optical coherence tomography and fluorescein angiography. British Journal of Ophthalmology. 2014;98(12):1612\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChung EJ, Roh MI, Kwon OW, Koh HJ. Effects of macular ischemia on the outcome of intravitreal bevacizumab therapy for diabetic macular edema. Retina. 2008;28(7):957\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheung N, Mitchell P, Wong T. Diabetic retinopathy. Lancet [Internet]. Elsevier Ltd; 2010.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVirgili G, Parravano M, Menchini F, Evans JR. Anti-vascular endothelial growth factor for diabetic macular oedema. Cochrane Database of Systematic Reviews. 2014(10).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStewart MW, Narayanan R, Gupta V, Rosenfeld PJ, Martin DF, Chakravarthy U. Counterfeit Avastin in India: punish the criminals, not the patients. American Journal of Ophthalmology. 2016;170:228\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurakami T, Yoshimura N. Structural changes in individual retinal layers in diabetic macular edema. Journal of diabetes research. 2013;2013.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAvery RL, Gordon GM. Systemic Safety of Prolonged Monthly Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema: A Systematic Review and Meta-analysis. JAMA Ophthalmol. 2016 Jan;134(1):21 \u0026ndash; 9. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamaophthalmol.2015.4070\u003c/span\u003e\u003cspan address=\"10.1001/jamaophthalmol.2015.4070\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 26513684.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCai S, Bressler NM. Aflibercept, bevacizumab or ranibizumab for diabetic macular oedema: recent clinically relevant findings from DRCR.net Protocol T. Curr Opin Ophthalmol. 2017 Nov;28(6):636\u0026ndash;643. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/ICU.0000000000000424\u003c/span\u003e\u003cspan address=\"10.1097/ICU.0000000000000424\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 28837425.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStef\u0026aacute;nsson E. The therapeutic effects of retinal laser treatment and vitrectomy. A theory based on oxygen and vascular physiology. Acta Ophthalmologica Scandinavica. 2001;79(5):435\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaba Al Rashaed J. Combined therapy for diabetic macular edema. Middle East African journal of ophthalmology. 2013;20(4):315.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoheilian M, Ramezani A, Bijanzadeh B, Yaseri M, Ahmadieh H, Dehghan MH, et al. Intravitreal bevacizumab (avastin) injection alone or combined with triamcinolone versus macular photocoagulation as primary treatment of diabetic macular edema. Retina. 2007;27(9):1187\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSolaiman KA, Diab MM, Abo-Elenin M. Intravitreal bevacizumab and/or macular photocoagulation as a primary treatment for diffuse diabetic macular edema. Retina. 2010;30(10):1638\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZou L, Lai H, Zhou Q, Xiao F. Lasting controversy on ranibizumab and bevacizumab. Theranostics. 2011;1:395.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBressler SB, Qin H, Beck RW, Chalam KV, Kim JE, Melia M, et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Archives of Ophthalmology. 2012;130(9):1153\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSolaiman KA, Diab MM, Dabour SA. Repeated intravitreal bevacizumab injection with and without macular grid photocoagulation for treatment of diffuse diabetic macular edema. Retina. 2013;33(8):1623\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064\u0026ndash;77. e35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTorres-Costa S, Ramos D, Brand\u0026atilde;o E, Carneiro \u0026Acirc;, Rosas V, Rocha-Sousa A, et al. Incidence of endophthalmitis after intravitreal injection with and without topical antibiotic prophylaxis. European Journal of Ophthalmology. 2020:1120672120902028.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLemos V, Cabugueira A, Noronha M, Pinto LA, Reina M, Branco J, et al. Intraocular pressure in eyes receiving intravitreal antivascular endothelial growth factor injections. Ophthalmologica. 2015;233(3\u0026ndash;4):162\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYannuzzi NA, Patel SN, Bhavsar KV, Sugiguchi F, Freund KB. Predictors of Sustained Intraocular Pressure Elevation in Eyes Receiving Intravitreal Anti\u0026ndash;Vascular Endothelial Growth Factor Therapy. American journal of ophthalmology. 2014;158(2):319\u0026ndash;27. e2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKiddee W, Montriwet M. Intraocular pressure changes in non-glaucomatous patients receiving intravitreal anti-vascular endothelial growth factor agents. PloS one. 2015;10(9):e0137833.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReis GM, Grigg J, Chua B, Lee A, Lim R, Higgins R, et al. Incidence of Intraocular Pressure Elevation following Intravitreal Ranibizumab (Lucentis) for Age-related Macular Degeneration. Journal of current glaucoma practice. 2017;11(1):3\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYanagida Y, Ueta T. Systemic safety of ranibizumab for diabetic macular edema: meta-analysis of randomized trials. Retina. 2014;34(4):629\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, Antoszyk AN, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. The New England journal of medicine. 2015;372(13):1193\u0026ndash;203.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, et al. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial. Ophthalmology. 2016;123(6):1351\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAvery RL, Castellarin AA, Steinle NC, Dhoot DS, Pieramici DJ, See R, et al. Systemic pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and ranibizumab. Retina (Philadelphia, Pa). 2017;37(10):1847.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZarbin MA, Dunger-Baldauf C, Haskova Z, Koovejee P, Mousseau MC, Margaron P, et al. Vascular Safety of Ranibizumab in Patients With Diabetic Macular Edema: A Pooled Analysis of Patient-Level Data From Randomized Clinical Trials. JAMA Ophthalmol. 2017;135(5):424\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNetwork DRCR. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology. 2007;114(10):1860\u0026ndash;7. e7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePell\u0026eacute; G, Shweke N, Van Huyen J-PD, Tricot L, Hessa\u0026iuml;ne S, Fr\u0026eacute;meaux-Bacchi V, et al. Systemic and kidney toxicity of intraocular administration of vascular endothelial growth factor inhibitors. American journal of kidney diseases. 2011;57(5):756\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJamrozy-Witkowska A, Kowalska K, Jankowska-Lech I, Terelak-Borys B, Nowosielska A, Grabska-Liberek I. Complications of intravitreal injections\u0026ndash;own experience. Klinika oczna. 2011;113(4\u0026ndash;6):127\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKameda Y, Babazono T, Uchigata Y, Kitano S. Renal function after intravitreal administration of vascular endothelial growth factor inhibitors in patients with diabetes and chronic kidney disease. J Diabetes Investig. 2018;9(4):937\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Kafrelsheikh University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"aflibercept, ranibizumab, bevacizumab, Diabetic Macular Edema, Muller cells, vascular endothelial growth factor (VEGF)","lastPublishedDoi":"10.21203/rs.3.rs-2172497/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2172497/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eDiabetic macular edema (DME) is the most common cause of visual impairment in patients with diabetes mellitus. The pathogenesis of DME is complex and multifactorial. DME can be diagnosed using noncontact stereoscopic biomicroscopy, contact lens biomicroscopy, Fundus fluorescein angiography (FFA), and Optical Coherence Tomography (OCT). Intravitreal anti-vascular endothelial growth factor (VEGF) agents have been investigated in the treatment of DME. This study aims to investigate safety of intravitreal anti VEGF during six-month follow up.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eSixty patients with type I or II diabetes mellitus complaining from central involved DME were recruited for this longitudinal study. All patients were subjected to full history taking, complete ophthalmological examination, systemic evaluation, FFA and OCT imaging. Patients were subdivided into three groups, 20 patients each: Ranibizumab group, Bevacizumab group and Aflibercept group.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAfter 6-month follow-up, the ranibizumab group showed slightly higher systemic cardiovascular and cerebrovascular accidents rates, while the Bevacizumab group showed insignificant higher risk of ocular inflammation and endophthalmitis, aflibercept has the least incidence of ocular adverse effects.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eAnti VEGF intravitreal injections are relatively safe for treatment of DME. Aflibercept showed the least incidence of ocular side effects. The current study suggested that intravitreal anti-VEGF could be administered safely to diabetic patients with decreased glomerular filtration rate (GFR).\u003c/p\u003e","manuscriptTitle":"Safety of intravitreal anti VEGF injections in diabetic macular edema","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-10-17 19:54:54","doi":"10.21203/rs.3.rs-2172497/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d1bebba8-d5fd-48b7-87f5-c454e9e01fa3","owner":[],"postedDate":"October 17th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":16278868,"name":"Ophthalmology"}],"tags":[],"updatedAt":"2022-10-17T19:54:54+00:00","versionOfRecord":[],"versionCreatedAt":"2022-10-17 19:54:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2172497","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2172497","identity":"rs-2172497","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}