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Leung KCP, Au SCL. Dosing intervals in Comparison of one-year real-world outcomes between red (670 nm) subthreshold micropulse laser treatment and intravitreal aflibercept injection for treatment-naïve diabetic macular edema. Photodiagnosis Photodyn Ther 2025; 51:104484. [PMID: 39818405 DOI: 10.1016/j.pdpdt.2025.104484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/01/2025] [Accepted: 01/13/2025] [Indexed: 01/18/2025]
Affiliation(s)
| | - Sunny Chi Lik Au
- Department of Ophthalmology, Tung Wah Eastern Hospital, Hong Kong.
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Erdal E. Injectable nanogels to improve triamcinolone acetonide delivery and toxicity on the treatment of eye diseases. J Biomater Appl 2025; 39:498-509. [PMID: 39208349 DOI: 10.1177/08853282241277345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Triamcinolone acetonide (TA) is a corticosteroid, and widely used in the treatment of eye diseases such as macular edema, proliferative vitreoretinopathy, and chronic uveitis. It's also used in diseases such as osteoarthritis and rheumatoid arthritis. Despite the width of its usage, it has toxicity in the eye. Nanogels are advantageous in applying toxic and low bioavailability drugs thanks to their swelling ability and stability. In the presented study, to minimize the disadvantages of TA, and to reach the drug into the back segment of the eye, TA-loaded chitosan (CS) nanogel (CS-TA Nanogel) has been prepared, and in vitro characterized. CS-TA nanogels were prepared by ionic gelation and characterized by SEM, FTIR, and TGA. Drug release profile, and in vitro cytotoxicity was determined to evaluate the efficacy of nanogels for intravitreal eye applications. DNA damage, and oxidative stress caused by nanogels in eye endothelial cells were investigated. CS and CS-TA nanogels were synthesized in the sizes range 200-300 nm with an overall positive charge surface. The loading efficiency of TA on nanogels was determined as 50%. Cells exposed to 250 µg/ml free TA showed 74% viability, while this rate was 90% in cells exposed to CS-TA nanogels. 8-OHdG levels were determined as 54.93 ± 1.118 ng/mL in control cells and 92.47 ± 0.852 ng/mL in cells exposed to 250 µg/ml TA. TA both induces oxidative stress and causes DNA damage in HRMEC cells. However, administration of TA with carrier increased cell viability, total antioxidant capacity, and reduced oxidative DNA damage.
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Affiliation(s)
- Ebru Erdal
- Faculty of Medicine, Advanced Technologies Application and Research Center, Ankara Yıldırım Beyazıt University, Ankara, Turkey
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3
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Abbas MA, Al-Wassit AS, Ismail M. The Effect of Pan-Retinal Photocoagulation on Central Macular Thickness in a Sample of Iraqi Patients With Proliferative Diabetic Retinopathy. Cureus 2024; 16:e67616. [PMID: 39310639 PMCID: PMC11416820 DOI: 10.7759/cureus.67616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2024] [Indexed: 09/25/2024] Open
Abstract
OBJECTIVE To evaluate the effect of pan-retinal photocoagulation (PRP) on central macular thickness (CMT) in a sample of Iraqi patients with proliferative diabetic retinopathy (PDR). METHODS This prospective study was conducted at Ghazi Al-Hariri for Surgical Specialties Hospital, Baghdad, from March 2024 to May 2024. A total of 24 eyes from 18 treatment-naive PDR patients with no previous diabetic macular edema (DME) were enrolled. Each eye received PRP in two sessions, one week apart, using the Nidek GYC 500 laser system. CMT was measured at baseline and four weeks after the second PRP session using the Topcon DRI Triton Plus optical coherence tomography (OCT). Statistical analyses, including paired t-tests and Shapiro-Wilk tests for normality, were performed to evaluate changes in CMT. RESULTS The mean CMT increased from 258.4 ± 30.7 microns at baseline to 269.9 ± 36.8 microns post PRP, with a mean increase of 11.5 ± 26.3 microns. This increase was statistically significant (p = 0.042). The Shapiro-Wilk test confirmed that the data were approximately normally distributed both before (W = 0.960, p = 0.445) and after (W = 0.931, p = 0.103) PRP treatment. CONCLUSION PRP significantly increases CMT in PDR patients, although no additional treatment for macular edema was necessary. These findings align with previous studies, suggesting that PRP-induced macular thickening is a common outcome. Further research is recommended to explore long-term effects and potential mitigation strategies.
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Affiliation(s)
- Mohammad A Abbas
- Surgery, Ophthalmology Unit, Ghazi Al-Hariri for Surgical Specialties Hospital, Medical City Complex, Baghdad, IRQ
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Blanot M, Casaroli-Marano RP, Mondéjar-Medrano J, Sallén T, Ramírez E, Segú-Vergés C, Artigas L. Aflibercept Off-Target Effects in Diabetic Macular Edema: An In Silico Modeling Approach. Int J Mol Sci 2024; 25:3621. [PMID: 38612432 PMCID: PMC11011561 DOI: 10.3390/ijms25073621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 03/08/2024] [Accepted: 03/13/2024] [Indexed: 04/14/2024] Open
Abstract
Intravitreal aflibercept injection (IAI) is a treatment for diabetic macular edema (DME), but its mechanism of action (MoA) has not been completely elucidated. Here, we aimed to explore IAI's MoA and its multi-target nature in DME pathophysiology with an in silico (computer simulation) disease model. We used the Therapeutic Performance Mapping System (Anaxomics Biotech property) to generate mathematical models based on the available scientific knowledge at the time of the study, describing the relationship between the modulation of vascular endothelial growth factor receptors (VEGFRs) by IAI and DME pathophysiological processes. We also undertook an enrichment analysis to explore the processes modulated by IAI, visualized the effectors' predicted protein activity, and specifically evaluated the role of VEGFR1 pathway inhibition on DME treatment. The models simulated the potential pathophysiology of DME and the likely IAI's MoA by inhibiting VEGFR1 and VEGFR2 signaling. The action of IAI through both signaling pathways modulated the identified pathophysiological processes associated with DME, with the strongest effects in angiogenesis, blood-retinal barrier alteration and permeability, and inflammation. VEGFR1 inhibition was essential to modulate inflammatory protein effectors. Given the role of VEGFR1 signaling on the modulation of inflammatory-related pathways, IAI may offer therapeutic advantages for DME through sustained VEGFR1 pathway inhibition.
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Affiliation(s)
- Morgane Blanot
- Anaxomics Biotech S.L., 08007 Barcelona, Spain; (M.B.); (E.R.); (C.S.-V.); (L.A.)
| | - Ricardo Pedro Casaroli-Marano
- Department of Surgery (FMCS), Universitat de Barcelona, 08007 Barcelona, Spain
- Hospital Clínic de Barcelona (IDIBAPS), Universitat de Barcelona, 08007 Barcelona, Spain
| | | | - Thaïs Sallén
- Bayer Hispania S.L., 08970 Sant Joan Despí, Spain; (J.M.-M.); (T.S.)
| | - Esther Ramírez
- Anaxomics Biotech S.L., 08007 Barcelona, Spain; (M.B.); (E.R.); (C.S.-V.); (L.A.)
| | - Cristina Segú-Vergés
- Anaxomics Biotech S.L., 08007 Barcelona, Spain; (M.B.); (E.R.); (C.S.-V.); (L.A.)
- Research Programme on Biomedical Informatics (GRIB), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08002 Barcelona, Spain
| | - Laura Artigas
- Anaxomics Biotech S.L., 08007 Barcelona, Spain; (M.B.); (E.R.); (C.S.-V.); (L.A.)
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Gabriel S, Aljundi W, Munteanu C, Weinstein I, Seitz B, Abdin AD. Impact of Pachychoroid and DRIL on the Treatment of Diabetic Macular Oedema with Intravitreal Bevacizumab. Klin Monbl Augenheilkd 2024. [PMID: 38354750 DOI: 10.1055/a-2231-6479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024]
Abstract
PURPOSE To evaluate the long-term outcome of intravitreal bevacizumab in eyes with diabetic macular oedema (DME) following a PRN (pro re nata) regimen. Additionally, we investigated the effect of the presence of disorganisation of the retinal inner layers (DRILs) and pachychoroid (PC) at baseline on clinical outcome. METHODS This retrospective study included 112 naïve eyes with DME that were followed up for 2 years. All eyes were treated with six initial bevacizumab injections at monthly intervals and then received treatment according to a PRN regimen. In case of poor response to bevacizumab, therapy was switched to other agents. Main outcome measures included: best-corrected visual acuity (BCVA), central macular thickness (CMT), and number of intravitreal injections (IVI s). In addition, we examined the effect of the presence of DRILs and PC at baseline on clinical outcome. RESULTS BVCA improved significantly and CMT decreased significantly during the first 2 years of treatment. The number of IVI s per eye was 11.1 ± 4.8 at the end of the second year. Treatment had to be switched to other agents in 47 eyes (42%). The timing of switching was 12.4 ± 6.1 months after a mean of 9.2 ± 3.3 IVI s. Patients with DRILs at baseline (29.5%) had significantly worse BCVA at all time points before and after treatment, although CMT was significantly lower before treatment and comparable to patients without DRILs during treatment. Patients with PC at baseline (35.7%) had no significant differences in BVCA and CMT at all time points compared with patients without PC. CONCLUSIONS This study demonstrates statistically significant functional and anatomical improvement in patients with DME treated with intravitreal bevacizumab after 2 years. However, more than 40% of eyes required a switch in therapy. The presence of DRILs at baseline had a negative effect whereas the presence of PC at baseline had no effect on clinical outcome.
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Affiliation(s)
- Sara Gabriel
- Ophthalmology, Saarland University Hospital and Saarland University Faculty of Medicine, Homburg/Saar, Germany
| | - Wissam Aljundi
- Ophthalmology, Saarland University Hospital and Saarland University Faculty of Medicine, Homburg/Saar, Germany
| | - Cristian Munteanu
- Ophthalmology, Saarland University Hospital and Saarland University Faculty of Medicine, Homburg/Saar, Germany
| | - Isabel Weinstein
- Ophthalmology, Saarland University Hospital and Saarland University Faculty of Medicine, Homburg/Saar, Germany
| | - Berthold Seitz
- Ophthalmology, Saarland University Hospital and Saarland University Faculty of Medicine, Homburg/Saar, Germany
| | - Alaa Din Abdin
- Ophthalmology, Saarland University Hospital and Saarland University Faculty of Medicine, Homburg/Saar, Germany
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Nozaki M, Ando R, Kimura T, Kato F, Yasukawa T. The Role of Laser Photocoagulation in Treating Diabetic Macular Edema in the Era of Intravitreal Drug Administration: A Descriptive Review. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1319. [PMID: 37512130 PMCID: PMC10385537 DOI: 10.3390/medicina59071319] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 07/11/2023] [Accepted: 07/15/2023] [Indexed: 07/30/2023]
Abstract
Background and Objectives: This study aimed to elucidate the role of laser photocoagulation therapy in the treatment of diabetic macular edema (DME) as an alternative to, or in conjunction with, the first-line treatment, anti-vascular endothelial growth factor (VEGF). Materials and Methods: A comprehensive literature search to identify studies that evaluated the efficacy of laser photocoagulation therapy in the management of DME was performed. The relevant findings of the efficacy of focal/grid laser therapy from data in randomized, controlled trials were synthesized, and the potential of new laser technologies, such as navigated laser systems, pattern scan lasers, and subthreshold lasers, was explored. The usefulness of multimodal imaging-guided laser therapy was also evaluated, with a focus on the potential contribution to anti-VEGF therapy. Results: Focal laser photocoagulation targeting microaneurysms remains an effective therapeutic approach to chronic refractory edema, despite the widespread use of anti-VEGF therapy. To achieve the best possible treatment outcomes, precise identification of microaneurysms is essential. This requires the use of multimodal imaging-guided, highly accurate, minimally invasive coagulation techniques. Subthreshold laser therapy can also reduce the frequency of anti-VEGF injections and minimize treatment burden. Conclusions: Further studies are needed to determine the optimal timing and settings for laser photocoagulation therapy and the potential of new laser technologies in the management of DME. Nevertheless, laser photocoagulation therapy plays an important role in the management of DME, in conjunction with anti-VEGF therapy.
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Affiliation(s)
- Miho Nozaki
- Department of Ophthalmology, Laser Eye Center, Nagoya City University East Medical Center, Nagoya 464-8547, Japan
- Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Ryota Ando
- Department of Ophthalmology, Laser Eye Center, Nagoya City University East Medical Center, Nagoya 464-8547, Japan
| | - Toshiya Kimura
- Department of Ophthalmology, Laser Eye Center, Nagoya City University East Medical Center, Nagoya 464-8547, Japan
| | - Fusae Kato
- Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
- Department of Ophthalmology, Toyota Kosei Hospital, Toyota 470-0396, Japan
| | - Tsutomu Yasukawa
- Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
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Muniyandi A, Hartman GD, Song Y, Mijit M, Kelley MR, Corson TW. Beyond VEGF: Targeting Inflammation and Other Pathways for Treatment of Retinal Disease. J Pharmacol Exp Ther 2023; 386:15-25. [PMID: 37142441 PMCID: PMC10289243 DOI: 10.1124/jpet.122.001563] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 03/17/2023] [Accepted: 04/03/2023] [Indexed: 05/06/2023] Open
Abstract
Neovascular eye diseases include conditions such as retinopathy of prematurity, proliferative diabetic retinopathy, and neovascular age-related macular degeneration. Together, they are a major cause of vision loss and blindness worldwide. The current therapeutic mainstay for these diseases is intravitreal injections of biologics targeting vascular endothelial growth factor (VEGF) signaling. Lack of universal response to these anti-VEGF agents coupled with the challenging delivery method underscore a need for new therapeutic targets and agents. In particular, proteins that mediate both inflammatory and proangiogenic signaling are appealing targets for new therapeutic development. Here, we review agents currently in clinical trials and highlight some promising targets in preclinical and early clinical development, focusing on the redox-regulatory transcriptional activator APE1/Ref-1, the bioactive lipid modulator soluble epoxide hydrolase, the transcription factor RUNX1, and others. Small molecules targeting each of these proteins show promise for blocking neovascularization and inflammation. The affected signaling pathways illustrate the potential of new antiangiogenic strategies for posterior ocular disease. SIGNIFICANCE STATEMENT: Discovery and therapeutic targeting of new angiogenesis mediators is necessary to improve treatment of blinding eye diseases like retinopathy of prematurity, diabetic retinopathy, and neovascular age-related macular degeneration. Novel targets undergoing evaluation and drug discovery work include proteins important for both angiogenesis and inflammation signaling, including APE1/Ref-1, soluble epoxide hydrolase, RUNX1, and others.
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Affiliation(s)
- Anbukkarasi Muniyandi
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute (A.M., G.D.H., Y.S., M.R.K., T.W.C.), Department of Pediatrics, Herman B Wells Center for Pediatric Research (M.M., M.R.K.), Stark Neurosciences Research Institute (G.D.H., T.W.C.), Departments of Pharmacology and Toxicology (M.R.K., T.W.C.) and Biochemistry and Molecular Biology (M.R.K., T.W.C.), and Melvin and Bren Simon Comprehensive Cancer Center (M.R.K., T.W.C.), Indiana University School of Medicine, Indianapolis, Indiana
| | - Gabriella D Hartman
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute (A.M., G.D.H., Y.S., M.R.K., T.W.C.), Department of Pediatrics, Herman B Wells Center for Pediatric Research (M.M., M.R.K.), Stark Neurosciences Research Institute (G.D.H., T.W.C.), Departments of Pharmacology and Toxicology (M.R.K., T.W.C.) and Biochemistry and Molecular Biology (M.R.K., T.W.C.), and Melvin and Bren Simon Comprehensive Cancer Center (M.R.K., T.W.C.), Indiana University School of Medicine, Indianapolis, Indiana
| | - Yang Song
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute (A.M., G.D.H., Y.S., M.R.K., T.W.C.), Department of Pediatrics, Herman B Wells Center for Pediatric Research (M.M., M.R.K.), Stark Neurosciences Research Institute (G.D.H., T.W.C.), Departments of Pharmacology and Toxicology (M.R.K., T.W.C.) and Biochemistry and Molecular Biology (M.R.K., T.W.C.), and Melvin and Bren Simon Comprehensive Cancer Center (M.R.K., T.W.C.), Indiana University School of Medicine, Indianapolis, Indiana
| | - Mahmut Mijit
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute (A.M., G.D.H., Y.S., M.R.K., T.W.C.), Department of Pediatrics, Herman B Wells Center for Pediatric Research (M.M., M.R.K.), Stark Neurosciences Research Institute (G.D.H., T.W.C.), Departments of Pharmacology and Toxicology (M.R.K., T.W.C.) and Biochemistry and Molecular Biology (M.R.K., T.W.C.), and Melvin and Bren Simon Comprehensive Cancer Center (M.R.K., T.W.C.), Indiana University School of Medicine, Indianapolis, Indiana
| | - Mark R Kelley
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute (A.M., G.D.H., Y.S., M.R.K., T.W.C.), Department of Pediatrics, Herman B Wells Center for Pediatric Research (M.M., M.R.K.), Stark Neurosciences Research Institute (G.D.H., T.W.C.), Departments of Pharmacology and Toxicology (M.R.K., T.W.C.) and Biochemistry and Molecular Biology (M.R.K., T.W.C.), and Melvin and Bren Simon Comprehensive Cancer Center (M.R.K., T.W.C.), Indiana University School of Medicine, Indianapolis, Indiana
| | - Timothy W Corson
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute (A.M., G.D.H., Y.S., M.R.K., T.W.C.), Department of Pediatrics, Herman B Wells Center for Pediatric Research (M.M., M.R.K.), Stark Neurosciences Research Institute (G.D.H., T.W.C.), Departments of Pharmacology and Toxicology (M.R.K., T.W.C.) and Biochemistry and Molecular Biology (M.R.K., T.W.C.), and Melvin and Bren Simon Comprehensive Cancer Center (M.R.K., T.W.C.), Indiana University School of Medicine, Indianapolis, Indiana
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Virgili G, Curran K, Lucenteforte E, Peto T, Parravano M. Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis. Cochrane Database Syst Rev 2023; 2023:CD007419. [PMID: 38275741 PMCID: PMC10294542 DOI: 10.1002/14651858.cd007419.pub7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2024]
Abstract
Background Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) can reduce oedema, improve vision, and prevent further visual loss. These drugs have replaced laser photocoagulation as the standard of care for people with DMO. In the previous update of this review, we found moderate-quality evidence that, at 12 months, aflibercept was slightly more effective than ranibizumab and bevacizumab for improving vision in people with DMO, although the difference may have been clinically insignificant (less than 0.1 logarithm of the minimum angle of resolution (logMAR), or five Early Treatment Diabetic Retinopathy Study (ETDRS) letters, or one ETDRS line). Objectives The objective of this updated review was to compare the effectiveness and safety of the different anti-VEGF drugs in RCTs at longer followup (24 months). Search methods We searched various electronic databases on 8 July 2022. Selection criteria We included randomised controlled trials (RCTs) that compared any anti-angiogenic drug with an anti-VEGF mechanism of action versus another anti-VEGF drug, another treatment, sham, or no treatment in people with DMO. Data collection and analysis We used standard Cochrane methods for pairwise meta-analysis and we augmented this evidence using network meta-analysis (NMA) methods. We used the Stata 'network' meta-analysis package for all analyses. We used the CINeMA (Confidence in Network Meta-Analysis) web application to grade the certainty of the evidence. Main results We included 23 studies (13 with industry funding) that enrolled 3513 people with DMO (median central retinal thickness (CRT) 460 microns, interquartile range (IQR) 424 to 482) and moderate vision loss (median best-corrected visual acuity (BCVA) 0.48 logMAR, IQR 0.42 to 0.55. One study that investigated ranibizumab versus sham and one study that mainly enrolled people with subclinical DMO and normal BCVA were not suitable for inclusion in the efficacy NMA. Consistent with the previous update of this review, we used ranibizumab as the reference drug for efficacy, and control (including laser, observation, and sham) as the reference for systemic safety. Eight trials provided data on the primary outcome (change in BCVA at 24 months, in logMAR: lower is better). We found no evidence of a difference between the following interventions and ranibizumab alone: aflibercept (mean difference (MD) -0.05 logMAR, 95% confidence interval (CI) -0.12 to 0.02; moderate certainty); bevacizumab (MD -0.01 logMAR, 95% CI -0.13 to 0.10; low certainty), brolucizumab (MD 0.00 logMAR, 95% CI -0.08 to 0.07; low certainty), ranibizumab plus deferred laser (MD 0.00 logMAR, 95% CI -0.11 to 0.10; low certainty), and ranibizumab plus prompt laser (MD 0.03 logMAR, 95% CI -0.04 to 0.09; very low certainty). We also analysed BCVA change at 12 months, finding moderate-certainty evidence of increased efficacy with brolucizumab (MD -0.07 logMAR, 95%CI -0.10 to -0.03 logMAR), faricimab (MD -0.08 logMAR, 95% CI -0.12 to -0.05), and aflibercept (MD -0.07 logMAR, 95 % CI -0.10 to -0.04) compared to ranibizumab alone, but the difference could be clinically insignificant. Compared to ranibizumab alone, NMA of six trials showed no evidence of a difference with aflibercept (moderate certainty), bevacizumab (low certainty), or ranibizumab with prompt (very low certainty) or deferred laser (low certainty) regarding improvement by three or more ETDRS lines at 24 months. There was moderate-certainty evidence of greater CRT reduction at 24 months with brolucizumab (MD -23 microns, 95% CI -65 to -1 9) and aflibercept (MD -26 microns, 95% CI -53 to 0.9) compared to ranibizumab. There was moderate-certainty evidence of lesser CRT reduction with bevacizumab (MD 28 microns, 95% CI 0 to 56), ranibizumab plus deferred laser (MD 63 microns, 95% CI 18 to 109), and ranibizumab plus prompt laser (MD 72 microns, 95% CI 25 to 119) compared with ranibizumab alone. Regarding all-cause mortality at the longest available follow-up (20 trials), we found no evidence of increased risk of death for any drug compared to control, although effects were in the direction of an increase, and clinically relevant increases could not be ruled out. The certainty of this evidence was low for bevacizumab (risk ratio (RR) 2.10, 95% CI 0.75 to 5.88), brolucizumab (RR 2.92, 95% CI 0.68 to 12.58), faricimab (RR 1.91, 95% CI 0.45 to 8.00), ranibizumab (RR 1.26, 95% CI 0.68 to 2.34), and very low for conbercept (RR 0.33, 95% CI 0.01 to 8.81) and aflibercept (RR 1.48, 95% CI 0.79 to 2.77). Estimates for Antiplatelet Trialists Collaboration arterial thromboembolic events at 24 months did not suggest an increase with any drug compared to control, but the NMA was overall incoherent and the evidence was of low or very low certainty. Ocular adverse events were rare and poorly reported and could not be assessed in NMAs. Authors' conclusions There is limited evidence of the comparative efficacy and safety of anti-VEGF drugs beyond one year of follow-up. We found no clinically important differences in visual outcomes at 24 months in people with DMO, although there were differences in CRT change. We found no evidence that any drug increases all-cause mortality compared to control, but estimates were very imprecise. Evidence from RCTs may not apply to real-world practice, where people in need of antiangiogenic treatment are often under-treated, and the individuals exposed to these drugs may be less healthy than trial participants.
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Key Words
- Angiogenesis Inhibitors [adverse effects, *therapeutic use]
- Aptamers, Nucleotide [adverse effects, therapeutic use]
- Bevacizumab [adverse effects, therapeutic use]
- Diabetic Retinopathy [*complications]
- Laser Coagulation [methods]
- Macular Edema [*drug therapy, etiology, surgery]
- Network Meta-Analysis
- Quality of Life
- Randomized Controlled Trials as Topic
- Ranibizumab [adverse effects, therapeutic use]
- Receptors, Vascular Endothelial Growth Factor [therapeutic use]
- Recombinant Fusion Proteins [adverse effects, therapeutic use]
- Triamcinolone [adverse effects, therapeutic use]
- Vascular Endothelial Growth Factor A [*antagonists & inhibitors]
- Visual Acuity [*drug effects, physiology]
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Affiliation(s)
- Gianni Virgili
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | | | - Ersilia Lucenteforte
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Tunde Peto
- Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - Mariacristina Parravano
- Ophthalmology, Fondazione G.B. Bietti per lo studio e la ricerca in Oftalmolologia-IRCCS, Rome, Italy
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Sodhi GS, Haq Z, Aggarwal N, Boucher N, Emerson GG, Hahn P. Evolving Treatment Patterns in Diabetic Macular Edema Between 2015 and 2020. JOURNAL OF VITREORETINAL DISEASES 2023; 7:199-202. [PMID: 37188218 PMCID: PMC10170625 DOI: 10.1177/24741264231156096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
Purpose: To explore the recent evolution of diabetic macular edema (DME) treatment practice patterns over 5 years among retina specialists in the United States. Methods: This retrospective analysis assessed 306 700 eyes with newly diagnosed DME from the Vestrum Health database between January 2015 and October 2020. The year-over-year and cumulative 5-year distributions of eyes treated with antivascular endothelial growth factor (anti-VEGF) agents, steroids, focal laser, or any combination and those of untreated eyes were calculated. Changes from baseline visual acuity were assessed. Results: Yearly treatment patterns changed significantly from 2015 (n = 18056) to 2020 (n = 11042). The proportion of untreated patients declined over time (32.7% vs 27.7%; P < .001), the use of anti-VEGF monotherapy increased (43.5% vs 61.8%; P < .001), the use of focal laser monotherapy declined (9.7% vs 3.0%; P < .001), and the use of steroid monotherapy remained stable (0.9% vs 0.7%; P = 1.000). Of eyes that maintained follow-up for 5 years (from 2015 to 2020), 16.3% were untreated while 77.5% were treated with anti-VEGF agents (as monotherapy or combination therapy). Vision gains in treated patients remained approximately stable from 2015 (3.6 letters) to 2020 (3.5 letters). Conclusions: From 2015 to 2020, treatment patterns for DME evolved toward greater anti-VEGF monotherapy, stable steroid monotherapy, less laser monotherapy, and fewer untreated eyes.
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Affiliation(s)
| | - Zeeshan Haq
- Retina Consultants of Minnesota, Edina, MN, USA
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Lukacs R, Schneider M, Nagy ZZ, Sandor GL, Kaan K, Asztalos A, Enyedi L, Pek G, Barcsay G, Szabo A, Borbandy A, Kovacs I, Resch MD, Papp A. Seven-year outcomes following intensive anti-vascular endothelial growth factor therapy in patients with exudative age-related macular degeneration. BMC Ophthalmol 2023; 23:110. [PMID: 36932356 PMCID: PMC10022151 DOI: 10.1186/s12886-023-02843-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 03/06/2023] [Indexed: 03/19/2023] Open
Abstract
BACKGROUND Anti-vascular endothelial growth factor (VEGF) therapy is currently the most effective therapy of exudative age-related macular degeneration (AMD). The aim of this study was to assess long-term benefits of intensive aflibercept and ranibizumab anti-VEGF therapy in patients with exudative AMD. METHODS Two clinical trial sites recruited their original subjects for a re-evaluation 7 years after the baseline visit of the phase-3 Vascular Endothelial Growth Factor (VEGF) Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration (VIEW 2) trial. Forty-seven eyes of 47 patients with AMD originally treated with ranibizumab (14 eyes) or aflibercept (33 eyes) were included. RESULTS Mean number of injections was 17.8 ± 3.0 during participation in the VIEW 2 trial. Fourteen of 47 (30%) eyes were given additional injections with a mean number of 5.7 ± 4.5 after the trial. At a mean follow-up time of 82 ± 5 months best corrected visual acuity (BCVA) remained stable or improved (≤ 10 letters lost) in 55% of patients in the entire study population, in 43% in the ranibizumab group and in 60% in the aflibercept group. In both groups combined mean BCVA was 54 ± 13 letters at baseline, 65 ± 17 letters at the end of the intensive phase and 45 ± 25 letters at the end of follow-up. There was no statistically significant difference in BCVA between the two groups at baseline (p = 0.88) and at the end of follow-up (p = 0.40). Macular atrophy was observed in 96% of eyes, average area was 7.22 ± 6.31 mm2 with no statistically significant difference between groups (p = 0.47). Correlation between BCVA at end-of-follow-up and the area of atrophy was significant (p < 0.001). At the end of follow-up, fluid was detected in 7 of 47 eyes (15%) indicating disease activity. CONCLUSION Long-term efficacy of aflibercept and ranibizumab was largely consistent. Following a two-year intensive therapy with as-needed regimen, BCVA was maintained or improved in almost half of the patients and in the ranibizumab group and more than half of the patients in the aflibercept group with very few injections. In a remarkable proportion of eyes, BCVA declined severely which underlines the need for long-term follow-ups and may indicate a more prolonged intensive therapy. TRIAL REGISTRATIONS VIEW 2 study: ClinicalTrials.gov ID: NCT00637377, date of registration: March 18, 2008. Long-term follow-up: IRB nr.: SE RKEB 168/2022, ClinicalTrials.gov ID: NCT05678517, date of registration: December 28, 2022, retrospectively registered.
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Affiliation(s)
- Regina Lukacs
- Department of Ophthalmology, Flor Ferenc Hospital of Pest County, Kistarcsa, Hungary
| | - Miklos Schneider
- grid.11804.3c0000 0001 0942 9821Department of Ophthalmology, Semmelweis University, Maria u. 39, Budapest, H-1085 Hungary
- grid.475435.4Department of Ophthalmology, Rigshospitalet, Glostrup, Denmark
| | - Zoltan Zsolt Nagy
- grid.11804.3c0000 0001 0942 9821Department of Ophthalmology, Semmelweis University, Maria u. 39, Budapest, H-1085 Hungary
| | - Gabor Laszlo Sandor
- grid.11804.3c0000 0001 0942 9821Department of Ophthalmology, Semmelweis University, Maria u. 39, Budapest, H-1085 Hungary
| | - Kinga Kaan
- grid.11804.3c0000 0001 0942 9821Department of Ophthalmology, Semmelweis University, Maria u. 39, Budapest, H-1085 Hungary
| | - Antonia Asztalos
- grid.414174.3Department of Ophthalmology, Bajcsy-Zsilinszky Hospital, Budapest, Hungary
| | - Lajos Enyedi
- grid.414174.3Department of Ophthalmology, Bajcsy-Zsilinszky Hospital, Budapest, Hungary
| | - Gyorgy Pek
- grid.414174.3Department of Ophthalmology, Bajcsy-Zsilinszky Hospital, Budapest, Hungary
| | - Gyorgy Barcsay
- grid.11804.3c0000 0001 0942 9821Department of Ophthalmology, Semmelweis University, Maria u. 39, Budapest, H-1085 Hungary
| | - Antal Szabo
- grid.11804.3c0000 0001 0942 9821Department of Ophthalmology, Semmelweis University, Maria u. 39, Budapest, H-1085 Hungary
| | - Agnes Borbandy
- grid.11804.3c0000 0001 0942 9821Department of Ophthalmology, Semmelweis University, Maria u. 39, Budapest, H-1085 Hungary
| | - Illes Kovacs
- grid.11804.3c0000 0001 0942 9821Department of Ophthalmology, Semmelweis University, Maria u. 39, Budapest, H-1085 Hungary
| | - Miklos Denes Resch
- grid.11804.3c0000 0001 0942 9821Department of Ophthalmology, Semmelweis University, Maria u. 39, Budapest, H-1085 Hungary
| | - Andras Papp
- grid.11804.3c0000 0001 0942 9821Department of Ophthalmology, Semmelweis University, Maria u. 39, Budapest, H-1085 Hungary
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11
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Chung YR, Lee KH, Lee K. Clinical Application of Intravitreal Aflibercept Injection for Diabetic Macular Edema Comparing Two Loading Regimens. Medicina (B Aires) 2023; 59:medicina59030558. [PMID: 36984559 PMCID: PMC10054468 DOI: 10.3390/medicina59030558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 03/14/2023] Open
Abstract
Background and Objectives: We investigated and compared the efficacy of three and five monthly loading regimens of an intravitreal aflibercept injection (IVA) in patients with diabetic macular edema (DME). Materials and Methods: This was a retrospective study that included patients diagnosed with DME and treated with an either three or five monthly aflibercept loading regimen from July 2018 to March 2022. Information on clinical characteristics and changes in the central retinal thickness (CRT) were obtained from medical records. Results: In total, 44 eyes of 44 patients with DME treated with IVA were included in this study, with 30 eyes treated with 3-monthly loadings (three-loading group) and 14 eyes with 5-monthly loadings (five-loading group). The mean CRT significantly decreased from the baseline one month after loading in both the three-loading and five-loading groups (p < 0.001). Four cases were refractory to treatment in the three-loading group, while there were no cases of refractory DME in the five-loading group. The stability rate was significantly higher in the five-loading group at three months after loading (p = 0.033). Conclusions: Five-monthly loading regimens of IVA might be favorable for DME considering the rate of refractory cases, stable duration, and the importance of early responsiveness to IVA in DME.
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Affiliation(s)
- Yoo-Ri Chung
- Department of Ophthalmology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Kyung Ho Lee
- Love Eye Clinic, Hwaseong 18309, Republic of Korea
| | - Kihwang Lee
- Department of Ophthalmology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
- Correspondence: ; Tel.: +82-31-219-7814
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12
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Vargas-Peirano M, Verdejo C, Vergara-Merino L, Loézar C, Hoehmann M, Pérez-Bracchiglione J. Intravitreal antivascular endothelial growth factor in diabetic macular oedema: scoping review of clinical practice guidelines recommendations. Br J Ophthalmol 2023; 107:313-319. [PMID: 34906962 DOI: 10.1136/bjophthalmol-2021-319504] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 11/23/2021] [Indexed: 11/04/2022]
Abstract
BACKGROUND Diabetic macular oedema (DME) is a worldwide major cause of low vision and blindness. Intravitreal antivascular endothelial growth factor (anti-VEGF) constitutes an effective treatment. Clinical practice guidelines (CPGs) are synthesis documents that seek to improve patient care. OBJECTIVES To identify CPGs that make anti-VEGF recommendations for DME and to assess their reporting quality and their considerations when making recommendations. ELIGIBILITY CRITERIA CPGs published between December 2009 and December 2019 that make explicit anti-VEGF recommendations in DME. SOURCES OF EVIDENCE Sensitive search strategy in Embase, Google Scholar and hand-searching on 165 websites. METHODS We extracted information from each CPG with a previously piloted sheet. Two independent authors applied theAppraisal of Guidelines, Research and Evaluation tool (AGREE-II) assessment for each CPG. RESULTS The 21 included CPGs recommend anti-VEGF for DME, but there is a wide variation among the clinical aspects included, such as location of DME, visual acuity required, therapeutical alternatives or discontinuation. Most have a poor quality of reporting based on the AGREE-II tool assessment, especially those developed by ophthalmological societies, those that have an exclusive content about DME, and those where most of their authors disclose conflict of interest (COI) with pharmaceutical industry or where their authors did not report COIs. Pharmaceutical-sponsored CPGs did not use systematic reviews (SRs) to support their recommendations. Very few recommendations consider patient values and preferences, equity, acceptability and feasibility of the intervention. CONCLUSIONS Most of the CPGs that made recommendations of anti-VEGF for DME have poor quality of reporting, do not use SRs and do not consider patients' values and preferences.
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Affiliation(s)
- Manuel Vargas-Peirano
- Interdisciplinary Center for Health Studies (CIESAL), Universidad de Valparaiso, Vina del Mar, Chile
- Ophthalmology Service, Hospital Mario Sanchez Vergara, La Calera, Chile
- School of Medicine, Universidad de Valparaiso, Vina del Mar, Chile
| | - Catalina Verdejo
- School of Medicine, Universidad de Valparaiso, Vina del Mar, Chile
| | - Laura Vergara-Merino
- Interdisciplinary Center for Health Studies (CIESAL), Universidad de Valparaiso, Vina del Mar, Chile
- School of Medicine, Universidad de Valparaiso, Vina del Mar, Chile
| | - Cristóbal Loézar
- Interdisciplinary Center for Health Studies (CIESAL), Universidad de Valparaiso, Vina del Mar, Chile
- School of Medicine, Universidad de Valparaiso, Vina del Mar, Chile
- Ophthalmology Service, Hospital Naval Almirante Nef, Viña del Mar, Chile
| | - Martin Hoehmann
- School of Medicine, Universidad de Valparaiso, Vina del Mar, Chile
- Ophthalmology Service, Hospital Carlos Van Buren, Valparaiso, Chile
| | - Javier Pérez-Bracchiglione
- Interdisciplinary Center for Health Studies (CIESAL), Universidad de Valparaiso, Vina del Mar, Chile
- School of Medicine, Universidad de Valparaiso, Vina del Mar, Chile
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13
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Sood A, Baishnab S, Gautam I, Choudhary P, Lang DK, Jaura RS, Singh TG. Exploring various novel diagnostic and therapeutic approaches in treating diabetic retinopathy. Inflammopharmacology 2023; 31:773-786. [PMID: 36745243 DOI: 10.1007/s10787-023-01143-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 01/20/2023] [Indexed: 02/07/2023]
Abstract
Diabetic retinopathy is regarded as a common manifestation of diabetes mellitus, being a prominent cause of visual impairment and blindness. This microvascular complication is marked by the appearance of microaneurysms, elevated vascular permeability, capillary blockage, and proliferation of neovasculature. The etiology behind retinopathy is ambiguous and the efficacy of current treatment strategies is minimal. Early diagnosis of this complication using a biomarker with high sensitivity and specificity is very essential for providing better therapeutic strategies. The current available therapeutic options are limited with various adverse effects. Laser treatment is not beneficial in all the situations, economic constraints being the major challenge. Surgical interventions are employed when pharmacotherapy and laser treatment fail. New pharmacological treatments are becoming a necessity for treating the condition. This review highlights the use of various diagnostic tools, emerging biomarkers for early detection of diabetic retinopathy, pathological mechanisms associated with the disease, current therapeutic approaches used and future strategies for more enhanced treatment options and more potent pharmacological actions.
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Affiliation(s)
- Ankita Sood
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Suman Baishnab
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Isha Gautam
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Priya Choudhary
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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14
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Hatano M, Higashijima F, Yoshimoto T, Ogata T, Ohta M, Kobayashi Y, Wakuta M, Yanai R, Kimura K. Evaluation of microaneurysms as predictors of therapeutic response to anti-VEGF therapy in patients with DME. PLoS One 2022; 17:e0277920. [PMID: 36441722 PMCID: PMC9704562 DOI: 10.1371/journal.pone.0277920] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 10/25/2022] [Indexed: 11/29/2022] Open
Abstract
Administration of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is the first-line therapy for diabetic macular oedema (DME). However, some patients show no or insufficient response to repeated anti-VEGF injections. Therefore, it is necessary to identify factors that can predict this resistance against anti-VEGF treatment. Presence of microaneurysms (MAs) is a predictor of the development and progression of DME, but its relationship with the treatment response to the anti-VEGF agents is not well known. Therefore, we aimed to elucidate the relationship between the distribution of MAs and the response to anti-VEGF therapy in patients with DME. The number of MAs was measured before anti-VEGF therapy in each region using fluorescein angiography, indocyanine green angiography (IA), and optical coherence tomography angiography. Patients with DME were divided into the responder and non-responder groups after three loading phases. Differences in the distribution of MAs between the groups were investigated. Pre-treatment IA revealed more MAs in the nasal area in the non-responder group than in the responder group (10.7 ± 10.7 and 5.7 ± 5.7, respectively, in the nasal macula) (1.4 ± 2.1 and 0.4 ± 0.7, respectively, in the nasal fovea). Whereas, pre-treatment FA and OCTA could not reveal significantly difference between the groups. Detection of MAs in the nasal macula using pre-treatment IA may indicate resistance to anti-VEGF therapy. We recommend the clinicians confirm the presence of MAs in the nasal macula, as shown by IA, as a predictor of therapeutic response to anti-VEGF therapy in patients with treatment naive DME.
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Affiliation(s)
- Makoto Hatano
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi, Japan
| | - Fumiaki Higashijima
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi, Japan
| | - Takuya Yoshimoto
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi, Japan
| | - Tadahiko Ogata
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi, Japan
| | - Manami Ohta
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi, Japan
| | - Yuka Kobayashi
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi, Japan
| | - Makiko Wakuta
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi, Japan
| | - Ryoji Yanai
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi, Japan
| | - Kazuhiro Kimura
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi, Japan
- * E-mail:
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15
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Uludag G, Hassan M, Matsumiya W, Pham BH, Chea S, Trong Tuong Than N, Doan HL, Akhavanrezayat A, Halim MS, Do DV, Nguyen QD. Efficacy and safety of intravitreal anti-VEGF therapy in diabetic retinopathy: what we have learned and what should we learn further? Expert Opin Biol Ther 2022; 22:1275-1291. [PMID: 35818801 PMCID: PMC10863998 DOI: 10.1080/14712598.2022.2100694] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 07/08/2022] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Diabetic retinopathy (DR) is one of the most frequent microvascular complications of diabetes that can lead to blindness. Laser treatment has been the gold standard treatment for diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) for many years. Recently, the role of vascular endothelial growth factor (VEGF) has been established in the pathogenesis of DR, and the use of intravitreal anti-VEGF therapy has gained popularity for the management of DR. AREAS COVERED This review includes a brief overview of the efficacy and safety of currently available (bevacizumab, ranibizumab, and aflibercept) and potential future (brolucizumab, faricimab, and KSI-301) anti-VEGF agents in patients with DR based mainly on publicly available data from phase 1, 2 and 3 clinical trials. EXPERT OPINION Clinical trials investigating the efficacy of intravitreal bevacizumab, ranibizumab, and aflibercept injections demonstrated favorable functional and anatomical outcomes in patients with DME. Moreover, the use of these anti-VEGF agents showed a significant improvement in the severity of DR. Recent clinical research for future anti-VEGF molecules aims to provide higher target-protein binding affinity and prolonged therapeutic effect. Brolucizumab, faricimab, and KSI-301 are three novel anti-VEGF agents that demonstrate promising data for the management of DME and potentially DR.
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Affiliation(s)
- Gunay Uludag
- Byers Eye Institute, Stanford University, Palo Alto, CA, USA
| | - Muhammad Hassan
- Byers Eye Institute, Stanford University, Palo Alto, CA, USA
| | - Wataru Matsumiya
- Byers Eye Institute, Stanford University, Palo Alto, CA, USA
- Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Brandon Huy Pham
- Byers Eye Institute, Stanford University, Palo Alto, CA, USA
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami, Miami, FL, USA
| | - Sophaktra Chea
- Byers Eye Institute, Stanford University, Palo Alto, CA, USA
| | | | - Hien Luong Doan
- Byers Eye Institute, Stanford University, Palo Alto, CA, USA
| | | | - Muhammad Sohail Halim
- Byers Eye Institute, Stanford University, Palo Alto, CA, USA
- Ocular Imaging Research and Reading Center, Sunnyvale, CA, USA
| | - Diana V Do
- Byers Eye Institute, Stanford University, Palo Alto, CA, USA
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16
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Liberski S, Wichrowska M, Kocięcki J. Aflibercept versus Faricimab in the Treatment of Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema: A Review. Int J Mol Sci 2022; 23:9424. [PMID: 36012690 PMCID: PMC9409486 DOI: 10.3390/ijms23169424] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 12/02/2022] Open
Abstract
Diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) are common retinal vascular diseases responsible for most blindness in the working-age and older population in developed countries. Currently, anti-VEGF agents that block VEGF family ligands, including ranibizumab, bevacizumab (off-label use), brolucizumab, and aflibercept, are the first-line treatment for nAMD and DME. However, due to the complex pathophysiological background of nAMD and DME, non-response, resistance during anti-VEGF therapy, and relapses of the disease are still observed. Moreover, frequent injections are a psychological and economic burden for patients, leading to inadequate adhesion to therapy and a higher risk of complications. Therefore, therapeutic methods are strongly needed to develop and improve, allowing for more satisfactory disease management and lower treatment burden. Currently, the Ang/Tie-2 pathway is a promising therapeutic target for retinal vascular diseases. Faricimab is the first bispecific monoclonal antibody for intravitreal use that can neutralize VEGF and Ang-2. Due to the prolonged activity, faricimab allows extending the interval between successive injections up to three or four months in nAMD and DME patients, which can be a significant benefit for patients and an alternative to implanted drug delivery systems.
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Affiliation(s)
- Sławomir Liberski
- Department of Ophthalmology, Poznan University of Medical Sciences, ul. Augustyna Szamarzewskiego 84, 61-848 Poznan, Poland
| | - Małgorzata Wichrowska
- Department of Ophthalmology, Poznan University of Medical Sciences, ul. Augustyna Szamarzewskiego 84, 61-848 Poznan, Poland
- Doctoral School, Poznan University of Medical Sciences, ul. Bukowska 70, 60-812 Poznan, Poland
| | - Jarosław Kocięcki
- Department of Ophthalmology, Poznan University of Medical Sciences, ul. Augustyna Szamarzewskiego 84, 61-848 Poznan, Poland
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17
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Tatsumi T, Takatsuna Y, Oshitari T, Kaiho T, Kawasaki Y, Shiko Y, Sugawara T, Baba T, Yamamoto S. Randomized clinical trial comparing intravitreal aflibercept combined with subthreshold laser to intravitreal aflibercept monotherapy for diabetic macular edema. Sci Rep 2022; 12:10672. [PMID: 35739147 PMCID: PMC9226173 DOI: 10.1038/s41598-022-14444-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 06/07/2022] [Indexed: 11/25/2022] Open
Abstract
To compare the efficacy and safety of intravitreal aflibercept with three loading doses + pro re nata regimen combined with subthreshold laser application to that of IVA monotherapy on eyes with diabetic macular edema. This was a phase 4 clinical trial with a prospective, randomized, and parallel investigator-driven protocol. Patients with DME were randomly assigned to the IVA monotherapy group (n = 25) or the IVA + SL combination therapy group (n = 26). The main outcome measures were the number of IVA injections and the changes in the best-corrected visual acuity (BCVA) and the central retinal thickness (CRT) at the final evaluation at 96 weeks. The mean number of IVA injections in the monotherapy group was 5.86 ± 2.43 and it was 6.05 ± 2.73 in the IVA + SL group at 96 weeks, and this difference was not significant (P = 0.83). The differences in the mean changes of the CRT (P = 0.17) and the BCVA (P = 0.31) were also not significant between the two groups throughout the follow-up period. We conclude that adjunct of SL to anti-VEGF therapy does not reduce the number of necessary intravitreal injections.
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Affiliation(s)
- Tomoaki Tatsumi
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba, Chiba, 260-8670, Japan.
| | - Yoko Takatsuna
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba, Chiba, 260-8670, Japan. .,Department of Ophthalmology, Chiba Rosai Hospital, 2-16, Tatsumidaihigashi, Ichihara, Chiba, 290-0003, Japan.
| | - Toshiyuki Oshitari
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba, Chiba, 260-8670, Japan.,Department of Ophthalmology, International University of Health and Welfare School of Medicine, 4-3, Kozunomori, Narita, Chiba, 286-8686, Japan
| | - Tomomi Kaiho
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba, Chiba, 260-8670, Japan
| | - Yohei Kawasaki
- Biostatistics Section, Clinical Research Center, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.,Faculty of Nursing, Japanese Red Cross College of Nursing, 4-1-3, Hiroo, Shibuya-ku, Tokyo, 150-0012, Japan
| | - Yuki Shiko
- Biostatistics Section, Clinical Research Center, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Takeshi Sugawara
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba, Chiba, 260-8670, Japan.,Chiba University Hospital Translational Research and Development Center, 1-8-1, Inohana, Chuo-ku, Chiba, Chiba, 260-8670, Japan
| | - Takayuki Baba
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba, Chiba, 260-8670, Japan
| | - Shuichi Yamamoto
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba, Chiba, 260-8670, Japan
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18
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Sheu SJ, Yang CH, Lai CC, Wu PC, Chen SJ. One-year outcomes of the treat-and-extend regimen using aflibercept for the treatment of diabetic macular edema. J Chin Med Assoc 2022; 85:246-251. [PMID: 34974510 DOI: 10.1097/jcma.0000000000000680] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Optimal regimen using intravitreal aflibercept injections for diabetic macular edema (DME) in clinical practice remains to be elucidated. The purpose of this study is to evaluate a treat-and-extend (TAE) approach using intravitreal aflibercept in participants with center-involved DME. METHODS A 52-week open-label, prospective, multicenter, interventional study was conducted between August 2015 and November 2017 in Taiwan. Adults with diabetes mellitus and center-involved DME who have best-corrected visual acuity (BCVA) of 73 to 24 Early Treatment Diabetic Retinopathy Study letters and central retinal thickness (CRT) >300 μm were included. Participants received five monthly loading doses of 2 mg intravitreal aflibercept, followed by a TAE regimen with a four-week increment/decrement interval over 48 weeks; the maximum interval was 12 weeks. Main outcomes included changes in BCVA and CRT from baseline to week 52, additional anatomical outcomes, and treatment burden parameters. RESULTS Forty-five participants with mean (SD) age of 63.7 (8.3) years were analyzed. At baseline, mean (SD) BCVA and CRT were 58.3 (11.9) letters and 434.4 (116.8) μm, respectively. Changes from baseline in BCVA and CRT were +8.3 (9.3) letters and -138.2 (150.0) μm (both p < 0.001) at week 52, respectively. In addition, 22% (10/45) of patients gained ≥15 letters, 14% (6/44) of participants achieved ≥2-level improvement in diabetic retinopathy severity, and 51% (23/45) demonstrated dry retina at week 52 compared with 13% (6/45) at baseline. In total, 87% (39/45) of patients reached disease stability, entering TAE at week 20. Subsequently, 89% (40/45) of patients reached maximum interval at week 52. Mean (SD) number of injections was 7.7 (1.5) over a period of 52 weeks. CONCLUSION This straightforward and practical TAE regimen using intravitreal aflibercept injections resulted in favorable clinical outcomes with minimal treatment burden for DME at week 52.
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Affiliation(s)
- Shwu-Jiuan Sheu
- Department of Ophthalmology, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan, ROC
| | - Chang-Hao Yang
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan, ROC
| | - Chi-Chun Lai
- Department of Ophthalmology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan, ROC
| | - Pei-Chang Wu
- Department of Ophthalmology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan, ROC
| | - Shih-Jen Chen
- Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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COMPARISON OF INTRAVITREAL DEXAMETHASONE IMPLANT AND AFLIBERCEPT IN PATIENTS WITH TREATMENT-NAIVE DIABETIC MACULAR EDEMA WITH SEROUS RETINAL DETACHMENT. Retina 2021; 40:1044-1052. [PMID: 30950970 DOI: 10.1097/iae.0000000000002537] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
PURPOSE To compare the efficacy and safety of intravitreal dexamethasone (DEX) implant versus aflibercept in patients with treatment-naive diabetic macular edema with inflammatory biomarkers. METHODS Ninety-eight eyes of 62 treatment-naive patients with diabetic macular edema with serous retinal detachment and hyperreflective foci were enrolled. Each patient was randomized to receive either aflibercept or DEX implant treatment. The treatment protocol included 3 monthly injections of 2 mg of aflibercept as a loading phase in the anti-vascular endothelial growth factor group and 0.7 mg of DEX implant in the DEX group and then pro re nata treatment. Primary outcome measures were mean changes in visual acuity and central retinal thickness at the end of the 12-month follow-up. RESULTS Forty-eight eyes of 29 patients were received DEX implant, and 50 eyes of 33 patients received the aflibercept injection. Mean central retinal thickness decreased from 615.2 µm at baseline to 297.7 µm at 12 months in the DEX group (P < 0.001) and from 576.5 µm to 367.4 µm in the aflibercept group (P < 0.001). Except for the first month, mean central retinal thickness reduction was significantly higher in the DEX group (P < 0.05, Mann-Whitney U Test). Visual acuity improved significantly at the end of the follow-ups (46.3-52.7 Early Treatment Diabetic Retinopathy Study letters in the DEX group and 47.5-56.8 Early Treatment Diabetic Retinopathy Study letters in the aflibercept group at 12 months, P < 0.001, paired-sample t-test). Adjusting by baseline values, the increase in mean visual acuity during the 12-month follow-ups favored the aflibercept group (P < 0.01), 25% of the DEX-treated eyes and 42% of the aflibercept treated eyes experienced 10 or more Early Treatment Diabetic Retinopathy Study letters visual gain (P: 0.058). The DEX group received significantly fewer (2.6 vs. 7.2) injections (P: 0.001). CONCLUSION It was observed that the both of DEX implant and aflibercept were effective and safe in treatment-naive diabetic macular edema patients with inflammatory phenotype. Anatomical results were found to be better in the DEX group, and functional results were found to be better in the aflibercept group. In pseudophakic eyes, the functional superiority of aflibercept ceased to exist, and the low number of injections in the DEX implant group was seen as an advantage.
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Ngo Ntjam N, Thulliez M, Paintaud G, Salvo F, Angoulvant D, Pisella PJ, Bejan-Angoulvant T. Cardiovascular Adverse Events With Intravitreal Anti-Vascular Endothelial Growth Factor Drugs: A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA Ophthalmol 2021; 139:2778626. [PMID: 33856414 PMCID: PMC8050790 DOI: 10.1001/jamaophthalmol.2021.0640] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 02/15/2021] [Indexed: 12/21/2022]
Abstract
IMPORTANCE Systemic safety of intravitreal anti-vascular endothelial growth factor (anti-VEGF) is a matter of debate and regular updates are necessary. OBJECTIVE To evaluate systemic adverse events (SAEs) associated with intravitreal anti-VEGF drugs compared with non-anti-VEGF treatments in patients with ocular diseases. DATA SOURCES Electronic searches were conducted in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases from inception to July 7, 2020. STUDY SELECTION Randomized clinical trials conducted in adults with retinal diseases who received intravitreal anti-VEGF drugs. DATA EXTRACTION AND SYNTHESIS Studies and treatment characteristics and outcome data were extracted and analyzed, and study quality was evaluated. MAIN OUTCOMES AND MEASURES Main outcomes were major cardiovascular events (MACEs) and total mortality. Secondary outcomes included nonocular hemorrhage, components of MACEs, other cardiovascular outcomes, serious SAEs, and all SAEs. RESULTS A total of 74 randomized clinical trials were analyzed: 32 trials (43%) included 14 190 patients with age-related macular degeneration (AMD), 24 (32%) included 5424 patients with diabetic retinopathy (diabetic macular edema or proliferative diabetic retinopathy), 17 trials (23%) included 3757 patients with retinal vein occlusion, and 1 trial (1%) included 122 patients with myopic choroidal neovascularization. Anti-VEGF drug administration did not increase MACEs compared with control agents (odds ratio [OR], 1.16; 95% CI, 0.85-1.58) or total mortality (OR, 1.27; 95% CI, 0.82-1.96). There was an interaction (subgroup difference, P = .04) in mortality risk depending on the underlying disease with an increase (OR, 1.80; 95% CI, 1.03-3.16; P = .04) in the risk of death in patients with diabetic retinopathy; however, no increase was observed in patients with AMD or retinal vein occlusion. Administration of anti-VEGF drugs increased the risk of nonocular hemorrhage (OR, 1.46; 95% CI, 1.01-2.10), mainly in patients with AMD. CONCLUSIONS AND RELEVANCE Intravitreal anti-VEGF was not associated with an increase in MACEs in the trials examined herein. Increased mortality in patients with diabetes and nonocular hemorrhages, especially in those with AMD, could represent a safety signal, but the evidence was not strong. However, continued surveillance of SAEs remains warranted.
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Affiliation(s)
- Nadège Ngo Ntjam
- Hospital Pharmacy, CHRU de Tours, Tours, France
- EA 4245, T2I (Transplantation, Immunity & Inflammation), Université de Tours, Tours, France
- Medical Pharmacology Department, CHRU de Tours, Tours, France
| | - Marie Thulliez
- Ophthalmology Department, CHU de Montpellier, Montpellier, France
| | - Gilles Paintaud
- EA 4245, T2I (Transplantation, Immunity & Inflammation), Université de Tours, Tours, France
- Medical Pharmacology Department, CHRU de Tours, Tours, France
| | - Francesco Salvo
- Medical Pharmacology Department, CHU Pellegrin, Bordeaux, France
- Bordeaux Population Health Research Center, U1219, Université de Bordeaux, Bordeaux, France
| | - Denis Angoulvant
- EA 4245, T2I (Transplantation, Immunity & Inflammation), Université de Tours, Tours, France
- Cardiology Department, CHRU de Tours, Tours, France
| | | | - Theodora Bejan-Angoulvant
- EA 4245, T2I (Transplantation, Immunity & Inflammation), Université de Tours, Tours, France
- Medical Pharmacology Department, CHRU de Tours, Tours, France
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21
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Comparison of the efficacy of aflibercept and ranibizumab after a 3-month loading dose in patients with diabetic macular edema. JOURNAL OF SURGERY AND MEDICINE 2021. [DOI: 10.28982/josam.850861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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22
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Outcomes of a 2-year treat-and-extend regimen with aflibercept for diabetic macular edema. Sci Rep 2021; 11:4488. [PMID: 33627712 PMCID: PMC7904904 DOI: 10.1038/s41598-021-83811-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 02/08/2021] [Indexed: 12/26/2022] Open
Abstract
This prospective, open-label, single-arm, non-randomized clinical trial, assessed the efficacy of a 2-year treat-and-extend (T&E) regimen involving intravitreal aflibercept injection (IAI), with the longest treatment interval set to 16 weeks, and adjunct focal/grid laser in diabetic macula edema (DME) patients. We examined 40 eyes (40 adults) with fovea-involving DME from 8 Japanese centers between April 2015 and February 2017. Participants received IAI with an induction period featuring monthly injections and a subsequent T&E period featuring 8–16-week injection interval, adjusted based on optical coherence tomography findings. The primary endpoints were mean changes in the best-corrected visual acuity (BCVA) and central subfield macular thickness (CST) from baseline. Thirty patients (75%) completed the 2-year follow-up. The mean BCVA and CST changed from 60.5 ± 15.6 letters and 499.2 ± 105.6 µm at baseline to 66.6 ± 17.1 letters (P = 0.217) and 315.2 ± 79.0 µm (P < 0.001), respectively, after 2 years. The treatment interval was extended to 12 and 16 weeks in 6.7% and 66.7% of patients, respectively, at the end of 2 years. The T&E aflibercept regimen with the longest treatment interval set to 16 weeks, with adjunct focal/grid laser may be a rational 2-year treatment strategy for DME.
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Yozgat Z, Doğan M, Sabaner MC, Gobeka HH, Yazgan Akpolat S. Impacts of intravitreal anti-VEGF therapy on retinal anatomy and neurophysiology in diabetic macular edema. Int Ophthalmol 2021; 41:1783-1798. [PMID: 33606153 DOI: 10.1007/s10792-021-01737-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 02/01/2021] [Indexed: 11/26/2022]
Abstract
PURPOSE To evaluate anatomical and neuroretinal functional aspects in patients with diabetic macular edema (DME) after intravitreal anti-vascular endothelial growth factor (VEGF) therapy, in particular aflibercept. MATERIALS AND METHODS This prospective single-centered interventional study was performed at Afyonkarahisar Health Science University Faculty of Medicine, Department of Ophthalmology, where 32 eyes of 32 patients with DME were investigated. All patients received five intravitreal aflibercept injections on a monthly basis and were followed up for ≥ 6 months. After a comprehensive ophthalmological examination, including the measurements of visual acuity and intraocular pressure, and an antero-posterior segment slit-lamp biomicroscopy before and after full pupil dilation, fundus fluorescein angiography and optical coherence tomography were performed at baseline and during the third and sixth months post-therapy. Microperimetry and multifocal electroretinography were also performed at baseline and during the sixth months. RESULTS Mean visual acuity increased from 0.73 to 0.57 and 0.33 logarithm of the minimum angle of resolution (logMAR) during the third and sixth months, respectively (p < 0.001). Changes in intraocular pressure were not statistically significant (p = 0.472). There was statistically significantly decreased mean central macular thickness from 390.2 μm to 242.6 and 289.7 μm during the third and sixth months, respectively (p < 0.001). Significantly improved fixation patterns during the sixth month, along with significantly increased macular sensitivity from 8.2 to 14.2 dB (p < 0.001) and significantly decreased local deficit from - 10.3 to 5.5 dB (p < 0.001) were observed. Further, there was a significantly increased N1 amplitude in the first ring and significantly increased P1 amplitude in all rings (p for each parameter < 0.05). There was also significantly decreased N1 wave implicit time in all rings and significantly decreased P1 wave in the second, third, fourth and fifth rings (p for each parameter < 0.05). CONCLUSIONS Patients with DME showed profound improvement in the retinal neurophysiological function, which was also accompanied by anatomical and ultrastructural integrity recovery after intravitreal aflibercept therapy. In the pathogenesis of DME, the influence of neurodegeneration has been increasingly gaining significant attention. Consequently, the need to assess neurophysiological effects of anti-VEGF therapy using a variety of diagnostic measures like electrophysiological studies and multimodal imaging technologies is undeniably growing.
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Affiliation(s)
- Zübeyir Yozgat
- Afyonkarahisar Health Sciences University, Afyonkarahisar, Turkey
| | - Mustafa Doğan
- Afyonkarahisar Health Sciences University, Afyonkarahisar, Turkey.
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Yang Y, Dunbar H. Clinical Perspectives and Trends: Microperimetry as a trial endpoint in retinal disease. Ophthalmologica 2021; 244:418-450. [PMID: 33567434 DOI: 10.1159/000515148] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 02/03/2021] [Indexed: 11/19/2022]
Abstract
Endpoint development trials are underway across the spectrum of retinal disease. New validated endpoints are urgently required for the assessment of emerging gene therapies and in preparation for the arrival of novel therapeutics targeting early stages of common sight-threatening conditions such as age-related macular degeneration. Visual function measures are likely to be key candidates in this search. Over the last two decades, microperimetry has been used extensively to characterize functional vision in a wide range of retinal conditions, detecting subtle defects in retinal sensitivity that precede visual acuity loss and tracking disease progression over relatively short periods. Given these appealing features, microperimetry has already been adopted as an endpoint in interventional studies, including multicenter trials, on a modest scale. A review of its use to date shows a concurrent lack of consensus in test strategy and a wealth of innovative disease and treatment-specific metrics which may show promise as clinical trial endpoints. There are practical issues to consider, but these have not held back its popularity and it remains a widely used psychophysical test in research. Endpoint development trials will undoubtedly be key in understanding the validity of microperimetry as a clinical trial endpoint, but existing signs are promising.
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Affiliation(s)
- Yesa Yang
- UCL Institute of Ophthalmology, University College London, London, United Kingdom
- Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom
| | - Hannah Dunbar
- UCL Institute of Ophthalmology, University College London, London, United Kingdom
- Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom
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25
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Treat-and-extend therapy with aflibercept for diabetic macular edema: a prospective clinical trial. Jpn J Ophthalmol 2021; 65:354-362. [PMID: 33559843 DOI: 10.1007/s10384-021-00820-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 12/03/2020] [Indexed: 10/22/2022]
Abstract
PURPOSE To investigate the efficacy and safety of a treat-and-extend (T&E) regimen using aflibercept (Eylea) for diabetic macular edema (DME). STUDY DESIGN Prospective, open-label, multicenter, single-arm, nonblinded clinical study. METHODS Forty eyes of 40 patients with DME received a T&E regimen of intravitreal aflibercept injection (IAI) with the longest treatment interval set to 16 weeks and adjunct focal/grid laser for 1 year. An intent-to-treat analysis was performed using the same last-observation-carried-forward method. A per-protocol analysis was also performed for patients who completed a 1-year T&E regimen. The primary endpoints were mean changes in best-corrected visual acuity (BCVA) and central subfield macular thickness (CST) from baseline. Secondary endpoints included IAI-interval extension and resultant IAI numbers and the association between an early response to IAI and final BCVA gain at 1 year. RESULTS Thirty-one patients (77.5%) completed the 1-year aflibercept T&E regimen. In these per-protocol participants, the mean CST improvement/reduction was 187.3 ± 145.0 µm (P < .001), but the mean BCVA gain was limited to 4.3 ± 12.2 letters (P = .782). Subanalysis revealed that eyes that gained ≥ 4 letters (median at week 12) after the initial 3 consecutive IAIs (induction phase) achieved greater vision improvement (13.8 ± 9.5 letters) than did the residual eyes (- 4.3 ± 9.2 letters) at 1 year (P < .001). Treatment intervals were extended to 12 and 16 weeks in 16.1% (5/31) and 45.2% (14/31) of the patients, respectively. The mean IAI number was 7.0 ± 1.1. CONCLUSIONS The results of this study suggest that although the BCVA improvement might be somewhat less than that of frequent treatment, a T&E aflibercept regimen with the longest treatment interval set to 16 weeks is a realizable rational strategy for DME treatment over 1 year.
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26
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Pareja-Ríos A, de Armas-Ramos E, Aldea-Perona A, Bonaque-González S. Alone laser versus bevacizumab plus laser for diffuse diabetic macular edema (ALBA randomized trial). Ther Adv Ophthalmol 2021; 13:2515841420988210. [PMID: 33506177 PMCID: PMC7812399 DOI: 10.1177/2515841420988210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 12/23/2020] [Indexed: 11/24/2022] Open
Abstract
Purpose: To report the 12-month results of laser (treatment G1) versus intravitreal bevacizumab combined with laser (treatment G2) in patients with diffuse diabetic macular edema (DME). Methods: In this single-center randomized independent controlled trial, 32 patients were randomized to G1 (n = 15) or G2 (n = 17). In G1, laser was given at baseline and then pro re nata (PRN). In G2, three intravitreal bevacizumab (1.25 mg) injections were given once every 6 weeks, then laser and then PRN. Analysis was performed by treatment as administered. This study was registered in clinicaltrials.gov as NCT01572350 and EU Clinical Trial Registry as 2009-014654-15. Results: G2 was superior to G1 improving best corrected visual acuity (BCVA) with respect baseline (+8.0 vs + 3.0; p < 0.01). At month 12, a significantly greater proportion of patients had a BCVA letter score >15 and >73 in G2 (3 of 15 (20%) and 8 of 15 (53%), respectively) versus G1 (1 of 17 (6%) and 4 of 18 (23%), respectively). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire, at 12 months was statistically indistinguishable between both groups. Conclusion: G2 provided superior visual acuity gains over G1 in patients with visual impairment due to center-involving diffuse DME, associated with significant gains in VFQ-25 scores.
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Affiliation(s)
- Alicia Pareja-Ríos
- Servicio de Oftalmología, Hospital Universitario de Canarias, C/Ofra s/n, 38320 San Cristóbal de La Laguna, Santa Cruz de Tenerife, Islas Canarias, Spain
| | - Elena de Armas-Ramos
- Department of Ophthalmology, University Hospital of the Canary Islands, San Cristóbal de La Laguna, Spain
| | - Ana Aldea-Perona
- Department of Ophthalmology, University Hospital of the Canary Islands, San Cristóbal de La Laguna, Spain
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27
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Gore A, Kadar T, Dachir S, Horwitz V. Therapeutic measures for sulfur mustard-induced ocular injury. Toxicol Lett 2021; 340:58-66. [PMID: 33440228 DOI: 10.1016/j.toxlet.2021.01.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 12/28/2020] [Accepted: 01/04/2021] [Indexed: 02/07/2023]
Abstract
The use of sulfur mustard (SM) in global terrorism is still a relevant threat to both civilian population and military personnel. Casualties exposed to SM may present mild, moderate or severe acute ocular lesions followed by a complete ocular resolution, chronic lesions or re-emerged ocular pathologies after a latent period. Current treatment for SM-induced ocular injury is based mainly on the clinical manifestation at the different stages of the injury and includes pharmaceutical and surgical interventions. These therapeutic measures are beneficial but not sufficient, and the ocular injury remains a continuous challenge for medical professionals. This review focuses on treatment experience carried out in humans and studied in animal models, for both SM-induced ocular acute injury and late pathology. In general, therapeutic measures are based on clinical features of the ocular injury or on the involvement of specific factors during the ocular injury that point out towards potential treatments. Anti-inflammatory treatments and limbal stem cell transplantation techniques were developed based on the clinical manifestation of the ocular injury. Optional therapies for impaired corneal innervation and endothelium are suggested for future research. Additionally, studies on potential treatments with anti-matrix metalloproteinase (MMP), anti-vascular endothelial growth factor (VEGF) and anti-IL-6 agents are discussed. Consequently, future studies may reveal the potential of additional pharmacological and biological treatments or advanced cellular and molecular biology methods to serve as novel therapeutic measures and techniques for this complicated ocular injury.
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Affiliation(s)
- Ariel Gore
- Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, 74100, Israel.
| | - Tamar Kadar
- Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, 74100, Israel
| | - Shlomit Dachir
- Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, 74100, Israel
| | - Vered Horwitz
- Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, 74100, Israel.
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Gale MJ, Scruggs BA, Flaxel CJ. Diabetic eye disease: A review of screening and management recommendations. Clin Exp Ophthalmol 2021; 49:128-145. [DOI: 10.1111/ceo.13894] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 12/04/2020] [Accepted: 12/13/2020] [Indexed: 12/20/2022]
Affiliation(s)
- Michael J. Gale
- Casey Eye Institute, Department of Ophthalmology Oregon Health & Science University Portland Oregon USA
| | - Brittni A. Scruggs
- Casey Eye Institute, Department of Ophthalmology Oregon Health & Science University Portland Oregon USA
| | - Christina J. Flaxel
- Casey Eye Institute, Department of Ophthalmology Oregon Health & Science University Portland Oregon USA
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29
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Zamorano LS, Calero Magaña P, García Cisneros E, Martínez AV, Martín LF. Cocoa olein glycerolysis with lipase Candida antarctica in a solvent free system. GRASAS Y ACEITES 2020. [DOI: 10.3989/gya.0794191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
In this paper we present the valorization of cocoa olein obtained from the acid fat-splitting of soapstocks. The aim is to develop a solvent free process (enzymatically catalyzed) to maximize the production of a final product with high content of monoglycerides (MAG) and diglycerides (DAG). The effect of the enzyme dose, glycerol content, reaction times as well as the modification of the raw material and pressure were studied. The yield of the reaction increased up to 90-95% when using a vacuum of 2-3 mbar at 65 °C, enough to evaporate the water which is generated as a by-product, an enzyme dose of 1% and molar ratio oil:glycerol of 1:2. The highest yield in terms of MAG and DAG production was obtained by starting from a raw material which was rich in free acidity (FFA), rendering oil with 33.4 and 44.2% MAG and DAG, respectively. Short reaction times (6-8 h) were observed compared to previously reported results (24 h).
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30
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Li AS, Veerappan M, Mittal V, Do DV. Anti-VEGF agents in the management of diabetic macular edema. EXPERT REVIEW OF OPHTHALMOLOGY 2020. [DOI: 10.1080/17469899.2020.1806713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Angela S. Li
- Stanford University School of Medicine, Stanford University, Palo Alto, CA, USA
- Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA, USA
| | - Malini Veerappan
- Stanford University School of Medicine, Stanford University, Palo Alto, CA, USA
- Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA, USA
| | - Vaishali Mittal
- Stanford University School of Medicine, Stanford University, Palo Alto, CA, USA
- Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA, USA
| | - Diana V. Do
- Stanford University School of Medicine, Stanford University, Palo Alto, CA, USA
- Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA, USA
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31
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Shen W, Teo KYC, Wood JPM, Vaze A, Chidlow G, Ao J, Lee SR, Yam MX, Cornish EE, Fraser-Bell S, Casson RJ, Gillies MC. Preclinical and clinical studies of photobiomodulation therapy for macular oedema. Diabetologia 2020; 63:1900-1915. [PMID: 32661752 DOI: 10.1007/s00125-020-05189-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 04/16/2020] [Indexed: 12/23/2022]
Abstract
AIMS/HYPOTHESIS Diabetic macular oedema (DME) is the leading cause of visual impairment in people with diabetes. Intravitreal injections of vascular endothelial growth factor inhibitors or corticosteroids prevent loss of vision by reducing DME, but the injections must be given frequently and usually for years. Here we report laboratory and clinical studies on the safety and efficacy of 670 nm photobiomodulation (PBM) for treatment of centre-involving DME. METHODS The therapeutic effect of PBM delivered via a light-emitting diode (LED) device was tested in transgenic mice in which induced Müller cell disruption led to photoreceptor degeneration and retinal vascular leakage. We also developed a purpose-built 670 nm retinal laser for PBM to treat DME in humans. The effect of laser-delivered PBM on improving mitochondrial function and protecting against oxidative stress was studied in cultured rat Müller cells and its safety was studied in pigmented and non-pigmented rat eyes. We then used the retinal laser to perform PBM in an open-label, dose-escalation Phase IIa clinical trial involving 21 patients with centre-involving DME. Patients received 12 sessions of PBM over 5 weeks for 90 s per treatment at a setting of 25, 100 or 200 mW/cm2 for the three sequential cohorts of 6-8 patients each. Patients were recruited from the Sydney Eye Hospital, over the age of 18 and had centre-involving DME with central macular thickness (CMT) of >300 μm with visual acuity of 75-35 Log minimum angle of resolution (logMAR) letters (Snellen visual acuity equivalent of 20/30-20/200). The objective of this trial was to assess the safety and efficacy of laser-delivered PBM at 2 and 6 months. The primary efficacy outcome was change in CMT at 2 and 6 months. RESULTS LED-delivered PBM enhanced photoreceptor mitochondrial membrane potential, protected Müller cells and photoreceptors from damage and reduced retinal vascular leakage resulting from induced Müller cell disruption in transgenic mice. PBM delivered via the retinal laser enhanced mitochondrial function and protected against oxidative stress in cultured Müller cells. Laser-delivered PBM did not damage the retina in pigmented rat eyes at 100 mW/cm2. The completed clinical trial found a significant reduction in CMT at 2 months by 59 ± 46 μm (p = 0.03 at 200 mW/cm2) and significant reduction at all three settings at 6 months (25 mW/cm2: 53 ± 24 μm, p = 0.04; 100 mW/cm2: 129 ± 51 μm, p < 0.01; 200 mW/cm2: 114 ± 60 μm, p < 0.01). Laser-delivered PBM was well tolerated in humans at settings up to 200 mW/cm2 with no significant side effects. CONCLUSIONS/INTERPRETATION PBM results in anatomical improvement of DME over 6 months and may represent a safe and non-invasive treatment. Further testing is warranted in randomised clinical trials. TRIAL REGISTRATION ClinicalTrials.gov NCT02181400 Graphical abstract.
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Affiliation(s)
- Weiyong Shen
- Save Sight Institute, Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, 8 Macquarie Street, Sydney, NSW, 2000, Australia
| | - Kelvin Yi Chong Teo
- Save Sight Institute, Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, 8 Macquarie Street, Sydney, NSW, 2000, Australia
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Republic of Singapore
| | - John P M Wood
- Department of Ophthalmology and Visual Sciences, Adelaide Health and Medical Sciences Building, University of Adelaide, Adelaide, SA, 5000, Australia
| | - Anagha Vaze
- Save Sight Institute, Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, 8 Macquarie Street, Sydney, NSW, 2000, Australia
- Sydney Eye Hospital, 8 Macquarie Street, Sydney, NSW, 2000, Australia
| | - Glyn Chidlow
- Department of Ophthalmology and Visual Sciences, Adelaide Health and Medical Sciences Building, University of Adelaide, Adelaide, SA, 5000, Australia
| | - Jack Ao
- Department of Ophthalmology and Visual Sciences, Adelaide Health and Medical Sciences Building, University of Adelaide, Adelaide, SA, 5000, Australia
| | - So-Ra Lee
- Save Sight Institute, Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, 8 Macquarie Street, Sydney, NSW, 2000, Australia
| | - Michelle X Yam
- Save Sight Institute, Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, 8 Macquarie Street, Sydney, NSW, 2000, Australia
| | - Elisa E Cornish
- Save Sight Institute, Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, 8 Macquarie Street, Sydney, NSW, 2000, Australia
- Sydney Eye Hospital, 8 Macquarie Street, Sydney, NSW, 2000, Australia
| | - Samantha Fraser-Bell
- Save Sight Institute, Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, 8 Macquarie Street, Sydney, NSW, 2000, Australia
- Sydney Eye Hospital, 8 Macquarie Street, Sydney, NSW, 2000, Australia
| | - Robert J Casson
- Department of Ophthalmology and Visual Sciences, Adelaide Health and Medical Sciences Building, University of Adelaide, Adelaide, SA, 5000, Australia.
| | - Mark C Gillies
- Save Sight Institute, Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, 8 Macquarie Street, Sydney, NSW, 2000, Australia.
- Sydney Eye Hospital, 8 Macquarie Street, Sydney, NSW, 2000, Australia.
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Kutlutürk Karagöz I, Allahverdiyev A, Bağırova M, Abamor EŞ, Dinparvar S. Current Approaches in Treatment of Diabetic Retinopathy and Future Perspectives. J Ocul Pharmacol Ther 2020; 36:487-496. [DOI: 10.1089/jop.2019.0137] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Affiliation(s)
- Işıl Kutlutürk Karagöz
- Depatment of Bioengineering, Yıldız Technical University, Istanbul, Turkey
- Department of Ophthalmology, Ümraniye Trn. And Rch. Hospital, Istanbul, Turkey
| | - Adil Allahverdiyev
- Depatment of Bioengineering, Yıldız Technical University, Istanbul, Turkey
| | - Melehat Bağırova
- Depatment of Bioengineering, Yıldız Technical University, Istanbul, Turkey
| | - Emrah Şefik Abamor
- Depatment of Bioengineering, Yıldız Technical University, Istanbul, Turkey
| | - Sahar Dinparvar
- Depatment of Bioengineering, Yıldız Technical University, Istanbul, Turkey
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Comet A, Gascon P, Ramtohul P, Donnadieu B, Denis D, Matonti F. INVICTUS: Intravitreal anti-VEGF and dexamethasone implant comparison for the treatment of diabetic macular edema: A 12 months follow-up study. Eur J Ophthalmol 2020; 31:754-758. [PMID: 32507032 DOI: 10.1177/1120672120930603] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
PURPOSE To compare the efficacy of intravitreal injections (IVI) of ranibizumab (Lucentis®, Novartis, Basel, Switzerland; RAN), aflibercept (Eylea®, Bayer, Leverkusen, Germany; AFL) and dexamethasone implant (Ozurdex®, Allergan, Irvine, California; DXI) in the treatment of naive diabetic macular oedema (DME) during a 12-month follow-up, in real life. METHODS Nineteen eyes treated with RAN, 20 with AFL and 21 with DXI were analysed from inclusion up to 12 months (M12) with intermediate analysis at M6. Best corrected visual acuity (BCVA), fundus and central retinal thickness (CRT) using spectral-domain optical coherence tomography (SD-OCT; Spectralis/HRA, Heidelberg Engineering, Germany) were performed at inclusion, M3, M6 and M12. RESULTS BCVA improved until 67.9 letters ±13.3 SD (+5.5 letters) at M6 and 69.6 letters ±12 SD (+7.2 letters) at 12 months for RAN group (p = 0.036). For the AFL group it improved until 63.6 letters ±15.2 SD (+6.6 letters) at M6 and 67.5 letters ±12.2 SD (+8.5 letters) at 12 months (p = 0.014). Lastly DXI group improved by 66.9 letters ±15.1 SD (+7.9 letters) at M6 and 68.4 letters ±11.2 SD (+9.4 letters) at 12 months (p = 0.0023). CRT decreased by 124.4 µm at M6 and 99.3 µm at M12 in RAN group, 144.3 µm and 101.5 µm in AFL group and finally 95.6 µm and 162.7 µm in DXI group. CONCLUSION In summary, these three drugs provide an efficient treatment option with an acceptable benefit-risk ratio for the treatment of naive patients with DME, whether on BCVA or CRT on the first year of treatment.
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Affiliation(s)
- Alban Comet
- Ophthalmology Department, Hôpital Nord, Aix-Marseille University, Chemin des Bourrely, Marseille, France
| | - Pierre Gascon
- Ophthalmology Department, Hôpital Nord, Aix-Marseille University, Chemin des Bourrely, Marseille, France
| | - Prithvi Ramtohul
- Ophthalmology Department, Hôpital Nord, Aix-Marseille University, Chemin des Bourrely, Marseille, France
| | - Benjamin Donnadieu
- Ophthalmology Department, Hôpital Nord, Aix-Marseille University, Chemin des Bourrely, Marseille, France
| | - Danièle Denis
- Ophthalmology Department, Hôpital Nord, Aix-Marseille University, Chemin des Bourrely, Marseille, France
| | - Frédéric Matonti
- Institut de Neurosciences de la Timone, Aix-Marseille University, Marseille, France
- Centre Paradis Monticelli, Bis Rue Paradis, Marseille, France
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Mansour SE, Kiernan DF, Roth DB, Eichenbaum D, Holekamp NM, Kaba S, Werts E. Two-year interim safety results of the 0.2 µg/day fluocinolone acetonide intravitreal implant for the treatment of diabetic macular oedema: the observational PALADIN study. Br J Ophthalmol 2020; 105:414-419. [PMID: 32461262 PMCID: PMC7907551 DOI: 10.1136/bjophthalmol-2020-315984] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 04/07/2020] [Accepted: 04/21/2020] [Indexed: 01/11/2023]
Abstract
Background The 0.2 µg/day fluocinolone acetonide (FAc) implant delivers continuous, low-dose, intravitreal corticosteroid for the treatment of diabetic macular oedema (DMO). This ongoing, 3-year, observational clinical trial provides long-term, ‘real-world’ safety results for the FAc implant in DMO. Methods This 24-month interim analysis of a prospective, observational study investigated patients with DMO receiving the commercially available intravitreal 0.2 µg/day FAc implant. The primary outcome was incidence of intraocular pressure (IOP)-lowering procedures. Other IOP-related signals and their relationship to previous corticosteroid exposure, best-corrected visual acuity, central subfield thickness (CST), ocular adverse events and frequency of other treatments were also measured. Results Data were collected from 95 previously steroid-challenged patients (115 study eyes) for up to 36 months pre-FAc and 24 months post-FAc implant. Mean IOP for the overall population remained stable post-FAc compared with pre-FAc implant. IOP-related procedures remained infrequent (two IOP-lowering surgeries pre-FAc; two trabeculoplasties and four IOP-lowering surgeries post-FAc). Mean visual acuity was stable post-FAc (mean improvement of 1–3 letters) and fewer DMO treatments were required per year following FAc implant. Mean CST was significantly reduced at 24 months post-FAc implant (p<0.001) and the percentage of patients with CST ≤300 µm was significantly increased (p=0.041). Conclusion Few IOP-related procedures were reported during the 24 months post-FAc implant. Positive efficacy outcomes were noted after treatment, with stabilisation of vision and reduction in inflammation, demonstrated by CST. The FAc implant has a favourable benefit–risk profile in the management of DMO, especially when administered after a prior steroid challenge. Trial registration number NCT02424019.
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Affiliation(s)
- Sam E Mansour
- Ophthalmology, George Washington University, Washington, District of Columbia, USA .,Virginia Retina Center, Warrenton, Virginia, USA
| | - Daniel F Kiernan
- Ophthalmic Consultants of Long Island, Rockville Center, New York, New York, USA
| | - Daniel B Roth
- Ophthalmology, Rutger Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
| | - David Eichenbaum
- Retina Vitreous Associates of Florida, St Petersburg, Florida, USA.,Ophthalmology, University of South Florida Morsani College of Medicine, Tampa, Florida, USA
| | | | - Samer Kaba
- Alimera Sciences, Alpharetta, Georgia, USA
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Sharma S, Joshi SN, Karki P. HbA1c as a predictor for response of bevacizumab in diabetic macular oedema. BMJ Open Ophthalmol 2020; 5:e000449. [PMID: 32426522 PMCID: PMC7228525 DOI: 10.1136/bmjophth-2020-000449] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 04/21/2020] [Accepted: 04/30/2020] [Indexed: 12/21/2022] Open
Abstract
Objective To study the influence of glycosylated haemoglobin (HbA1c) on response of bevacizumab in patients with diabetic macular oedema. Methods and Analysis A total of 37 eyes of 37 patients with vision loss due to diabetic macular oedema treated with bevacizumab were included in this study. Participants received monthly intravitreal bevacizumab (0.05 mL/1.25 mg) for 3 months. Results There were 17 patients with baseline HbA1c ≤7% (<53mmol/mol) and 20 patients with baseline HbA1c >7% (>53mmol/mol) treated with bevacizumab included in the study. The mean improvement in visual acuity at 3 months was 0.50 logMAR in HbA1c ≤7%(<53mmol/mol) group and 0.33 logMAR in HbA1c >7%(>53mmol/mol) group (95% CI,-0.05-0.38; p=0.13). The mean central macular thickness (CMT) reduction was −229.76 µm in patients with a baseline HbA1c ≤7% (<53 mmol/mol) and −145.20 µm in patients with HbA1c of >7% (>53mmol/mol) (95% CI,12.98-156.14; p=0.022). Conclusion Our study suggests that baseline glycaemic control can affect the treatment outcome of intravitreal bevacizumab in the management of diabetic macular oedema and the response was found to be better in patients with good glycaemic control (low HbA1c).
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Affiliation(s)
| | - Sagun Narayan Joshi
- Department of Retina, B.P. Koirala Lions Center for Ophthalmic Studies, Institute of Medicine, Kathmandu, Nepal
| | - Pratap Karki
- Department of Retina, B.P. Koirala Lions Center for Ophthalmic Studies, Institute of Medicine, Kathmandu, Nepal
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Dolinko AH, Chwa M, Atilano SR, Kenney MC. African and Asian Mitochondrial DNA Haplogroups Confer Resistance Against Diabetic Stresses on Retinal Pigment Epithelial Cybrid Cells In Vitro. Mol Neurobiol 2020; 57:1636-1655. [PMID: 31811564 PMCID: PMC7123578 DOI: 10.1007/s12035-019-01834-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 11/12/2019] [Indexed: 01/09/2023]
Abstract
Diabetic retinopathy (DR) is the most common cause of blindness for individuals under the age of 65. This loss of vision can be due to ischemia, neovascularization, and/or diabetic macular edema, which are caused by breakdown of the blood-retina barrier at the level of the retinal pigment epithelium (RPE) and inner retinal vasculature. The prevalence of diabetes and its complications differ between Caucasian-Americans and certain minority populations, such as African-Americans and Asian-Americans. Individuals can be classified by their mitochondrial haplogroups, which are collections of single nucleotide polymorphisms (SNPs) in mitochondrial DNA (mtDNA) representing ancient geographic origins of populations. In this study, we compared the responses of diabetic human RPE cybrids, cell lines containing identical nuclei but mitochondria from either European (maternal European) or maternal African or Asian individuals, to hypoxia and high glucose levels. The African and Asian diabetic ([Afr+Asi]/DM) cybrids showed (1) resistance to both hyperglycemic and hypoxic stresses; (2) downregulation of pro-apoptotic indicator BAX; (3) upregulation of DNA methylation genes, such as DNMT3A and DNMT3B; and (4) resistance to DNA demethylation by the methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-dC) compared to European diabetic (Euro/DM) cybrids. Our findings suggest that mitochondria from African and Asian diabetic subjects possess a "metabolic memory" that confers resistance against hyperglycemia, hypoxia, and demethylation, and that this "metabolic memory" can be transferred into the RPE cybrid cell lines in vitro.
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Affiliation(s)
- Andrew H Dolinko
- Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA, 92697, USA
- Department of Ophthalmology Research, Gavin Herbert Eye Institute, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Road, Irvine, CA, 92697, USA
| | - Marilyn Chwa
- Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA, 92697, USA
| | - Shari R Atilano
- Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA, 92697, USA
| | - M Cristina Kenney
- Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA, 92697, USA.
- Department of Ophthalmology Research, Gavin Herbert Eye Institute, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Road, Irvine, CA, 92697, USA.
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Incidence and treatment outcomes of secondary epiretinal membrane following intravitreal injection for diabetic macular edema. Sci Rep 2020; 10:528. [PMID: 31953511 PMCID: PMC6969073 DOI: 10.1038/s41598-020-57509-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 01/02/2020] [Indexed: 12/14/2022] Open
Abstract
The purpose of this study was to investigate the incidence of secondary epiretinal membrane (ERM) after intravitreal injection and the effect of ERM on visual acuity and central macular thickness (CMT) in patients with diabetic macular edema (DME). We included 147 eyes of 95 patients over 18 years old who were diagnosed with DME from 2012 to 2016, treated with intravitreal injection, and followed-up more than 24 months. Mean CMT in the ERM group was significantly thicker than in the non-ERM group after 9, 12, 18, and 24 months. Secondary ERM developed in 9.5% of patients during follow-up. Compared to other agents, the incidence of secondary ERM was significantly higher after intravitreal injection of dexamethasone implant. Among patients in the ERM group, the mean decrease of CMT between pre-injection and 2 weeks post-injection was significantly less after secondary ERM formation than before ERM formation. Secondary ERM formation was significantly associated with the number of intravitreal injections and the use of dexamethasone implant. Therefore, secondary ERM develops more frequently as the number of intravitreal injections increases and after intravitreal dexamethasone implant injection. The therapeutic effects of intravitreal injections for DME patients decrease after secondary ERM formation.
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Wei Q, Wan Z, Hu Y, Peng Q. Cytokine and Chemokine Profile Changes in Patients After Intravitreal Conbercept Injection for Diabetic Macular Edema. Drug Des Devel Ther 2019; 13:4367-4374. [PMID: 31920286 PMCID: PMC6935285 DOI: 10.2147/dddt.s222004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 12/05/2019] [Indexed: 11/23/2022] Open
Abstract
Purpose This study aimed to investigate the concentrations of cytokines and chemokines in diabetic macular edema (DME) eyes before and during therapy with the intravitreal injection of conbercept (IVC) and to identify associations with disease activity. Methods The Bio-Plex® 200 System and the Bio-PlexTM Human Cytokine Standard 27-Plex, Group I (Bio-Rad, Hercules, California, USA) were used to detect cytokine levels in aqueous humour. Experimental aqueous humour samples were collected from 18 patients with DME at the same time that IVC was performed at baseline and at 1 month. Control aqueous humour samples were collected from 16 patients undergoing cataract surgery. Results Significantly higher concentrations of vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), IL-8, eotaxin, granulocyte colony stimulating factor (G-CSF), interferon gamma-induced protein 10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1) were found in the aqueous humour of DME patients than cataract patients. One month after IVC, the intraocular concentrations of VEGF were significantly lower in the eyes of DME patients than at baseline. No other cytokines were significantly altered by conbercept therapy. Best-corrected visual acuity (BCVA) slightly improved following IVC compared with that at baseline, although this difference was not significant, and central macular thickness (CMT) significantly decreased 1 month after IVC treatment. Conclusion Angiogenic, inflammatory and growth factors are involved in the development of DME. With the exception of VEGF, IVC did not cause significant differences in any inflammatory cytokines or growth factors in DME patients. CMT is related to VEGF levels in aqueous humour.
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Affiliation(s)
- Qingquan Wei
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, People's Republic of China
| | - Zhongqi Wan
- School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu Province, People's Republic of China
| | - Yongcheng Hu
- Department of Ophthalmology, Bayannuer Paralympic Eye Hospital, Inner Mongolia 015000, People's Republic of China
| | - Qing Peng
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, People's Republic of China
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Allingham MJ, Mettu PS, Cousins SW. Aldosterone as a mediator of severity in retinal vascular disease: Evidence and potential mechanisms. Exp Eye Res 2019; 188:107788. [PMID: 31479654 PMCID: PMC6802292 DOI: 10.1016/j.exer.2019.107788] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 08/30/2019] [Indexed: 12/27/2022]
Abstract
Diabetic retinopathy (DR) and retinal vein occlusion (RVO) are the two most common retinal vascular diseases and are major causes of vision loss and blindness worldwide. Recent and ongoing development of medical therapies including anti-vascular endothelial growth factor and corticosteroid drugs for treatment of these diseases have greatly improved the care of afflicted patients. However, severe manifestations of retinal vascular disease result in persistent macular edema, progressive retinal ischemia and incomplete visual recovery. Additionally, choroidal vascular diseases including neovascular age-related macular degeneration (NVAMD) and central serous chorioretinopathy (CSCR) cause vision loss for which current treatments are incompletely effective in some cases and highly burdensome in others. In recent years, aldosterone has gained attention as a contributor to the various deleterious effects of retinal and choroidal vascular diseases via a variety of mechanisms in several retinal cell types. The following is a review of the role of aldosterone in retinal and choroidal vascular diseases as well as our current understanding of the mechanisms by which aldosterone mediates these effects.
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Affiliation(s)
- Michael J Allingham
- Department of Ophthalmology, Duke University Medical Center, Durham, NC, United States.
| | - Priyatham S Mettu
- Department of Ophthalmology, Duke University Medical Center, Durham, NC, United States
| | - Scott W Cousins
- Department of Ophthalmology, Duke University Medical Center, Durham, NC, United States
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Comet A, Gascon P, Sauvan L, Donnadieu B, Matonti F. INVICTUS: intravitreal anti-VEGF and dexamethasone implant comparison for the treatment of diabetic macular edema: a 6 months follow-up Study. Acta Ophthalmol 2019; 97:e937-e938. [PMID: 30741468 DOI: 10.1111/aos.14057] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Alban Comet
- Ophthalmology department Aix‐Marseille University Hôpital Nord Marseille France
| | - Pierre Gascon
- Ophthalmology department Aix‐Marseille University Hôpital Nord Marseille France
- Institut de Neurosciences de la Timone Aix‐Marseille University Marseille France
| | - Lauren Sauvan
- Ophthalmology department Aix‐Marseille University Hôpital Nord Marseille France
| | - Benjamin Donnadieu
- Ophthalmology department Aix‐Marseille University Hôpital Nord Marseille France
| | - Frédéric Matonti
- Ophthalmology department Aix‐Marseille University Hôpital Nord Marseille France
- Institut de Neurosciences de la Timone Aix‐Marseille University Marseille France
- Centre Paradis Monticelli Marseille France
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Lim SW, Bandala-Sanchez E, Kolic M, Rogers SL, McAuley AK, Lim LL, Wickremasinghe SS. The Influence of Intravitreal Ranibizumab on Inflammation-associated Cytokine Concentrations in Eyes With Diabetic Macular Edema. Invest Ophthalmol Vis Sci 2019; 59:5382-5390. [PMID: 30452591 DOI: 10.1167/iovs.17-23325] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose To evaluate the effect of intravitreal ranibizumab injections on aqueous concentrations of angiogenic or inflammatory cytokines in patients with diabetic macular edema (DME). Methods Thirty eyes of 25 patients with center-involved DME were recruited to the study. All had a central macular thickness (CMT) of >300 μm and best-corrected visual acuity (BCVA) between 28 and 70 logMAR letters (Snellen equivalent 20/320-20/40). At baseline, all eyes had 0.1 mL of aqueous collected before ranibizumab treatment. At week 4, a second ranibizumab injection was administered and at week 8, aqueous sampling was repeated before a third ranibizumab injection. From week 12, all eyes were followed at 4-weekly intervals and the need for ranibizumab treatment was determined by BCVA and CMT measurements. Levels of 32 cytokines were assessed at baseline and at week 8 using a multiplex array assay. Results Following two consecutive ranibizumab injections, there was a statistically significant reduction in VEGF (P < 0.00001), as well as IL-1β (P = 0.00006), IL-7 (P = 0.00002), IL-8 (P = 0.00023), IL-10 (P < 0.00001), IL-12 (P < 0.00001), IL-17 (P = 0.00024), MCP-1 (P = 0.00023), and TNF-α (P < 0.00001). There was also an upregulation of soluble VEGF receptor-2 (P = 0.00004). A P < 0.0015 was considered significant in this study. Conclusions Ranibizumab treatment influences various inflammatory cytokine concentrations in addition to reducing aqueous VEGF concentrations in patients with DME. This may contribute to its therapeutic effect in patients with DME.
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Affiliation(s)
- Shueh Wen Lim
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria, Australia
| | | | - Maria Kolic
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria, Australia
| | - Sophie L Rogers
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria, Australia
| | - Annie K McAuley
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria, Australia.,Department of Epidemiology and Preventative Medicine, Monash University, Australia
| | - Lyndell L Lim
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria, Australia
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Unfolded Protein Response Pathways Correlatively Modulate Endoplasmic Reticulum Stress Responses in Rat Retinal Müller Cells. J Ophthalmol 2019; 2019:9028483. [PMID: 30918720 PMCID: PMC6409019 DOI: 10.1155/2019/9028483] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 12/23/2018] [Accepted: 01/23/2019] [Indexed: 11/30/2022] Open
Abstract
Background Endoplasmic reticulum stress (ERS) in the retinal Müller cells is a key factor contributing to the retinal inflammation and vascular leakage in diabetic retinopathy (DR). This study was to investigate the underlying mechanisms through which the 3 main unfolded protein response (UPR) pathways regulate ERS and to examine the expression levels of vascular endothelial growth factor (VEGF) in Müller cells in vitro. Methods Rat Müller cell lines were stimulated with high glucose to mimic a diabetic environment in vitro. PKR-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) were downregulated or upregulated with shRNA or overexpression plasmids. The transfected Müller cells were cultivated in high glucose medium for 48 hours. Expression of glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), X-box binding protein 1 (XBP1), ATF6, and VEGF was examined with immunofluorescence and western blot. Results Our data indicated that ERS was found in both high glucose and osmotic control groups. Overexpression or downregulation of UPR pathways effectively increased or reduced the production of GRP78, ATF4, XBP1, ATF6, and VEGF, respectively. These 3 signaling pathways had similar regulatory effects on VEGF. Conclusion The 3 UPR-mediated inflammatory pathways were dependent on each other. Inhibition any of these signaling pathways in UPR might be a potential therapeutic target for DR.
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Teja S, Sawatzky L, Wiens T, Maberley D, Ma P. Ozurdex for refractory macular edema secondary to diabetes, vein occlusion, uveitis and pseudophakia. Can J Ophthalmol 2019; 54:540-547. [PMID: 31564342 DOI: 10.1016/j.jcjo.2018.12.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 12/14/2018] [Accepted: 12/17/2018] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To analyze the functional and morphological effects of the intravitreal dexamethasone implant (Ozurdex, Allergan) on patients with macular edema secondary to retinal vein occlusion (RVO), diabetic retinopathy (DME), posterior noninfectious uveitis (NIU), or pseudophakic Irvine-Gass syndrome (IGS). METHODS 144 charts were retrospectively reviewed; 100 eyes met inclusion criteria for analysis: at least one intravitreal dexamethasone implant injection, refractory to antivascular endothelial growth factor, and had ≥6 months of follow-up postinsertion. The primary outcome was the efficacy of the dexamethasone implant in reducing macular edema as measured by reduction in central retinal thickness (CRT). Secondary outcomes included visual acuity (VA), duration of treatment efficacy (measured by time to next treatment), and safety. The Wilcoxon signed-rank test was used to compare values from baseline, and Kaplan-Meier survival curves were used to analyze time to retreatment. RESULTS There were 28 patients with RVO, 30 with DME, 24 with posterior NIU, and 18 with IGS. VA improved from baseline to month 6 in all groups, but was not statistically significant. CRT improved in all 4 groups, and was statistically significant for DME (p = 0.008) and NIU (p = 0.05). At 3 months, 34 patients (41.5%) required retreatment; by month 6, 46 patients (56.1%) required retreatment. There was a large variation between the groups in number of patients requiring intraocular pressure (IOP)-lowering medications. Two patients needed IOP-lowering surgery. One patient developed endophthalmitis. CONCLUSION The use of intravitreal dexamethasone implants in patients with refractory retinal diseases is well tolerated and results in consistently improved anatomic outcomes, but the positive anatomic outcomes are not necessarily correlated to improvements in visual function. Patients who are treated earlier in the disease process will had better outcomes. This patient population were refractory to treatment and, therefore, have less-predictable functional outcomes.
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Affiliation(s)
- Salina Teja
- Department of Ophthalmology & Visual Sciences, University of British Columbia, Vancouver, B.C..
| | - Lauren Sawatzky
- Department of Ophthalmology & Visual Sciences, University of British Columbia, Vancouver, B.C
| | - Theresa Wiens
- Department of Ophthalmology & Visual Sciences, University of British Columbia, Vancouver, B.C
| | - David Maberley
- Department of Ophthalmology & Visual Sciences, University of British Columbia, Vancouver, B.C
| | - Patrick Ma
- Department of Ophthalmology & Visual Sciences, University of British Columbia, Vancouver, B.C
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Moulin TA, Adjei Boakye E, Wirth LS, Chen J, Burroughs TE, Vollman DE. Yearly Treatment Patterns for Patients with Recently Diagnosed Diabetic Macular Edema. Ophthalmol Retina 2018; 3:362-370. [PMID: 31014689 DOI: 10.1016/j.oret.2018.11.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 11/26/2018] [Accepted: 11/30/2018] [Indexed: 01/18/2023]
Abstract
PURPOSE To describe the treatment patterns and the predictors of different treatment standards in recently diagnosed diabetic macular edema (DME) patients in a nationally representative sample. DESIGN A retrospective cohort study using administrative claims data from January 1, 2007, through March 31, 2015. Patients were grouped into yearly cohorts. PARTICIPANTS A total of 96 316 patients were included. METHODS Patients with a diagnosis of DME were identified using International Classification of Diseases, Ninth Edition, Clinical Modification, codes. Predictors of anti-vascular endothelial growth factor (VEGF) use and number of anti-VEGF injections per patient were assessed using generalized linear regression (logistic and negative binomial, respectively), and yearly trends in different treatments were analyzed with Mann-Kendall tests. MAIN OUTCOME MEASURES Predictors of anti-VEGF treatment and of anti-VEGF injections per patient and the changes in relative use of DME therapies per cohort. RESULTS Among those with any treatment, the odds of being prescribed anti-VEGF therapy increased by 700% from 2009 to 2014 and by 154% for those seen by a retina specialist. Those in the cohort of year 2014 received 3.5 times more injections than those in 2009, whereas those covered by Managed Medicare, Medicaid, and Medicare received 31%, 24%, and 11% less injections. Anti-VEGF were 11.6% of all DME treatments in 2009 increasing to 61.9% in 2014, while corticosteroids and focal laser procedures dropped from 6.1% to 3% and 75% to 24%, respectively. Procedures per patient (PPP) were much lower than those observed in clinical trials of anti-VEGF. Procedures per patient increased in the cases of aflibercept (from 1 in 2011 to 2.20 in 2014), bevacizumab (from 1.84 in 2009 to 3.40 in 2014), and ranibizumab (from 3.11 in 2009 to 4.48 in 2014), whereas applications of laser procedures and corticosteroids per patient remained roughly stable. CONCLUSIONS Year of diagnosis and being seen by a retina specialist were important predictors of receiving anti-VEGF therapy, and after one received such therapy, the number of additional injections was smaller for those with government-provided insurance. Anti-VEGF therapy has become a mainstay in DME treatment, with PPP, although relatively low, also increasing.
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Affiliation(s)
- Thiago A Moulin
- Saint Louis University Center for Health Outcomes Research (SLUCOR), St. Louis, Missouri.
| | - Eric Adjei Boakye
- Department of Population Science and Policy, Southern Illinois University School of Medicine, Springfield, Illinois; Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, Illinois
| | - Lorinette S Wirth
- Saint Louis University Center for Health Outcomes Research (SLUCOR), St. Louis, Missouri
| | - Jiajing Chen
- Saint Louis University Center for Health Outcomes Research (SLUCOR), St. Louis, Missouri
| | - Thomas E Burroughs
- Saint Louis University Center for Health Outcomes Research (SLUCOR), St. Louis, Missouri
| | - David E Vollman
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri
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Ghoraba HH, Leila M, Elgouhary SM, Elgemai EEM, Abdelfattah HM, Ghoraba HH, Heikal MA. Safety of high-dose intravitreal triamcinolone acetonide as low-cost alternative to anti-vascular endothelial growth factor agents in lower-middle-income countries. Clin Ophthalmol 2018; 12:2383-2391. [PMID: 30538421 PMCID: PMC6263217 DOI: 10.2147/opth.s185274] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Purpose The purpose of this study was to evaluate the safety of high-dose intravitreal triamcinolone acetonide (IVTA) as affordable low-cost alternative to anti-vascular endothelial growth factor (anti-vascular endothelial growth factor [anti-VEGF] agents) in lower-middle-income countries. Patients and methods This was a retrospective interventional non-comparative case series. The study recruited patients who received 20 mg IVTA for treating various retinal and optic nerve diseases over the past 5 years. Main outcome measure was assessment of complications secondary to high-dose IVTA. The crosstabs procedure was used to display the interaction between the variables tested. The ANOVA test was used to analyze the differences among group means. Results The study included 207 eyes of 168 patients. The main indication for high-dose IVTA were diabetic macular edema 64%, and macular edema secondary to retinal vein occlusion 19%. The mean follow-up period post-injection was 22 months. Mean number of injections was 1.3. Cataract developed in 54% of eyes. Glaucoma developed in 18.5% of eyes. Glaucoma surgery for intractable glaucoma attributed to high-dose IVTA was needed in 1% of eyes. Endophthalmitis and retinal detachment developed in one patient each. Conclusion High-dose IVTA is a safe and cost-effective alternative to anti-VEGF agents. Cataract formation and intraocular pressure rise do not pose major adverse effects when weighed against the risk of vision loss due to inability to afford anti-VEGF treatment.
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Affiliation(s)
- Hammouda Hamdy Ghoraba
- Department of Ophthalmology, Faculty of Medicine, Tanta University, Tanta, Egypt.,Department of Retina, Magrabi Eye Hospital, Tanta, Egypt
| | - Mahmoud Leila
- Retina Department, Research Institute of Ophthalmology, Giza, Egypt,
| | | | - Emad Eldin Mohamed Elgemai
- Department of Retina, Magrabi Eye Hospital, Tanta, Egypt.,Department of Ophthalmology, Damanhour Teaching Hospital, Damanhour, Egypt
| | - Haithem Mamon Abdelfattah
- Department of Retina, Magrabi Eye Hospital, Tanta, Egypt.,Department of Ophthalmology, Banha Teaching Hospital, Banha, Egypt
| | | | - Mohamed Amin Heikal
- Department of Ophthalmology, Faculty of Medicine, Benha University, Benha, Egypt
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Dexamethasone implant as an adjuvant therapy to ranibizumab loading dose in persistent diabetic macular edema. Int Ophthalmol 2018; 39:2179-2185. [PMID: 30470985 DOI: 10.1007/s10792-018-1053-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 11/17/2018] [Indexed: 10/27/2022]
Abstract
PURPOSE This study evaluates the effectiveness of a single-dose dexamethasone implant (DI) as an auxiliary therapy to continued intravitreal ranibizumab (IVR) treatment in patients with persistent diabetic macular edema (DME). METHODS Twenty-five pseudophakic eyes of 25 patients with DME who underwent a single injection of DI as an adjuvant therapy following an IVR loading dose were examined retrospectively. All patients were treatment naive and had a poor response to a loading dose of three consecutive monthly IVR injections. IVR treatments were continued pro re nata after the DI. The main outcome measures were changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT) at 1, 3, 6 and 8 months post-DI treatment. RESULTS After the IVR loading dose, the mean BCVA and CMT were 0.9 ± 0.6 LogMAR and 478.2 ± 107.8 µm, respectively. One month after the DI, the mean BCVA and CMT had improved to 0.6 ± 0.4 LogMAR (p = 0.005) and 313.8 ± 62.7 µm (p < 0.001), respectively. This improvement was maintained with mean 0.8 ± 0.8 IVR injections throughout the follow-up period. The final mean BCVA and CMT were 0.5 ± 0.5 LogMAR and 298.4 ± 71.5 µm. Subgroup analyses revealed that different DME types did not have any effect on CMT or BCVA improvement (p = 0.188, p = 0.136; respectively). CONCLUSION Adding DI results in rapid anatomical and visual improvement in patients who respond poorly to an IVR loading dose. Improvements may be maintained with additional IVR in follow-up.
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The potent small molecule integrin antagonist THR-687 is a promising next-generation therapy for retinal vascular disorders. Exp Eye Res 2018; 180:43-52. [PMID: 30472075 DOI: 10.1016/j.exer.2018.11.022] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 11/09/2018] [Accepted: 11/21/2018] [Indexed: 11/22/2022]
Abstract
Integrins are associated with various eye diseases such as diabetic retinopathy (DR) and wet age-related macular degeneration (AMD) and implicated in main pathologic disease hallmarks like neovascularization, inflammation, fibrosis and vascular leakage. Targeting integrins has the potential to attenuate these vision-threatening processes, independent of anti-vascular endothelial growth factor (VEGF) responsiveness. The current investigation characterized THR-687 as a novel pan RGD (arginylglycylaspartic acid) integrin receptor antagonist able to compete for binding with the natural ligand with nanomolar potency (e.g. αvβ3 (IC50 of 4.4 ± 2.7 nM), αvβ5 (IC50 of 1.3 ± 0.5 nM) and α5β1 (IC50 of 6.8 ± 3.2 nM)). THR-687 prevented the migration of human umbilical vein endothelial cells (HUVECs) into a cell-free area (IC50 of 258 ± 113 nM) as well as vessel sprouting in an ex vivo mouse choroidal explant model (IC50 of 236 ± 173 nM), and was able to induce the regression of pre-existing vascular sprouts. Moreover, combined intravitreal and intraperitoneal administration of THR-687 potently inhibited VEGF-induced leakage in the mouse retina. In addition, THR-687 injected intravitreally at 3 different dose levels (0.45 mg, 2.25 mg or 4.5 mg/eye) potently inhibited neovascularization-induced leakage in the cynomolgus laser-induced choroidal neovascularization (CNV) model. These data suggest that THR-687 is a promising drug candidate for the treatment of vision-threatening retinal vascular eye diseases such as DR and wet AMD.
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Değirmenci MFK, Demirel S, Batıoğlu F, Özmert E. Short-term Efficacy of Micropulse Yellow Laser in Non-center-involving Diabetic Macular Edema: Preliminary Results. Turk J Ophthalmol 2018; 48:245-249. [PMID: 30405946 PMCID: PMC6216533 DOI: 10.4274/tjo.04657] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 03/30/2018] [Indexed: 12/01/2022] Open
Abstract
Objectives: The aim of this study was to evaluate the efficacy of micropulse yellow laser (MPL) on best corrected visual acuity (BCVA) and retinal thickness in patients with non-center-involving diabetic macular edema (DME). Materials and Methods: We retrospectively reviewed 9 eyes of 8 patients with non-center-involving DME who underwent MPL treatment between January 2015 and December 2016. BCVA (logMAR) and retinal thickness were evaluated before and 3 months after treatment. Maximum retinal thickness was determined manually from simultaneous spectral-domain optical coherence tomography images and recorded. The change in the measurements from before to after treatment was analyzed statistically. Results: Of the 8 patients, 3 were female and 5 were male. The mean age was 52.8 years. Two of the 9 eyes had received previous intravitreal anti-vascular endothelial growth factor injection(s). Median BCVA was improved 3 months after treatment, although the difference was not statistically significant (0.34 logMAR before and 0.29 logMAR after treatment). BCVA was improved in 4 eyes while it showed no change in the remaining 5 eyes. The mean retinal thickness was 470.6 μm at baseline and 416 μm at 3 months after MPL treatment (p=0.01). Retinal thickness decreased in all eyes after treatment. Conclusion: In this study, parafoveal retinal thickness showed significant decrease after MPL treatment in patients with DME. The limited increase in BCVA may be due to the inclusion of a low number of patients and only those with non-center-involving macular edema. MPL may be used as an alternative to conventional argon laser in non-center-involving DME.
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Affiliation(s)
| | - Sibel Demirel
- Ankara University Faculty of Medicine, Department of Ophthalmology, Ankara, Turkey
| | - Figen Batıoğlu
- Ankara University Faculty of Medicine, Department of Ophthalmology, Ankara, Turkey
| | - Emin Özmert
- Ankara University Faculty of Medicine, Department of Ophthalmology, Ankara, Turkey
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The role of placental growth factor (PlGF) and its receptor system in retinal vascular diseases. Prog Retin Eye Res 2018; 69:116-136. [PMID: 30385175 DOI: 10.1016/j.preteyeres.2018.10.006] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 10/23/2018] [Accepted: 10/26/2018] [Indexed: 12/20/2022]
Abstract
Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family. Upon binding to VEGF- and neuropilin-receptor sub-types, PlGF modulates a range of neural, glial and vascular cell responses that are distinct from VEGF-A. As PlGF expression is selectively associated with pathological angiogenesis and inflammation, its blockade does not affect the healthy vasculature. PlGF actions have been extensively described in tumor biology but more recently there has been accumulating preclinical evidence that indicates that this growth factor could have an important role in retinal diseases. High levels of PlGF have been found in aqueous humor, vitreous and/or retina of patients exhibiting retinopathies, especially those with diabetic retinopathy (DR) and neovascular age-related macular degeneration (nvAMD). Expression of this growth factor seems to correlate closely with many of the key pathogenic features of early and late retinopathy in preclinical models. For example, studies using genetic modification and/or pharmacological treatment to block PlGF in the laser-induced choroidal neovascularization (CNV) model, oxygen-induced retinopathy model, as well as various murine diabetic models, have shown that PlGF deletion or inhibition can reduce neovascularization, retinal leakage, inflammation and gliosis, without affecting vascular development or inducing neuronal degeneration. Moreover, an inhibitory effect of PlGF blockade on retinal scarring in the mouse CNV model has also been recently demonstrated and was found to be unique for PlGF inhibition, as compared to various VEGF inhibition strategies. Together, these preclinical results suggest that anti-PlGF therapy might have advantages over anti-VEGF treatment, and that it may have clinical applications as a standalone treatment or in combination with anti-VEGF. Additional clinical studies are clearly needed to further elucidate the role of PlGF and its potential as a therapeutic target in ocular diseases.
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