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Anti-vascular endothelial growth factor therapy for diabetic macular edema.

ABSTRACT: Diabetes mellitus is a serious health problem that affects over 350 million individuals worldwide. Diabetic retinopathy (DR), which is the most common microvascular complication of diabetes, is the leading cause of new cases of blindness in working-aged adults. Diabetic macular edema (DME) is an advanced, vision-limiting complication of DR that affects nearly 30% of patients who have had diabetes for at least 20 years and is responsible for much of the vision loss due to DR. The historic standard of care for DME has been macular laser photocoagulation, which has been shown to stabilize vision and reduce the rate of further vision loss by 50%; however, macular laser leads to significant vision recovery in only 15% of treated patients. Mechanisms contributing to the microvascular damage in DR and DME include the direct toxic effects of hyperglycemia, sustained alterations in cell signaling pathways, and chronic microvascular inflammation with leukocyte-mediated injury. Chronic retinal microvascular damage results in elevation of intraocular levels of vascular endothelial growth factor A (VEGF), a potent, diffusible, endothelial-specific mitogen that mediates many important physiologic processes, including but not limited to the development and permeability of the vasculature. The identification of VEGF as an important pathophysiologic mediator of DME suggested that anti-VEGF therapy delivered to the eye might lead to improved visual outcomes in this disease. To date, four different inhibitors of VEGF, each administered by intraocular injection, have been tested in prospective, randomized phase II or phase III clinical trials in patients with DME. The results from these trials demonstrate that treatment with anti-VEGF agents results in substantially improved visual and anatomic outcomes compared with laser photocoagulation, and avoid the ocular side effects associated with laser treatment. Thus, anti-VEGF therapy has become the preferred treatment option for the management of DME in many patients.

SUBMITTER: Boyer DS

PROVIDER: S-EPMC3855829 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Anti-vascular endothelial growth factor therapy for diabetic macular edema.

Boyer David S DS Hopkins J Jill JJ Sorof Jonathan J Ehrlich Jason S JS

Therapeutic advances in endocrinology and metabolism 20131201 6

Diabetes mellitus is a serious health problem that affects over 350 million individuals worldwide. Diabetic retinopathy (DR), which is the most common microvascular complication of diabetes, is the leading cause of new cases of blindness in working-aged adults. Diabetic macular edema (DME) is an advanced, vision-limiting complication of DR that affects nearly 30% of patients who have had diabetes for at least 20 years and is responsible for much of the vision loss due to DR. The historic standar ...[more]

PMID: 24324855

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Project description:PURPOSE:To assess systemic vascular endothelial growth factor (VEGF)-A levels after treatment with intravitreous aflibercept, bevacizumab, or ranibizumab. DESIGN:Comparative-effectiveness trial with participants randomly assigned to 2 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab after a re-treatment algorithm. PARTICIPANTS:Participants with available plasma samples (N = 436). METHODS:Plasma samples were collected before injections at baseline and 4-week, 52-week, and 104-week visits. In a preplanned secondary analysis, systemic-free VEGF levels from an enzyme-linked immunosorbent assay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES:Changes in the natural log (ln) of plasma VEGF levels. RESULTS:Baseline free VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were -0.30±0.61 pg/ml, -0.31±0.54 pg/ml, and -0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted confidence interval [CI]; P value) were -0.01 (-0.12 to +0.10; P = 0.89), -0.31 (-0.44 to -0.18; P < 0.001), and -0.30 (-0.43 to -0.18; P < 0.001) for aflibercept-bevacizumab, aflibercept-ranibizumab, and bevacizumab-ranibizumab, respectively. At 52 weeks, a difference in mean VEGF changes between bevacizumab and ranibizumab persisted (-0.23 [-0.38 to -0.09]; P < 0.001); the difference between aflibercept and ranibizumab was -0.12 (P = 0.07) and between aflibercept and bevacizumab was +0.11 (P = 0.07). Treatment group differences at 2 years were similar to 1 year. No apparent treatment differences were detected at 52 or 104 weeks in the cohort of participants not receiving injections within 1 or 2 months before plasma collection. Participants with (N = 9) and without (N = 251) a heart attack or stroke had VEGF levels that appeared similar. CONCLUSIONS:These data suggest that decreases in plasma free-VEGF levels are greater after treatment with aflibercept or bevacizumab compared with ranibizumab at 4 weeks. At 52 and 104 weeks, a greater decrease was observed in bevacizumab versus ranibizumab. Results from 2 subgroups of participants who did not receive injections within at least 1 month and 2 months before collection suggest similar changes in VEGF levels after stopping injections. It is unknown whether VEGF levels return to normal as the drug is cleared from the system or whether the presence of the drug affects the assay's ability to accurately measure free VEGF. No significant associations between VEGF concentration and systemic factors were noted.

Project description:Background: Antiangiogenic therapy with anti-vascular endothelial growth factor (VEGF) is commonly used to treat diabetic macular edema (DME), which can reduce edema, improve vision, and prevent further visual loss. There is little head-to-head trial data to guide the selection of an individual VEGF inhibitor. Therefore, we aimed to investigate the efficacy and safety of anti-VEGF for patients with DME and to assess the differences between clinically relevant options by using network meta-analysis (NMA). Methods: MEDLINE, Embase, the Cochrane Library, Web of Science, Chinese Biomedical Literature Database, Wanfang, China National Knowledge Infrastructure, and VIP databases were searched for published randomized controlled trials (RCTs) from their inception to November 2020. We included RCTs of anti-VEGF drugs (intravitreal aflibercept (IVT-AFL), intravitreal ranibizumab (IVR), and intravitreal conbercept (IVC)) treating adult patients who were diagnosed with DME, regardless of stage or duration of the disease. We estimated summary odds ratios (ORs) and mean differences (MDs) with 95% credible intervals (CrIs) using a Bayesian NMA. This study's registration number is CRD42021259335. Results: We identified 43 RCTs comprising 8,234 patients. Beneficial effects were observed in patients who used IVT-AFL compared with those who used other anti-VEGF therapies at 1-year follow-up on corrected visual acuity (BCVA) improvements (all patients: versus IVR: MD 2.83, 95% CrIs 1.64, 4.01, versus IVC: MD 2.41, 95% CrIs -0.52, 5.32; patients with worse baseline visual acuity (VA): versus IVR: MD 3.39, 95% CrIs 1.89, 4.9, versus IVC: MD 3.49, 95% CrIs 0.49, 6.44) and the proportion of patients with a gain of at least 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (all patients: versus IVR: OR 1.55, 95% CrIs 1.11, 2.17, versus IVC: OR 2.78, 95% CrIs 1.23, 6.04; patients with worse baseline VA: versus IVR: OR 2.05, 95% CrIs 1.18, 3.58, versus IVC: OR 2.85, 95% CrIs 1.24, 6.41). The effect of improvement in BCVA was identified for IVT-AFL compared to intravitreal bevacizumab. Based on the surface under the cumulative ranking curve (SUCRA), IVT-AFL had the highest probability of being the most effective option (99.9% and 99.5% in terms of the two primary outcomes, respectively). At the 2-year follow-up, numerical differences were identified favoring IVT-AFL; however, they did not reach statistical significance when comparing IVT-AFL to IVR. In the analysis of adverse events, IVT-AFL showed a lower risk of incidence of ocular adverse events compared to other anti-VEGF therapies at 1-year follow-up (versus IVR: OR 0.45, 95% CrIs 0.28, 0.7; versus IVC: OR 0.36, 95% CrIs 0.21, 0.63). Conclusion: IVT-AFL resulted in greater beneficial effects on BCVA and a higher proportion of patients with a gain of at least 15 ETDRS letters compared to IVR or IVC one year after treatment (especially in DME patients with worse baseline VA). In addition, fewer ocular adverse events occurred in the IVT-AFL group compared to the IVR or IVC groups. After two years, there was insufficient evidence to identify which anti-VEGF has superior efficacy or safety. Clinical Trial Registration: https://www.crd.york.ac.uk/prospero/, PROSPERO; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021259335, CRD42021259335.

Project description:BackgroundCentral retinal vein occlusion (CRVO) is a common retinal vascular disorder in which macular edema (ME) may develop, with a consequent reduction in visual acuity. The visual prognosis in CRVO-ME is poor in a substantial proportion of patients, especially those with the ischemic subtype, and until recently there has been no treatment of proven benefit. Macular grid laser treatment is ineffective, and whilst a few recent randomized controlled trials (RCTs) suggest short-term gains in visual acuity with intravitreal steroids for patients with non-ischemic CRVO-ME, there is no established treatment for ischemic CRVO-ME. Anti-vascular endothelial growth factor (anti-VEGF) agents have been used to treat ME resulting from a variety of causes and may represent a treatment option for CRVO-ME.ObjectivesTo investigate the effectiveness and safety of intravitreal anti-VEGF agents in the treatment of CRVO-ME.Search strategyWe searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2010, Issue 8), MEDLINE (January 1950 to August 2010), EMBASE (January 1980 to August 2010), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to August 2010), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (January 1937 to August 2010), OpenSIGLE (January 1950 to August 2010), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) and ClinicalTrials.gov (www.clinicaltrials.gov). There were no language or date restrictions in the search for trials. The electronic databases were last searched on 10 August 2010.Selection criteriaWe considered RCTs that compared intravitreal anti-VEGF agents of any dose or duration to sham injection or no treatment. We focused on studies that included individuals of any age or gender with unilateral or bilateral disease and a minimum of six months follow up. Secondarily, we considered non-randomized studies with the same criteria, but did not conduct a separate electronic search for these.Data collection and analysisTwo review authors independently assessed trial quality and extracted data.Main resultsWe found two RCTs that met the inclusion criteria after independent and duplicate review of the search results. These RCTs utilized different anti-VEGF agents which cannot be assumed to be directly comparable. We, therefore, performed no meta-analysis. Evidence from these trials and from other non-randomized case series is summarized in this review.Authors' conclusionsRanibizumab and pegaptanib sodium have shown promise in the short-term treatment of non-ischemic CRVO-ME. However, effectiveness and safety data from larger RCTs with follow up beyond six months are not yet available. There are no RCT data on anti-VEGF agents in ischemic CRVO-ME. The use of anti-VEGF agents to treat this condition therefore remains experimental.

Project description:BackgroundIntravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are the standard of care for diabetic macular edema (DME), a common complication of diabetes. This study aimed to identify factors influencing DME intravitreal anti-VEGF treatment outcomes in real-world practice.MethodsThis was a multi-center retrospective observational study using medical chart review of participants receiving anti-VEGF injections for DME (N = 248). Demographic and clinical variables were assessed for association with best corrected visual acuity (BCVA) and central macular thickness (CMT) outcomes using regression models.ResultsThere was a significant improvement in BCVA (p < 0.001) and CMT (p < 0.001) after 12 months of treatment, although 21% of participants had decreased BCVA, and 41% had a < 10% CMT reduction at 12 months. Higher baseline BCVA (p = 0.022, OR=-0.024, 95% CI=-0.046,-0.004) and longer duration of diabetic retinopathy (p = 0.048, OR=-0.064, 95% CI=-0.129,-0.001) were negative predictors for BCVA response, whereas Aflibercept treatment (p = 0.017, OR = 1.107, 95% CI = 0.220,2.051) compared with other drugs and a positive "early functional response" (p < 0.001, OR=-1.393, 95% CI=-1.946,-0.857) were positive predictors. A higher baseline CMT (p < 0.001, OR = 0.019, 95% CI = 0.012,0.0261) and an "early anatomical response", (p < 0.001, OR=-1.677, 95% CI=-2.456, -0.943) were predictors for greater reduction in CMT. Overall, the variables could predict only 23% of BCVA and 52% of CMT response.ConclusionsThe study shows a significant proportion of DME patients do not respond to anti-VEGF therapy and identifies several clinical predictors for treatment outcomes.Trial registrationThe study was approved through the Human Research Ethics Committee, University of Tasmania (approval number H0012902), and the Southern Adelaide Clinical Human Research Ethics Committee (approval number 86 - 067).

Dataset Information

Anti-vascular endothelial growth factor therapy for diabetic macular edema.

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Anti-vascular endothelial growth factor therapy for diabetic macular edema.

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