Identifying Genetic Risk Factors for Diabetic Macular Edema and the Response to Treatment.
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ABSTRACT:
SUBMITTER: Gurung RL
PROVIDER: S-EPMC7683113 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Identifying Genetic Risk Factors for Diabetic Macular Edema and the Response to Treatment.
Gurung Rajya L RL FitzGerald Liesel M LM McComish Bennet J BJ Verma Nitin N Burdon Kathryn P KP
Journal of diabetes research 20201112
Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus (DM). DR is complex and the term encompasses several clinical subtypes of diabetic eye disease, including diabetic macular edema (DME), the most frequent cause of central vision loss in DR patients. Both genetic and environmental factors contribute to the pathophysiology of DR and its subtypes. While numerous studies have identified several susceptibility genes for DR, few have investigated the impact of ...[more]
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Project description:PurposeThe Diabetic Macular Edema Treated with Ozurdex (DMEO) Trial measured aqueous pro-permeability factors (PPFs) in diabetic macular edema (DME) patients before and after injection of dexamethasone implant or vascular endothelial growth factor (VEGF)-neutralizing protein and correlated changes in levels with changes in excess foveal thickness (EFT) to identify potential PPFs contributing to DME.DesignProspective, randomized crossover clinical trial.MethodsTwenty DME patients randomized to dexamethasone implant or VEGF-neutralizing protein had aqueous taps and spectral-domain optical coherence tomography (SDOCT) at baseline and every 4 weeks for 28 weeks. Aqueous levels of 55 vasoactive proteins were measured with protein array. Crossover at week 16 provided changes in protein levels after each intervention in all 20 patients.ResultsAfter dexamethasone implant there was significant correlation between changes in levels of 13 vasoactive proteins with changes in EFT, including 3 known PPFs: angiopoietin-2 (r = 0.40, P = .001), hepatocyte growth factor (HGF; r = 0.31, P = .02), and endocrine gland-VEGF (EG-VEGF, r = 0.43, P < .001). Reduction of prolactin, insulin-like growth factor binding protein-3, and matrix metalloproteinase-9 correlated with edema reduction after injection of a VEGF-neutralizing protein as well as dexamethasone implant, suggesting their modulation is likely secondary to changes in edema rather than causative.ConclusionsCorrelation of edema reduction with reduction in the PPFs angiopoietin-2, HGF, and EG-VEGF provides potential insight into the multifactorial molecular mechanism by which dexamethasone implants reduce edema and suggest that additional study is needed to investigate the contributions of these 3 factors to chronic DME.
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Project description:Diabetic macular edema is the most common cause of visual impairment in patients with diabetes mellitus. The pathogenesis of macular edema is complex and multifactorial. For many years, laser photocoagulation has been considered the standard therapy for the treatment of diabetic macular edema; however, few patients achieve significant improvements in visual acuity. Today the intravitreal administration of anti-inflammatory or anti-angiogenic agents together with the use of laser photocoagulation represents the standard of care for the treatment of this complication. The intravitreal route of administration minimizes the systemic side effects of corticosteroids. Steroid-related ocular side effects are elevated intraocular pressure and cataract, while injection-related complications include endophthalmitis, vitreous hemorrhage, and retinal detachment. In order to reduce the risks and complications, intravitreal implants have been developed recently to provide sustained release of corticosteroids and reduce repeated injections for the management of diabetic macular edema. In this review, the efficacy, safety, and therapeutic potential of intravitreal corticosteroids in diabetic macular edema are discussed with a review of recent literature.
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Project description:BackgroundMacular edema is the most common cause of vision loss among patients with diabetes.ObjectiveTo determine the cost-effectiveness of different treatments of diabetic macular edema (DME).DesignMarkov model.Data sourcesPublished literature and expert opinion.Target populationPatients with clinically significant DME.Time horizonLifetime.PerspectiveSocietal.InterventionLaser treatment, intraocular injections of triamcinolone or a vascular endothelial growth factor (VEGF) inhibitor, or a combination of both.Outcome measuresDiscounted costs, gains in quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs).Results of base-case analysisAll treatments except laser monotherapy substantially reduced costs, and all treatments except triamcinolone monotherapy increased QALYs. Laser treatment plus a VEGF inhibitor achieved the greatest benefit, gaining 0.56 QALYs at a cost of $6975 for an ICER of $12 410 per QALY compared with laser treatment plus triamcinolone. Monotherapy with a VEGF inhibitor achieved similar outcomes to combination therapy with laser treatment plus a VEGF inhibitor. Laser monotherapy and triamcinolone monotherapy were less effective and more costly than combination therapy.Results of sensitivity analysisVEGF inhibitor monotherapy was sometimes preferred over laser treatment plus a VEGF inhibitor, depending on the reduction in quality of life with loss of visual acuity. When the VEGF inhibitor bevacizumab was as effective as ranibizumab, it was preferable because of its lower cost.LimitationLong-term outcome data for treated and untreated diseases are limited.ConclusionThe most effective treatment of DME is VEGF inhibitor injections with or without laser treatment. This therapy compares favorably with cost-effective interventions for other conditions.Primary funding sourceAgency for Healthcare Research and Quality.
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Project description:PurposeTo assess how patient choices (out-of-pocket costs, insurance plan, geographic region) impact initiation of therapy for diabetic macular edema (DME).DesignRetrospective cohort study using administrative medical claims data from a large, national insurer.ParticipantsAll patients newly diagnosed with DME from 2013 through 2016 were observed for 90 days after diagnosis or until first treatment was received.MethodsMultivariate logistic regression was used to create odds ratios comparing different baseline demographic and patient-related factors.Main outcome measuresThe primary outcome was the odds of receiving the different possible initial treatments for DME (anti-vascular endothelial growth factor [VEGF], focal laser treatment, steroids, or observation), no treatment, and not following up.ResultsOf the 6220 newly diagnosed DME patients, 3010 (48.4%) underwent a follow-up examination within 90 days of diagnosis, and of those, 1453 patients (48.3%) received treatment in the observation window, including 614 (20.4%) with bevacizumab, 191 (6.3%) with ranibizumab or aflibercept, 560 (18.6%) with focal laser, 38 (1.3%) with steroid injection, and 50 (1.7%) with an injection of an unspecified drug. Having a copay (vs. $0) lowered the odds of receiving any treatment (odds ratio [OR] = 0.60; 95% confidence interval [CI], 0.51-0.71; P < 0.001) and of receiving each treatment individually (anti-VEGF treatment: OR = 0.72; 95% CI, 0.59-0.88; bevacizumab: OR = 0.73; 95% CI, 0.59-0.91; ranibizumab or aflibercept: OR, 0.70; 95% CI, 0.49-0.99; focal laser: OR = 0.44; 95% CI, 0.35-0.55; P < 0.001). Contrary to having a copay, having a high deductible and type of insurance plan were not associated with initiating treatment (P > 0.41 for all comparisons). Patients in the Northeast showed lower odds of initiating anti-VEGF treatment (OR = 0.60; 95%CI, 0.44-0.82; P < 0.001) and specifically bevacizumab (OR = 0.47; 95% CI, 0.33-0.67; P < 0.001). Furthermore, Northeast patients who were treated with anti-VEGF showed a higher odds of receiving ranibizumab or aflibercept compared with bevacizumab (OR = 2.39; 95% CI, 1.31-4.37; P < 0.001). Southern Midwest patients showed a higher odds of treatment (anti-VEGF: OR = 1.35; 95%CI, 1.02-1.77; P < 0.001; bevacizumab: OR = 1.40; 95% CI, 1.04-1.87; focal laser: OR = 1.39; 95% CI, 1.01-1.89; P < 0.001).ConclusionsPatient choices such as copays and where they live are important factors in determining the initial choice of treatment for DME.
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Project description:The prevalence of persistent diabetic macular edema (DME) after months of anti-vascular endothelial growth factor therapy and its effect on visual acuity are unknown.To assess subsequent outcomes of eyes with DME persisting for 24 weeks after initiating treatment with 0.5 mg of ranibizumab.We performed post hoc, exploratory analyses of a randomized clinical trial from March 20, 2007, through January 29, 2014, from 117 of 296 eyes (39.5%) randomly assigned to receive ranibizumab with persistent DME (central subfield thickness ?250 ?m on time domain optical coherence tomography) through the 24-week visit.Four monthly intravitreous injections of ranibizumab and then as needed per protocol.Cumulative 3-year probabilities of chronic persistent DME (failure to achieve a central subfield thickness <250 ?m and at least a 10% reduction from the 24-week visit on at least 2 consecutive study visits) determined by life-table analyses, and at least 10 letter (?2 line) gain or loss of visual acuity among those eyes.The probability of chronic persistent DME among eyes with persistent DME at the 24-week visit decreased from 100% at the 32-week visit to 81.1% (99% CI, 69.6%-88.6%), 55.8% (99% CI, 42.9%-66.9%), and 40.1% (99% CI, 27.4%-52.4%) at the 1-, 2-, and 3-year visits, respectively. At 3 years, visual acuity improved in eyes with and without chronic persistent DME through the follow-up period, respectively, by a mean of 7 letters and 13 letters from baseline. Among 40 eyes with chronic persistent edema through 3 years, 17 (42.5%) (99% CI, 23.1%-63.7%) gained 10 letters or more from baseline, whereas 5 (12.5%) (99% CI, 2.8%-31.5%) lost 10 letters or more from baseline.These data suggest less than half of eyes treated for DME with intravitreous ranibizumab have persistent central-involved DME through 24 weeks after initiating treatment. Among the 40% that then have chronic persistent central-involved DME through 3 years, longer-term visual acuity outcomes appear to be slightly worse than in the 60% in which DME does not persist. Nevertheless, when following the treatment protocol used in this trial among eyes with vision impairment from DME, long-term improvement in visual acuity from baseline is typical and substantial (?2-line) loss of visual acuity is likely uncommon through 3 years, even when central-involved DME chronically persists.
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Project description:Diabetic macular edema (DME) resembles a chronic, low-grade inflammatory reaction, and is characterized by blood-retinal barrier (BRB) breakdown and retinal capillary leakage. Corticosteroids are of therapeutic benefit because of their anti-inflammatory, antiangiogenic, and BRB-stabilizing properties. Delivery modes include periocular and intravitreal (via pars plana) injection. To offset the short intravitreal half-life of corticosteroid solutions (~3 hours) and the need for frequent intravitreal injections, sustained-release intravitreal corticosteroid implants have been developed. Dexamethasone intravitreal implant provides retinal drug delivery for ?6 months and recently has been approved for use in the treatment of DME. Pooled findings (n=1,048) from two large-scale, randomized Phase III trials indicated that dexamethasone intravitreal implant (0.35 mg and 0.7 mg) administered at ?6-month intervals produced sustained improvements in best-corrected visual acuity (BCVA) and macular edema. Significantly more patients showed a ?15-letter gain in BCVA at 3 years with dexamethasone intravitreal implant 0.35 mg and 0.7 mg than with sham injection (18.4% and 22.2% vs 12.0%). Anatomical assessments showed rapid and sustained reductions in macular edema and slowing of retinopathy progression. Phase II study findings suggest that dexamethasone intravitreal implant is effective in focal, cystoid, and diffuse DME, in vitrectomized eyes, and in combination with laser therapy. Ocular complications of dexamethasone intravitreal implant in Phase III trials included cataract-related events (66.0% in phakic patients), intraocular pressure elevation ?25 mmHg (29.7%), conjunctival hemorrhage (23.5%), vitreous hemorrhage (10.0%), macular fibrosis (8.3%), conjunctival hyperemia (7.2%), eye pain (6.1%), vitreous detachment (5.8%), and dry eye (5.8%); injection-related complications (eg, retinal tear/detachment, vitreous loss, endophthalmitis) were infrequent (<2%). Dexamethasone intravitreal implant offers a viable treatment option for DME, especially in cases that are persistent or treatment (anti-vascular endothelial growth factor/laser) refractory.
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