Effects of Topically Administered Neuroprotective Drugs in Early Stages of Diabetic Retinopathy: Results of the EUROCONDOR Clinical Trial

Simó, Rafael; Hernández, Cristina; Porta, Massimo; Bandello, Francesco; Grauslund, Jakob; Harding, Simon; Aldington, S J; Egan, Catherine; Frydkjær-Olsen, Ulrik; García‐Arumí, José; Gibson, Jonathan; Lang, Gabriele E.; Lattanzio, Rosangela; Massin, Pascale; Midena, Edoardo; Ponsati, Berta; Ribeiro, Maria Luísa; Scanlon, Peter H; Lobo, Conceição; Costa, Miguel; Cunha-Vaz, Josè

doi:10.2337/db18-0682

Cited by 79 publications

(74 citation statements)

References 25 publications

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“…Furthermore, imbalance in levels of native neuroprotective factors in the retina such as somatostatin, insulin, PEDF, and ciliary neurotrophic factor (CNTF) can also be corrected by supplementation (61,(113)(114)(115). Moreover, topical administration of the neuroprotective drugs brimonidine and somatostatin appears to be useful in mitigating the worsening of preexisting retinal neurodysfunction in patients with diabetes (116).…”

Section: Treatment/prevention Of Neurodegenerationmentioning

confidence: 99%

Diabetic Retinopathy–An Underdiagnosed and Undertreated Inflammatory, Neuro-Vascular Complication of Diabetes

Sinclair

Schwartz

2019

Front. Endocrinol.

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Diabetes mellitus is a world-wide epidemic and diabetic retinopathy, a devastating, vision-threatening condition, is one of the most common diabetes-specific complications. Diabetic retinopathy is now recognized to be an inflammatory, neuro-vascular complication with neuronal injury/dysfunction preceding clinical microvascular damage. Importantly, the same pathophysiologic mechanisms that damage the pancreatic β-cell (e.g., inflammation, epigenetic changes, insulin resistance, fuel excess, and abnormal metabolic environment), also lead to cell and tissue damage causing organ dysfunction, elevating the risk of all complications, including diabetic retinopathy. Viewing diabetic retinopathy within the context whereby diabetes and all its complications arise from common pathophysiologic factors allows for the consideration of a wider array of potential ocular as well as systemic treatments for this common and devastating complication. Moreover, it also raises the importance of the need for methods that will provide more timely detection and prediction of the course in order to address early damage to the neurovascular unit prior to the clinical observation of microangiopathy. Currently, treatment success is limited as it is often initiated far too late and after significant neurodegeneration has occurred. This forward-thinking approach of earlier detection and treatment with a wider array of possible therapies broadens the physician's armamentarium and increases the opportunity for prevention and early treatment of diabetic retinopathy with preservation of good vision, as well the prevention of similar destructive processes occurring among other organs.

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Section: Treatment/prevention Of Neurodegenerationmentioning

confidence: 99%

Diabetic Retinopathy–An Underdiagnosed and Undertreated Inflammatory, Neuro-Vascular Complication of Diabetes

Sinclair

Schwartz

2019

Front. Endocrinol.

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“…31 Simó et al carried out a 2-year RCT to assess the efficacy of neuroprotective drug eye drops on retinal neurofunction in type 2 diabetic patients. 30 To test whether en face slab OCT imaging can assess temporal changes in the innermost retinal layer in diabetic eyes, we analyzed en face slab OCT image data from patients with DM who had been followed up with Cirrus HD-OCT for over 3 years. Our attempt turned out to be successful, as a statistically significant deterioration was observed in both assessments using OCT grading and color distribution analysis.…”

Section: Discussionmentioning

confidence: 99%

En face slab optical coherence tomography imaging successfully monitors progressive degenerative changes in the innermost layer of the diabetic retina

Katsuyama

Kusuhara

Asahara

et al. 2020

BMJ Open Diab Res Care

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ObjectiveTo evaluate the usefulness of en face slab optical coherence tomography (OCT) imaging for monitoring diabetic retinal neurodegeneration with supporting animal experimental data.Research design and methodsWe retrospectively examined 72 diabetic eyes over 3 years using Cirrus-HD OCT. Two-dimensional en face slab OCT images of the innermost retina were reconstructed and graded according to the ratio of dark area to total area, and relative red, green, and blue color area ratios were calculated and used as indexes for each en face slab OCT image. Values from en face OCT images were used for statistical analyses. To obtain insight into the pathogenesis of diabetic retinal neurodegeneration, we used the InsPr-Cre;Pdk1flox/flox diabetic mouse model.ResultsBoth OCT grade and relative red color area ratio significantly increased with the advancing stage of diabetic retinopathy (p=0.018 and 0.006, respectively). After a mean follow-up period of 4.6 years, the trend was unchanged in the analyses of 42 untreated eyes (p<0.001 and 0.001, respectively). Visual acuity showed a weak but significant negative correlation with the red color ratio on en face slab OCT images, but central retinal thickness did not exhibit a clinically meaningful correlation with values obtained from en face slab OCT images. Immunohistochemical analyses of InsPr-Cre;Pdk1flox/flox diabetic mice demonstrated the loss of ganglion axon bundles and thinning of laminin without apparent retinal vascular change at the age of 20 weeks.ConclusionsEn face slab OCT imaging would be a novel useful modality for the assessment of diabetic retinal neurodegeneration as it could detect subtle optical changes occurring in the innermost retina in diabetic eyes. Our animal experimental data suggest that dark areas observed on en face slab OCT images might be the impairment of the extracellular matrix as well as neurons.

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“…EUROCONDOR [NCT01726075] was a 96 week, European multicenter, prospective, interventional, phase II-III, randomized controlled clinical trial aimed at evaluating the effect of topical (eye drops) neuroprotective agents to arrest or prevent early retinal neurodegeneration in DR [14,15]. Briefly, 449 patients were recruited in 11 European centers and randomized 1:1:1 to topical treatment twice daily with a placebo, brimonidine tartrate 0.2%, or somatostatin 0.1%.…”

Section: Methodsmentioning

confidence: 99%

“…The EUROCONDOR study included a phase II-III randomized, controlled clinical trial aimed at evaluating the effects of topical neuroprotection in arresting or preventing early retinal neurodegeneration in DR [14,15]. The selected neuroprotective agents appear useful in preventing the worsening of preexisting retinal neurodysfunction [15]. This finding points to screening for retinal neurodysfunction as a critical issue, in order to identify a subset of patients in whom neuroprotective treatment might be of benefit.…”

Section: Introductionmentioning

confidence: 99%

The Usefulness of Serum Biomarkers in the Early Stages of Diabetic Retinopathy: Results of the EUROCONDOR Clinical Trial

Hernández

Porta

Bandello³

et al. 2020

JCM

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The main aim of this study was to evaluate the ability of serum biomarkers to predict the worsening of retinal neurodysfunction in subjects with type 2 diabetes. For this purpose, we measured selected molecules (N-epsilon-carboxy methyl lysine (CML), laminin P1 (Lam-P1), and asymmetric dimethylarginine (ADMA)) in the serum of 341 participants of the EUROCONDOR study at baseline, 24, and 48 weeks. Retinal neurodysfunction was assessed by measuring implicit time (IT) using multifocal electroretinography, and structural changes were examined by spectral domain–optical coherence tomography. The values of IT at baseline were directly correlated with baseline serum concentrations of CML (r = 0.135, p = 0.013). Furthermore, in the placebo group, increase in CML concentration throughout follow-up correlated with the IT (r = 0.20; p = 0.03). Baseline serum levels of CML also correlated with macular retinal thickness (RT) (r = 0.231; p < 0.001). Baseline Lam-P1 levels correlated with the increase of the RT at the end of follow-up in the placebo group (r = 0.22; p = 0.016). We provide evidence that CML may be a biomarker of both retinal neurodysfunction and RT, whereas Lam-P1 was associated with RT only. Therefore, circulating levels of these molecules could provide a complementary tool for monitoring the early changes of diabetic retinopathy (DR).

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Effects of Topically Administered Neuroprotective Drugs in Early Stages of Diabetic Retinopathy: Results of the EUROCONDOR Clinical Trial

Abstract: Clinical trial reg. no. NCT01726075, clinicaltrials.gov This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/

Cited by 79 publications

References 25 publications

Diabetic Retinopathy–An Underdiagnosed and Undertreated Inflammatory, Neuro-Vascular Complication of Diabetes

Diabetic Retinopathy–An Underdiagnosed and Undertreated Inflammatory, Neuro-Vascular Complication of Diabetes

En face slab optical coherence tomography imaging successfully monitors progressive degenerative changes in the innermost layer of the diabetic retina

The Usefulness of Serum Biomarkers in the Early Stages of Diabetic Retinopathy: Results of the EUROCONDOR Clinical Trial

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