Medical management for the prevention and treatment of diabetic macular edema

doi:10.1016/j.survophthal.2012.10.002

Survey of Ophthalmology

Volume 58, Issue 5, September–October 2013, Pages 459-465

https://doi.org/10.1016/j.survophthal.2012.10.002 Get rights and content

Abstract

Recent clinical trials have changed the management paradigm for diabetic macular edema (DME). There is an urgent need to identify the most effective ways of preventing retinopathy or intervening at an early, asymptomatic stage in order to preserve vision. The rise in the incidence of diabetes is a serious public health concern. Grading and screening programmes help to identify sight threatening diabetic retinopathy in the community early and facilitate timely referral to an ophthalmologist. Systemic therapies for DME target the key modifiable risk factors: metabolic and blood pressure control. There may also be a role for modification of the renin-angiotensin system and for lipid lowering agents. Improved glycemic and blood pressure control remain the most effective ways of reducing morbidity from DME. Fenofibrate also has beneficial effects, but the mechanism for this remains unclear. Multiple new treatments are in the pipeline, and these are expected to change our approach to DME for the first time in 30 years.

Introduction

Recent clinical trials (DRCR Procotol-I, RESOLVE) have changed the management paradigm for diabetic macular edema (DME). More sophisticated protocols than the ETDRS focal/grid laser for clinical significant macular edema (CSME) versus no laser will become more common. Given that most of the specifically ophthalmological treatments are suitable for fairly advanced disease in which vision has often already been lost, it is important to try to find ways of either preventing retinopathy or intervening at an early, asymptomatic stage in order to preserve vision. The prevention of ocular morbidity from diabetic retinopathy (DR) therefore requires that we consider other factors. These include the implications of the ways by which we grade the severity of DR and DME and the role played by screening programs. In addition, we need to consider carefully the effects of systemic treatment for diabetes on DR, and the potential for medical therapy to prevent the development or progression of DME. There have been mixed messages on the effects of systemic treatment on DR.²⁶ We highlight the key epidemiological issues, outline the role of grading systems and screening programs, and discuss the management options for DME in terms of systemic therapy that is directed at the key modifiable risk factors.

Section snippets

Epidemiology

In January 2011, over 220 million people worldwide had diabetes,^A and the World Health Organization projects that this will rise to 366 million by 2030.^B Type 2 diabetes in particular has reached epidemic proportions,⁹ the result of a combination of longevity and a rapid increase in obesity. This rise in the incidence of diabetes is a major public health concern8, 31 because it is likely to be followed by a rise in its associated complications. DR is the most common microvascular complication

Standardized grading systems

The main symptom of diabetic retinopathy is reduced vision, but this occurs only when the condition is advanced and may be irreversible.³⁰ Early changes in DR are generally asymptomatic, and treatment may be needed long before patients are aware of losing any vision.³⁰ Early changes need to be targeted in order to provide the best chance of preserving good visual acuity.

Staging or grading of diabetic retinopathy can be done in many different ways. Although the ETDRS group provided grading

Diabetic retinopathy screening programs

The purpose of a DR screening program is, therefore, to identify sight-threatening DR/DME early and facilitate timely referral to an ophthalmologist. Different approaches are taken in different countries. In the United Kingdom there are three DR screening programs. England and Wales share one, and Scotland and Northern Ireland each have their own. Screening is performed by digital fundus photography, and these photographs then undergo detailed analysis and grading by trained screeners who

Systemic therapy for DME

The main aims of systemic therapy in DR/DME are to reduce the risk of diabetic patients developing these conditions in the first place and to reduce the risk of progression of existing retinopathy or maculopathy to more severe, sight-threatening forms. Systemic therapies are designed to target the key modifiable risk factors, which in the case of both DR and DME are metabolic and blood pressure control. There may also be a role for modification of the renin-angiotensin system (RAS) and for

Conclusion

Improved glycemic control and blood pressure control remain the most effective ways of reducing morbidity from DR and DME. New data from large, well-designed studies such as ACCORD and ACCORD-Eye have raised interesting questions about study design, methods of measuring outcomes, and even about the pathophysiology of DR and DME. In particular, the way in which fenofibrate produces its beneficial effects on DR and DME remains unclear. There may be a “floor” effect in the lowering of blood

Method of literature search

The literature search was conducted on PubMed, using the search terms diabetic macular (edema OR oedema) (management OR treatment), and covered all articles from January 2010 to June 2012. From the results of this search we reviewed all articles that were published in English and selected those that were judged to be of clinical importance in terms of the medical management of diabetic macular edema. Where the key articles from our search cited other relevant peer-reviewed references,

Disclosure

The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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Cited by (34)

Efficacy and follow-up of anti-VEGF injections in diabetic macular edema in real-life practice at the Dijon university medical centre through the Save Sight Registries
2020, Journal Francais d'Ophtalmologie
Citation Excerpt :
Thus, treatment of DME is a major public health challenge. DME treatment consists in optimum control of diabetes and blood pressure [6] as well as therapeutic treatment. In most cases, intravitreal injections (IVT) are used.
To evaluate the efficacy of intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections (IVT) in diabetic macular edema (DME) in real-life practice using the Save Sight Registries (SSR).
We conducted an observational, single-centre, retrospective study in the department of ophthalmology of the Dijon University Hospital. We included treatment-naive patients who presented with DME between January 2016 and December 2017. Demographic and clinical data, follow-up visits, and treatments administered were entered into the SSR, an international online ophthalmic registry. Primary endpoints were the change in best-corrected visual acuity (BCVA) and central subfield thickness (CST) from baseline to 12 and 24 months.
Fifty-eight eyes of 43 patients with a mean [standard deviation (SD)] age of 67.1 [9.5] years were included. Forty-one eyes completed 12 months of follow-up, and 17 eyes completed 24 months of follow up. Median [SD] baseline BCVA was 56.1 [22.9] ETDRS letters and the median [95% confidence interval (95% CI)] baseline CST was 447.9 [161.0] micrometers (μm). Median [95% CI] improvement in BCVA from baseline to months 12 and 24 were respectively, +5.6 [+0.5; +10.7] ETDRS letters and +7.7 [−2.8; +18.2] ETDRS letters. The median [95% CI] decrease in CST from baseline to months 12 and 24 were respectively, −110.9 [−154.5; −67.3] μm and −125.5 [−198.0; −53.0] μm.
Our clinical practice can be evaluated easily with the SSR system. In real life, anti-VEGF IVT are an effective treatment for DME, which result in improved BCVA and decreased CST.
Évaluer l’efficacité des injections d’anti-VEGF et nos pratiques dans l’œdème maculaire diabétique (OMD) en vraie-vie grâce à l’utilisation du Save Sight Registries (SSR).
Il s’agit d’une étude observationnelle, monocentrique, rétrospective réalisée dans le service d’ophtalmologie du CHU de Dijon incluant les patients traités pour un OMD entre janvier 2016 et décembre 2017. Les données cliniques et démographiques, les visites de suivi, les traitements administrés ont été implémentés sur la plateforme internet du SSR. Les critères de jugement principaux étaient l’évolution de la meilleure acuité visuelle corrigée (MAVC) et de l’épaisseur centrale fovéolaire (ECF) entre l’inclusion et les visites à 12 mois et 24 mois.
Cinquante-huit yeux de 43 patients d’âge moyen [déviation standard] de 67,1 [5,9] ans ont été inclus. Quarante et un yeux ont poursuivi un suivi de 12 mois et 17 yeux de 24 mois. La médiane [DS] de la MAVC initiale était de 56,1 [9,22] lettres ETDRS et la médiane [intervalle de confiance 95% (IC 95%)] de l’ECF initiale était de 447,9 [161,0] micromètres (μm). Le gain médian [IC 95%] de la MAVC entre l’inclusion et le mois 12 et 24 était respectivement de +5,6 [+0,5; +10,7] et de +7,7 [−2,8; +18,2] lettres ETDRS. La diminution médiane [IC 95%] de l’ECF entre l’inclusion et le mois 12 et 24 était respectivement de −110,9 [−154,5; −67,3] μm et de −125,5 [−198,0; −53,0] μm.
Le SSR est utile pour l’évaluation de nos pratiques. Les injections d’anti-VEGF sont un traitement efficace de l’OMD.
Microvascular complications in diabetes: A growing concern for cardiologists
2019, International Journal of Cardiology
Citation Excerpt :
Epigenetic modifications were also shown in several genes coding for proteins mediating antioxidant [25,26], and pro-oxidant effects in the retina [27], and kidney [28–33]. The renin-angiotensin system (RAAS) has been implicated in the pathogenesis of MICRO: the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin type-1 receptor blockers (ARB), and their combination may delay both the onset and the progression of CKD and DR [34,35]. The endoplasmic reticulum stress (ERS) induced by misfolded proteins, and intracellular calcium perturbations, may play a role in the pathogenesis of MICRO [36]: unresolved ERS initiates signaling that promotes apoptosis.
Randomized, cross-sectional, and prospective studies have demonstrated that microvascular complications in patients with diabetes are not only the cause of blindness, renal failure and non-traumatic amputations, but also powerful predictors of cardiovascular complications. Beside the metabolic theory, the pathophysiology of diabetic microvascular complications is determined by the interaction among several factors, including epigenetic modifications and the reduced release of progenitor cells by the bone marrow, that contribute simultaneously to damage and impaired vascular protection against hyperglycemia. Identifying and preventing microvascular complications has the significant potential to reduce major adverse cardiovascular events. For these reasons, there may no longer be a rational to consider microangiopathy and macroangiopathy as entirely separate entities, but they should most likely be viewed as a continuum of the widespread vascular damage determined by diabetes mellitus.
Diabetic Retinopathy in Patients with Dyslipidemia: Development and Progression
2018, Ophthalmology Retina
Citation Excerpt :
However, these parallel and interrelated diseases progressed together, and the patients with DM and dyslipidemia presented an increased risk of all DR types in the long-term follow-up period. Regarding the effect of statin and fibrate use on DR, Keech et al57 showed that treatment with fenofibrate in individuals with type 2 DM reduces the need for laser treatment for DR, although the mechanism of this effect does not seem to be related to plasma concentrations of lipids.56,57 Gupta et al58 demonstrated that in patients with type 2 DM and dyslipidemia, oral atorvastatin therapy reduces the severity of hard-exudate formation and subfoveal lipid migration in clinically significant DME and can be a critical adjunct in the management of clinically significant macular edema.
To investigate the association of dyslipidemia with the development of diabetic retinopathy (DR).
A prospective cohort from the Longitudinal Health Insurance Database in Taiwan.
Patients with diabetes mellitus (DM) aged ≥18 years from this cohort.
A logistic regression model considering age, sex, and adapted Diabetes Complication Severity Index (aDCSI) including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy cardiovascular disease, cerebrovascular disease, peripheral arteriolar disease, and metabolic disease. We estimated the propensity score for disease assignment probability for each included patient with DM and dyslipidemia. For each patient, a comparison patient without dyslipidemia was matched with a propensity score using a greedy algorithm. The standardized mean differences method was used to measure the difference in means or proportions divided by the pooled standard deviation of a variable. We calculated the incidence densities of nonproliferative DR (NPDR), diabetic macular edema (DME), and proliferative DR (PDR) as total events divided by the sum of follow-up duration, and the incidence curves were measured using the Kaplan–Meier method. The log-rank test was applied to test the differences of incidence curves.
Hazard ratios (HRs) for DR.
Our results demonstrated that the cumulative incidence of NPDR, DME, and PDR significantly increased in patients with DM and dyslipidemia compared with those without before adjustment for covariates (P < 0.001). Adjusted HRs for NPDR, DME, and PDR in patients with dyslipidemia were 1.77 (95% confidence interval [CI] = 1.63–1.92), 2.34 (95% CI = 1.24–4.41), and 1.07 (95% CI = 0.91–1.27), respectively. The risks of NPDR, DME, and PDR increased in patients who had underlying complications according to the aDCSI. Only statin use had a protective effect against the development of NPDR (HR = 0.83; 95% CI = 0.76–0.90), but it had no effect on DME and PDR. The protective effect was not significantly different between patients with and without dyslipidemia.
Dyslipidemia is involved in the development of DR at an earlier stage, but the role of lipid-modulating agents in DR requires additional study.
Effect of Modifiable Risk Factors on the Incidence and Progression of Diabetic Retinopathy
2018, Current Management of Diabetic Retinopathy
The modifiable risk factors for diabetic retinopathy include glycemic control, hypertension, inhibition of the renin-angiotensin system, serum lipid levels, dietary intake of omega-3 fatty acids, physical activity, sedentary behavior, obesity, aspirin therapy, and smoking. Glycemic control is the most important modifiable risk factor for diabetic retinopathy. An exponential relationship between hemoglobin A1c (HgbA1c) and diabetic retinopathy progression has been demonstrated in multiple clinical trials. A target HgbA1c <7% is associated with a lower incidence and progression of retinopathy. Hypertension is also a primary risk factor due to the microvascular damage that may exacerbate the small vessel injury caused by elevated glucose levels. Blood pressure (BP) control can reduce the risk of retinopathy, but there may be a floor effect for systolic BP less than 120 mm Hg. Inhibition of the renin-angiotensin system by angiotensin converting enzyme inhibitors or angiotensin receptor blockers has been shown to reduce the progression of diabetic retinopathy. The reduction of lipid levels can reduce hard exudates and microaneurysms in diabetic retinopathy. In addition, multiple studies demonstrate that obesity increases the risk of retinopathy. There is also evidence that increased physical activity, reduced sedentary behavior, and increased dietary intake of omega-3 fatty acids may reduce retinopathy progression. Aspirin therapy and smoking are not linked to an increased risk of retinopathy. Eye care providers must communicate effectively with the patient's diabetes care team to encourage the management of systemic risk factors that can alter the course of the disease.
Automated diabetic macular edema (DME) grading system using DWT, DCT Features and maculopathy index
2017, Computers in Biology and Medicine
The cause of diabetic macular edema (DME) is due to prolonged and uncontrolled diabetes mellitus (DM) which affects the vision of diabetic subjects. DME is graded based on the exudate location from the macula. It is clinically diagnosed using fundus images which is tedious and time-consuming. Regular eye screening and subsequent treatment may prevent the vision loss. Hence, in this work, a hybrid system based on Radon transform (RT), discrete wavelet transform (DWT) and discrete cosine transform (DCT) are proposed for an automated detection of DME. The fundus images are subjected to RT to obtain sinograms and DWT is applied on these sinograms to extract wavelet coefficients (approximate, horizontal, vertical and diagonal). DCT is applied on approximate coefficients to obtain 2D-DCT coefficients. Further, these coefficients are converted into 1D vector by arranging the coefficients in zig-zag manner. This 1D signal is subjected to locality sensitive discriminant analysis (LSDA). Finally, various supervised classifiers are used to classify the three classes using significant features. Our proposed technique yielded a classification accuracy of 100% and 97.01% using two and seven significant features for private and public (MESSIDOR) databases respectively. Also, a maculopathy index is formulated with two significant parameters to discriminate the three groups distinctly using a single integer. Hence, our obtained results suggest that this system can be used as an eye screening tool for diabetic subjects for DME.
Dexamethasone reverses the effects of high glucose on human retinal endothelial cell permeability and proliferation in vitro
2016, Experimental Eye Research
Citation Excerpt :
Diabetic macular oedema (DMO), central retinal (macular) thickening due to the accumulation of fluid is the most common cause of visual loss resulting from diabetic retinopathy (DR), a microvascular complication (Ciulla et al., 2003; Klein et al., 1998; Resnikoff et al., 2004). The incidence of DR correlates with poor glycaemic control and hyperlipidaemia, and aggravated by uncontrolled systemic hypertension, renal disease and smoking (Bhagat et al., 2009; Bhavsar, 2006; Bhavsar and Tornambe, 2006; Kiire et al., 2013). DMO results from breakdown of the inner blood-retinal barrier which is maintained by retinal endothelial cell (REC) tight junction (TJ) complexes (Vitale et al., 1995), resulting in an increase in microvascular endothelial permeability.
Diabetic macular oedema (DMO), a leading cause of preventable visual loss in the working population, is caused by an increase in microvascular endothelial cell permeability, and its prevalence is on the increase in parallel with the rising worldwide prevalence of diabetes. It is known that retinal vascular leakage in DMO is contributed to by VEGF upregulation as well as non-VEGF dependent inflammatory pathways, and the potential use of anti-inflammatory agents such as the glucocorticoids, including dexamethasone are being extensively studied. However, the mechanisms of action of dexamethasone in DMO reduction are not fully understood. Using human primary retinal endothelial cells (REC) the in vitro effect of dexamethasone in modulating the proliferation, permeability and gene expression of key tight and adheren junction components, and the expression of angiopoietins (Ang) 1 and 2 in high (25 mM) glucose conditions were investigated. High glucose decreased REC proliferation, an effect that was reversed by dexamethasone. High glucose conditions significantly increased REC permeability and decreased claudin-5, occludin and JAM-A gene expression; dexamethasone was effective in partially reversing these changes, restoring EC permeability to the normal or near normal state. High glucose levels resulted in reduction of Ang1 secretion, although Ang2 levels were consistently high. DEX increased Ang1 and decreased Ang2, indicating that the balance of Ang1/Ang2 may be important in determining functional changes in REC under high glucose conditions.

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Major ReviewMedical management for the prevention and treatment of diabetic macular edema

Abstract

Introduction

Section snippets

Epidemiology

Standardized grading systems

Diabetic retinopathy screening programs

Systemic therapy for DME

Conclusion

Method of literature search

Disclosure

Lancet

Surv Ophthalmol

Am J Ophthalmol

Lancet

Lancet

Ophthalmology

Ophthalmology

Lancet

Diabetes Metab

Effects of intensive glucose lowering in type 2 diabetes

N Engl J Med

The National Diabetic Retinopathy Laser Treatment Audit, III: clinical outcomes

Eye

Ophthalmic examination among adults with diagnosed diabetes mellitus

JAMA

Angiotensin converting enzyme inhibitor treatment for young normotensive diabetic subjects: a two-year trial

Ann Ophthalmol

The Diabetic Retinopathy Candesartan Trials (DIRECT) Programme, rationale and study design

J Renin Angiotensin Aldosterone Syst

Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22

Arch Ophthalmol

21st-century treatment of diabetic retinopathy

Expert Rev Endocrinol Metab

Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies

Diabetes Care

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus

N Engl J Med

Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy

N Engl J Med

Grading diabetic retinopathy from stereoscopic fundus photographs: an extension of the modified Airlie House classification: ETDRS Report Number 10

Ophthalmology

Major Review
Medical management for the prevention and treatment of diabetic macular edema