research articles on diabetic macular edema

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• Indian J Ophthalmol
• v.66(12); 2018 Dec

Diabetic macular edema: Evidence-based management

David j browning.

Charlotte Eye, Ear, Nose, and Throat Associates, Charlotte, North Carolina, USA

Michael W Stewart

1 Department of Ophthalmology, Mayo Clinic, Jacksonville, Florida, USA

Diabetic macular edema (DME) is the most common cause of vision loss in patients with diabetic retinopathy with an increasing prevalence tied to the global epidemic in type 2 diabetes mellitus. Its pathophysiology starts with decreased retinal oxygen tension that manifests as retinal capillary hyperpermeability and increased intravascular pressure mediated by vascular endothelial growth factor (VEGF) upregulation and retinal vascular autoregulation, respectively. Spectral domain optical coherence tomography (SD-OCT) is the cornerstone of clinical assessment of DME. The foundation of treatment is metabolic control of hyperglycemia and blood pressure. Specific ophthalmic treatments include intravitreal anti-VEGF drug injections, intravitreal corticosteroid injections, focal laser photocoagulation, and vitrectomy, but a substantial fraction of eyes respond incompletely to all of these modalities resulting in visual loss and disordered retinal structure and vasculature visible on SD-OCT and OCT angiography. Efforts to close the gap between the results of interventions within randomized clinical trials and in real-world contexts, and to reduce the cost of care increasingly occupy innovation in the social organization of ophthalmic care of DME. Pharmacologic research is exploring other biochemical pathways involved in retinal vascular homeostasis that may provide new points of intervention effective in those cases unresponsive to current treatments.

Epidemiology and Risk Factors

Diabetic macular edema (DME) is the most common cause of visual loss in those with diabetic retinopathy and is increasing in prevalence globally.[ 1 , 2 , 3 ] The prevalence of DME in patients with diabetic retinopathy is 2.7%–11%[ 4 , 5 , 6 , 7 , 8 ] and it depends on the type of diabetes and the duration of the disease, but for both types 1 and 2 after 25-years duration, it approximates 30%. Systemic factors associated with DME include longer duration of diabetes, higher systolic blood pressure, and higher hemoglobin A1C. The sole ocular factor associated with DME is diabetic retinopathy severity as increasing severity is associated with increasing prevalence of DME.[ 9 , 10 , 11 ]

Genetics, Pathoanatomy, and Pathophysiology

The hypothesis that genetic risk and protective alleles exist for development of DME has not been tested with genome wide association studies of adequate size, but studies are underway.[ 12 ]

The capillaries in the macula are distributed in four strata within the inner retina with the exception of the single-level arrangement bordering the foveal avascular zone within the ganglion cell layer.[ 13 ] Farther from the fovea, the three additional levels of capillaries are found within the deep ganglion cell layer, inner plexiform layer/superficial inner nuclear layer, and deep inner nuclear layer, respectively.[ 14 ] These strata can be imaged by optical coherence tomography (OCT).[ 15 ]

Eighty percent of diabetes-related microaneurysms originate in the inner nuclear layer and its border zones[ 16 ] and are commonly found on the edges of nonperfused retina. Microaneurysms in DME do not preferentially cluster in any particular quadrant.[ 17 ] In DME, spectral domain (SD)-OCT angiography has shown microaneurysms and abnormal deep capillary networking in the superficial outer nuclear layer, a normally avascular zone.[ 18 ]

In center-involved diabetic macular edema (CIDME), the central macula is often thickest, an inversion of the normal morphology. In the foveal avascular zone, the only mechanism for extracellular fluid resorption is the retinal pigment epithelial (RPE) pump, which may explain the greater accumulation of edema fluid at this location.[ 19 ] An associated fundus sign is the appearance of the macular lipid star [ Fig. 1 ]. In 15%–30% of cases of DME, a subfoveal serous retinal detachment is present. Although the explanation for the subfoveal location of fluid is conjectural, one theory posits an impaired RPE pump due to decreased subfoveal choroidal circulation.[ 20 , 21 ]

A macular lipid star is a common fundus sign in diabetic macular edema and indicates that the center of the macula is a preferential site for accumulation of extracellular fluid

Breakdown of the inner blood–retina barrier rather than outer blood–retina barrier breakdown is more important to the formation of DME.[ 22 ] Diabetes causes a redistribution of occludin in retinal vascular endothelium.[ 23 ] The Muller cells proliferate in epiretinal membranes that exert traction on microvessels and increase their permeability. Astrocytes, which wrap their end feet around microvessels, decrease their production of glial fibrillary acidic protein in diabetes, which may alter the blood–retina barrier.[ 23 ]

Diabetes-related abnormalities of the vitreoretinal interface may promote the development DME. During the process of vitreous separation, the macula and the disk may adhere to the posterior hyaloid more firmly, and traction may contribute to blood retinal barrier breakdown and provide a scaffold for cellular proliferation, which further increases traction on the macula.[ 24 , 25 , 26 ] In eyes with DME, the internal limiting membrane has more adherent cellular elements on its vitreous side, is thicker, and has more heparin sulfate proteoglycan compared with the internal limiting membrane from nondiabetic eyes. Fibromuscular cells found in epiretinal blocks of tissue biopsied at the time of vitrectomy for DME may be the basis for tangential traction on the retina with concomitant increases in capillary permeability.[ 25 , 26 ]

In DME, the macula is thickened due to increased extracellular fluid derived from hyperpermeable retinal capillaries.[ 27 ] Prolonged hyperglycemia leads to reduced inner retinal oxygen tension, venous dilation, increased VEGF concentration within the retina, leukocyte stasis, and dysregulated growth factor levels, which together are associated with increased exudation of serum out of the retinal vasculature and into the extracellular space.[ 28 , 29 ] The RPE pump is overwhelmed by the exudation of serum and macular swelling results.[ 30 , 31 ]

A framework for understanding the pathophysiology of diabetic macular edema (DME) is the oxygen theory.[ 32 ] Prolonged periods of hyperglycemia lead to reduced perfusion of the inner retina and decreased inner retinal oxygen tension. The autoregulatory response of the retinal arterioles causes dilation, which leads to increased hydrostatic pressure in the intraretinal capillaries and venules as specified by Poiseuille's law.[ 31 ] The elevated intravascular pressure experienced by the capillaries may damage them.[ 31 , 32 ] Concomitantly, the decrease in retinal oxygen tension upregulates the synthesis of VEGF and other permeability factors, which increases microvasculature leakage. According to Starling's law, increased intravascular pressure and vascular permeability result in a net flow of water, ions, and macromolecules from the intravascular space into the extravascular space. Extracellular fluid is resorbed by re-entering the retinal vessels further downstream or through the choroid via the pumping action of the RPE.[ 32 , 33 ]

Many variables are suspected to modulate this process. The duration of diabetes and the integrated elevation of blood glucose reflected in the glycated hemoglobin (HbA1C) have proven pathophysiological importance. Retinal neurons and glial cells increase their production of VEGF, even before ophthalmoscopic evidence of capillary loss, associated with reduced occludin in capillary endothelial tight junctions.[ 23 , 34 ] Increased inflammation, characterized by leukostasis, accumulation of macrophages, intercellular adhesion molecule-1 activation (ICAM-1), and prostacyclin upregulation, is associated with capillary nonperfusion and breakdown of the blood–retina barrier.[ 29 , 35 ] Patients with DME have elevated vitreous levels of VEGF, ICAM-1, interleukin-6 (IL-6), and monocyte chemoattractant protein-1 compared with nondiabetic patients.[ 36 ] Inflammatory cytokines such as tumor necrosis factors alpha and beta, alpha 4 integrin, nitric oxide, and interleukin-1β mediate vascular permeability.[ 23 , 37 , 38 , 39 ] Many other small molecules and growth factors may contribute to the development of DME, although the details of the pertinent pathways are incompletely understood.[ 37 , 38 , 40 , 41 ] High lipid levels may cause endothelial dysfunction and increased vascular permeability through a local inflammatory response and higher levels of advanced glycation end products.[ 42 ] In addition to extracellular edema, intracellular edema may be relevant for DME. Dysregulated metabolism is associated with accumulation of intracellular osmotically active solutes that draw in water and cause cellular swelling.[ 31 ]

Decrease in subfoveal choroidal blood flow in type 2 diabetic patients with retinopathy may be relevant in the pathophysiology of DME. Eyes with DME have been reported to have a greater decrease in choroidal blood flow than eyes without DME, suggesting relative hypoxia of the RPE and outer retina, and consequent increased permeability of the outer blood retinal barrier.[ 20 ]

The vitreous may play a role in the pathogenesis of DME. Cross-linking and protein glycation are increased in the diabetic vitreous, which may explain instances of tangential macular traction that may induce DME.[ 43 , 44 ] Besides the direct effect of traction causing leakage from blood vessels or macular elevation with subretinal fluid, vitreous adherent to the macula may loculate mediators of vessel permeability in proximity to macular capillaries and may impede oxygenation of the retina, thereby causing venous dilation and increased edema via Starling's law or by upregulation of VEGF.[ 33 , 45 , 46 , 47 , 48 , 49 ]

This account of the pathophysiology of DME informs an understanding of how treatments for DME work [ Fig. 2 ]. Grid laser increases the oxygenation of the inner retina both by reducing the number of oxygen-consuming photoreceptors and by shortening the diffusion pathway to the inner retina for oxygen originating in the choroid.[ 32 , 50 ] Focal photocoagulation presumably works by destroying leakage sources such as microaneurysms but may also improve RPE pumping of sodium ions and water outward toward the choroid.[ 32 , 51 , 52 ] Anti-VEGF drugs work by blocking the permeability inducing effects of VEGF.[ 53 ] Corticosteroids reduce expression of the VEGF gene, differentially regulate expression of the various VEGF receptors, and have other non-VEGF-mediated effects such as decreasing leukocyte recruitment and production of ICAM-1, and inhibiting collagenase induction that reduce the permeability of retinal microvessels.[ 54 , 55 , 56 , 57 , 58 , 59 ] Vitrectomy may work by increasing intravitreal and secondarily inner retinal oxygen levels, leading to downregulation of VEGF synthesis, which decreases the permeability of microvessels.[ 32 , 60 ] In addition, vitrectomy may open compartments of loculated cytokines and relieve traction exerted on the macula by an altered vitreous.[ 60 , 61 ]

Schematic summarization of the mechanisms of action of the various treatments for diabetic macular edema. The color-filled blocks represent different treatment modalities for diabetic macular edema

Clinical Definitions

Diabetic macular edema.

Retinal thickening within one disk diameter of the center of the macula or definite hard exudates in this region.[ 62 ]

Center-involved diabetic macular edema

DME in which the fovea is involved.

Clinically significant macular edema

The situation in which at least one of the following criteria is fulfilled:

• Retinal thickening within 500 μm of the center of the macula
• Hard exudates within 500 μm of the center of the macula with adjacent retinal thickening
• One disk area of retinal thickening any part of which is within one disk diameter of the center of the macula.[ 63 ]

Focal and diffuse diabetic macular edema

These two terms have not been defined consistently in the literature.[ 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ] Focal edema is said to arise from microaneurysms, whereas diffuse edema is said to arise from generally dilated and hyperpermeable capillaries throughout the macula.[ 83 ] Focal DME has been reported to be more common than diffuse DME, but many cases of DME have mixed features making a clear distinction difficult.[ 51 , 80 , 84 , 85 , 86 , 87 ] Additional confusion may ensue because the term focal is used to describe a technique of applying laser directly to microaneurysms when treating DME with focal/grid photocoagulation.[ 63 , 88 ]

Other classifications of DME have been proposed. One scheme differentiates diffuse edema, cystoid macular edema, and serous retinal detachment based on OCT.[ 89 ] Attempts to correlate these subgroups to treatment outcomes have yielded inconsistent results, no consensus guidance exists on interventions for the proposed subtypes, and no DRCR network study has shown these DME classifications to help in clinical decision-making.[ 90 ]

Subclinical diabetic macular edema (SCDME)

The severity of DME may not reach the definition of CSME or CIDME. Clinical assessment of macular edema and OCT assessment of macular edema frequently disagree in this group of patients.[ 91 , 92 ] In addition, some eyes do not have clinically recognized DME, but macular thickening is detectable by OCT.[ 4 ] The term subclinical DME has been used to define both of these classes of DME that are less severe than clinically significant DME.[ 92 , 93 ]

Persistent diabetic macular edema

DME that has been treated without complete resolution is defined as persistent.[ 94 , 95 , 96 , 97 ] Persistent DME has been noted in a proportion of eyes treated by any modality, including focal laser photocoagulation, intravitreal injection of anti-VEGF drugs or corticosteroids, and vitrectomy. Different criteria have been applied for the number of treatments or duration of treatment required before applying the term. Some eyes have persistent edema despite all known treatments for DME.

Recurrent diabetic macular edema

Many cases exist in which DME resolves after treatment, but subsequently recurs.[ 98 , 99 ] Although DME can resolve spontaneously without treatment, and then recur, the term recurrent DME is used with reference to treated eyes with recurrences.

Methods of detection of DME

DME can be detected by stereoscopic slit-lamp examination using a fundus lens.[ 51 , 63 , 100 ] Direct ophthalmoscopy allows detection of lipid exudates but lacks stereopsis. Although lipid suggests associated macular thickening, the two findings are not synonymous; presence of lipid alone is an unreliable surrogate for DME.[ 101 , 102 ] Stereoscopic fundus photographs and fluorescein angiography can be used to assess the presence of DME but have been largely supplanted by OCT.[ 24 , 103 , 104 , 105 ]

The importance of OCT in diagnosing and managing DME cannot be overemphasized. The clinical diagnosis of DME as practiced in the Early Treatment Diabetic Retinopathy Study (ETDRS) era before OCT was beset by variability among clinicians.[ 51 , 106 ] In contrast, measurements made with OCT are highly reproducible.[ 107 , 108 , 109 , 110 , 111 ] In general, any change of macular thickness greater than 11% of a previous measurement exceeds OCT measurement variability and can be assumed to be a real change in macular thickness.[ 109 ] In addition to measurement variability, there is short-term fluctuation in macular thickness in DME. This refers to the variability noted over the course of days to even weeks when there is no trend in the changes.[ 112 ] Short-term fluctuation in DME is dependent on actual macular thickness and is larger than measurement variability.[ 113 ]

Of the many OCT indices that can be followed in the course of DME, the central subfield mean thickness (CST) is the best single measure.[ 114 , 115 ] It is more reproducible than center point thickness, yet is highly correlated ( r = 0.99) with the latter.[ 114 , 115 ] Total macular volume (TMV) correlates somewhat less well with CST ( r = 0.76), and there have been no conclusions drawn from analyzing TMV that would not have been drawn by studying CST instead.[ 94 , 104 ]

OCT was originally developed using time domain acquisition of images.[ 116 ] Subsequently instruments using spectral domain acquisition of images (SD-OCT) and swept-source OCT (SS-OCT) have been developed. SD-OCT and SS-OCT allow faster acquisition of images, denser sampling of the macula, and better imaging of the choroid and outer retina.[ 117 , 118 , 119 , 120 ] The normal values for SD-OCT and SS-OCT differ because the segmentation algorithms define the retina layers differently, and measurements are not interconvertible across instruments made by different companies.[ 118 , 119 , 121 ] The axial resolution of SD-OCT is 2–5 μm.[ 118 , 122 ] For the central subfield, the mean coefficient of variation of SD-OCT has been reported to be 0.66%.[ 118 ] The coefficient of repeatability for the central subfield thickness of SD-OCT is 5 μm.[ 123 ]

OCT is good for objectively measuring macular thickness, but macular thickening is only modestly correlated with visual acuity ( r = −0.52) perhaps due to variable duration of edema and ischemia.[ 23 , 124 ] Photoreceptor outer segment length, defined as the length between the ellipsoid zone and the RPE, and outer retinal layer thickness, defined as the length between the external limiting membrane (ELM) and the RPE, correlate better with visual acuity ( r = −0.81 and −0.65 to −0.8787, respectively).[ 125 , 126 , 127 ] Disorganization of the inner retinal layers (DRIL), defined as lack of definition of boundaries between ganglion cell-inner plexiform layer or inner-nuclear-outer-plexiform layers in ≥ 50% of the 1 mm central subfield, has been associated with worse visual acuity and less response to injections with bevacizumab or ranibizumab.[ 128 , 129 , 130 ] On average, each additional 100 μm of DRIL is associated with 6 ETDRS letters lost.[ 130 ]

Besides its usefulness in the detection of macular edema, OCT has value in following DME over time. SD-OCT provides enough detail regarding the outer retina that correlations of intactness of structures with visual outcomes are possible. Increased disruption of the ELM and ellipsoid zone (EZ) are associated with worse visual acuity outcomes.[ 131 , 132 ]

Natural History

The ETDRS provided natural history data regarding DME. Over 3 years of follow-up, the rate of moderate visual loss (15 letters on the ETDRS chart) was 8% per year.[ 63 ] Rates of visual loss increased according to the baseline visual acuity, with worse seeing eyes losing vision at a higher rate.[ 63 ] Rates of visual loss also increased according to baseline retinopathy severity, with eyes having more severe retinopathy losing vision at higher rates than eyes with less severe retinopathy.[ 63 ] Rates of visual acuity gain of at least 6 ETDRS letters in untreated eyes with DME and visual acuity of ≤ 20/40 over three years of follow-up were 20%–25%.[ 63 ] Of eyes with DME less severe than CSME (one subset of what has been termed subclinical DME) and observed without treatment, 22% and 25% progressed to CIDME at 1 and 3 years of follow-up, respectively.[ 63 ] In the OCT era, 31% of eyes with SCDME progressed to CSME over a median follow-up of 14 months.[ 93 ]

Chronic, untreated DME and refractory DME can lead to subretinal fibrosis, particularly if hard exudates are present, and by more subtle RPE pigmentary changes.[ 133 , 134 , 135 , 136 , 137 ]

Metabolic control and effects of drugs

Recognition of the risk factors for DME led to randomized clinical trials of better blood pressure control in attempts to reduce the prevalence of the condition. The Diabetes Control and Complications Trial showed that tight blood glucose control in patients with type 1 diabetes reduced the cumulative incidence of macular edema at 9-year follow-up by 29% and reduced the application of focal laser treatment for DME by half.[ 138 , 139 ] The United Kingdom Prospective Diabetes Study was an analogous randomized clinical trial of patients with type 2 diabetes. It showed that tighter blood glucose control reduced the requirement for laser treatment at 10 years by 29%, compared with looser control; 78% of the laser treatments were for DME.[ 140 ] It also showed that a mean systolic blood pressure reduction of 10 mm Hg and a diastolic blood pressure reduction of 5 mm Hg over a median follow-up of 8.4 years led to a 35% reduction in retinal laser treatments, of which 78% were for DME.[ 141 ]

Increased serum cholesterol levels are associated with increased severity and risk of retinal hard exudates.[ 142 , 143 ] Patients with abnormally elevated triglycerides and HDL cholesterol had worse visual acuity outcomes after focal/grid photocoagulation than did patients with normal levels in one small prospective study.[ 144 ]

Thiazolidinediones are oral agents used to treat type 2 diabetes. They are peroxisome proliferator-activated receptor γ agonists that work by enhancing insulin sensitivity. Pioglitazone and rosiglitazone are members of this class of drugs in common use. They have been associated with peripheral edema, pulmonary edema, and/or congestive heart failure, especially when used in combination with insulin. Plasma VEGF levels are higher in patients on thiazolidinediones than in patients not on these drugs.[ 145 ] Case reports and retrospective database cohort studies suggest that they can be associated with new or worsened DME as well, but in the ACCORD study, use of thiazolidinediones was not associated with prevalence of DME at baseline or incidence of DME over 4 years of follow-up.[ 146 , 147 ]

Improved control of diabetes, hypertension, and serum lipids is frequently underemphasized by the ophthalmologist because changes in systemic disease management are usually made by the internist, yet there is an intimate connection between these changes and retinal effects. A multifactorial intervention aimed at reducing glycated hemoglobin, elevated blood pressure, and elevated serum lipids can produce measurable effects in macular thickness in as little as 6 weeks and forms a rational foundation on which to apply specific ophthalmic interventions.[ 148 ]

Specific Ophthalmic Treatments

Focal/grid laser photocoagulation.

The ETDRS demonstrated superior visual outcomes with focal/grid laser for CSME compared with the natural history. Laser thus became the standard of care over the next 30 years.[ 63 ] Treatments were repeated at 4-month intervals if CSME persisted and treatable lesions or untreated, thickened, and nonperfused retina remained. The average patient received between three and four focal/grid laser treatments. ETDRS style focal/grid photocoagulation for DME has potential side effects including paracentral scotomas, subretinal fibrosis, and secondary choroidal neovascularization.[ 134 , 149 , 150 , 151 , 152 ]

The technique of focal/grid argon laser treatment has been modified over time. The most significant changes are embodied in the DRCR.net protocols that employ focal/grid photocoagulation. Rather than burns that can vary from 50 to 200 μm, all contemporary burns are 50 μm and they are less intense.[ 153 ] Yellow wavelength laser is acceptable in addition to green, but blue-green is not used because of concern over absorption by macular luteal pigment. Use of a guiding fluorescein angiogram is optional.[ 51 , 74 , 149 , 154 ] On average, for mild CIDME with CST in the range of 300–350 μm, one can expect that focal/grid laser will produce ~25 μm of macular thinning at the usual first follow-up interval of 3–4 months. For every 100 μm of additional baseline macular thickening above this threshold, one can expect that focal/grid laser will yield approximately 10 μm of additional macular thinning at the 3-to 4-month follow-up visit.[ 19 ] Visual acuity at this follow-up visit is, on average, unchanged from baseline.[ 154 , 155 , 156 , 157 ]

Subthreshold Laser Photocoagulation

Besides focal/grid suprathreshold laser treatment, diode laser micropulse laser has been used in case series and small randomized clinical trials.[ 158 , 159 , 160 ] Its advantages are absence of RPE scarring, no subsequent choroidal neovascularization, and elimination of paracentral visual field scotomas.[ 160 , 161 ] The disadvantages are that there is no visible endpoint for treatment, making it difficult to determine where treatment has and has not been given, and that there is no standardized, consensus set of treatment parameters or guidelines with respect to treatment within the foveal avascular zone. In addition, the reduction in macular edema after subthreshold laser photocoagulation occurs with a slower time course and more treatments are necessary to achieve elimination of edema.[ 160 ]

Intravitreal Injections of Corticosteroids

Corticosteroids were first used to treat DME in 2001.[ 162 ] Triamcinolone, dexamethasone, and fluocinolone have been used in many forms, including particulate suspensions, viscoelastic mixtures, and solid slow-release devices.[ 113 , 163 , 164 , 165 , 166 ] Many dosages and intervals between triamcinolone injections have been tried.[ 167 ] Although enthusiasm for serial intravitreal triamcinolone injections was initially high, protocol B of the DRCR network showed that focal laser led to superior visual acuity outcomes at 3 years relative to either triamcinolone 1 or 4 mg.[ 157 , 163 ] Since then, therapy with corticosteroids has taken a secondary role to anti-VEGF therapy. Side effects of cataract in phakic eyes and intraocular pressure elevation have accompanied all steroids studied, although to varying degrees.[ 157 , 168 ]

Slowly dissolving intravitreal dexamethasone implants (Ozurdex ® , Allergan, Irvine, CA, USA) are effective in treating DME although the visual acuity gains are generally less than with anti-VEGF injections.[ 90 , 169 ] In a 3-year randomized controlled trial, the 0.7 mg dexamethasone implant was associated with ≥ 15 letter improvement in best corrected visual acuity (BCVA) in 22.2% of patients compared to 12.0% in the sham group.[ 169 ] Over three years in phakic patients, 59.2% of eyes required cataract surgery; 41.5% of eyes required the use of ocular hypotensive therapy.[ 169 ] The long-term visual outcome of intravitreal dexamethasone implant therapy correlates with the 3-month treatment response.[ 170 ]

Intravitreal fluocinolone acetonide implants (Iluvien ® , Alimera, Alpharetta, GA, USA) last 3 years and, unlike the dexamethasone implant, do not dissolve. In the FAME trial, patients with persistent DME despite macular laser were randomized to low-dose (0.2 μg/day), high-dose (0.5 μg/day), or sham treatment. The percentage of eyes gaining at least 15 ETDRS letters at 24 months was 28.7% compared with 16.2% in the sham group. Cataract surgery was required in 74.9% of the low-dose fluocinolone group compared with 23.1% in the sham group. Glaucoma developed in 1.6% of eyes compared with 0.5% of sham eyes.[ 171 ]

Intravitreal Injections of Anti-VEGF Drugs

Anti-VEGF drugs include aptamers (pegaptanib), antibodies to VEGF (bevacizumab), antibody fragments to VEGF (ranibizumab), and fusion proteins, which combine a receptor for VEGF with the Fc fragment of an immunoglobulin (aflibercept and conbercept). The antibodies and fusion proteins bind all isoforms of VEGF-A; fusion proteins additionally bind VEGF-B and placental growth factor. Fusion proteins have higher affinity for VEGF and the potential for less frequent injection frequency in the treatment of DME.[ 172 , 173 ]

Bevacizumab (Avastin ® , Genentech, S. San Francisco, CA, USA/Roche, Basel, SW) is Food and Drug Administration (FDA)-approved for treatment of advanced solid cancers, but is widely used off-label in the treatment of DME. It is much less expensive than the FDA-approved ocular anti-VEGF drugs.[ 174 ] Ziv-aflibercept (Zaltrap ® , Regeneron, Tarrytown, NY, USA) is systemically formulated aflibercept in a buffered solution with a higher osmolarity (1,000 mOsm/L) than aflibercept.[ 175 ] In a rabbit model, intravitreal injection of ziv-aflibercept did not affect serum or intraocular osmolarity, and human studies are beginning to be published.[ 172 , 173 ]

The first anti-VEGF drug used to treat DME was pegaptanib (Macugen ® , Bausch and Lomb, Rochester, NY, USA), which selectively blocks the 165-isoform of VEGF.[ 176 ] Its promise was superseded by superior results obtained with anti-VEGF drugs that blocked all isoforms of VEGF. The efficacy of bevacizumab and ranibizumab were proven in randomized controlled clinical trials in 2010 and that of aflibercept in 2014.[ 177 , 178 , 179 ] A prospective, randomized, comparative effectiveness trial of these three drugs showed no difference in efficacy of the three drugs in eyes with center-involved DME and visual acuity of 20/40 or better at 1 or 2 years of follow-up.[ 174 ] However, in eyes with visual acuity of 20/50 or worse, aflibercept was superior to ranibizumab and bevacizumab at 1 year, whereas at 2 years, aflibercept was no longer superior to ranibizumab but remained superior to bevacizumab.[ 174 , 180 ] An example illustrating effectiveness of aflibercept, persistence of DME, and SD-OCT correlates of suboptimal visual acuity outcomes is shown in Fig. 3 .

Images of a 77-year-old man with type 2 diabetes mellitus, who developed diabetic macular edema of the left eye that reduced visual acuity to 20/63. (a) Red free fundus photography shows microaneurysms and one large blot hemorrhage above the fovea. Fluorescein angiography shows multiple hyperfluorescent microaneurysms in the mid-phase, and late leakage above the fovea in the late frame. (b) The spectral domain-optical coherence tomography on November 30, 2017 shows center-involved diabetic macular edema and subfoveal fluid. After 5 monthly aflibercept injections, the edema has decreased, but persistent edema is present. An ellipsoid zone defect (yellow arrow) is apparent

Approaches aimed at increasing the intravitreal concentration of anti-VEGF agents have not proved beneficial. The READ-3 clinical trial examining two doses of ranibizumab (0.5 and 2.0 mg) in DME showed that at 2 years, the 0.5 mg dose was associated with a better visual outcome.[ 181 , 182 ] Focal laser added from the outset to anti-VEGF does not improve visual acuity outcomes relative to its use in a deferred manner if incomplete drying of the macula occurs with anti-VEGF therapy.[ 183 ] Randomized clinical trials demonstrate that these general results apply across various racial and ethnic groups.[ 174 , 184 ] As a result, in 2018, serial anti-VEGF intravitreal injection monotherapy is the standard of care for treating DME in developed countries.

Although serial injections of anti-VEGF drugs are first-line therapy for DME, some patients do not respond or respond incompletely. In the RISE and RIDE trials, persistent macular thickening was found in 20%–25% of patients.[ 178 ] A secondary analysis of protocol T comparing intravitreal aflibercept, bevacizumab, and ranibizumab for CI-DME found that persistent DME through 24 weeks was found in 31.6%, 65.6%, and 41.5% of eyes receiving aflibercept, bevacizumab, and ranibizumab, respectively.[ 97 ] Despite their incomplete responses, the visual acuity outcomes of eyes with chronic persistent DME were similar to those of eyes with complete resolution of edema.[ 97 ] Similar results were found in a secondary analysis of protocol I comparing intravitreal ranibizumab with prompt or deferred focal laser to intravitreal triamcinolone with prompt focal laser for CI-DME.[ 185 ]

A concomitant effect of anti-VEGF treatment for DME is improvement in retinopathy severity or slowing of the rate of progression of retinopathy. This effect has been noted with ranibizumab and aflibercept.[ 179 ] For aflibercept, there is an association between baseline retinopathy severity and proportion of patients achieving ≥ 2-step severity score improvement.[ 186 ] Another concomitant effect is thinning of the choroid.[ 187 , 188 , 189 ] In treatment naïve CIDME, 3–6 months of bevacizumab or ranibizumab was associated with choroidal thinning.[ 190 , 191 ]

No better results have been reported than those of RISE and RIDE using a monthly injections regimen. In the READ-2 trial, when less than monthly injection frequency after 2 years was succeeded by 1 year of monthly injections, additional statistically significant improvement in visual acuity was attainable (mean of 3.1 additional ETDRS letters).[ 192 ] However, RESOLVE, RESTORE, and DRCR network protocols I and T have demonstrated that similar outcomes can be achieved with monthly injections for 3–4 months followed by OCT and visual acuity guided prn follow-up treatment that decreases the number of injections required to produce the visual outcome.[ 193 , 194 ] Despite safety concerns that intravitreal anti-VEGF drugs could raise the risk of cardiovascular complications in patients with diabetes, there is no consistent evidence that this is the case.[ 174 , 194 , 195 , 196 ]

Bevacizumab is more cost-effective in treating DME than ranibizumab or aflibercept.[ 197 , 198 ] Medicare reimbursement for anti-VEGF drugs varies widely. In 2012, Medicare reimbursement was $50 for bevacizumab and $1,903 for ranibizumab.[ 174 ] The unit dose cost of aflibercept approximates that for ranibizumab for the treatment of macular degeneration, but the smaller approved dose of ranibizumab (0.3 mg) in the US means that the cost of ranibizumab is approximately 60% that of aflibercept. The cost differences arise because bevacizumab is not approved for intraocular use by the FDA, whereas ranibizumab and aflibercept are FDA-approved for intraocular use. Factors that influence which drugs are used include patient-factors and physician-factors. Patient-factors include Medigap insurance coverage and out-of-pocket costs. Physician-factors include Medicare drug repayment policies, industry economic incentives, and risks associated with compounding of bevacizumab.[ 199 ]

Combined Intravitreal Anti-VEGF and Corticosteroid Injections

Combination intravitreal bevacizumab and triamcinolone has not been found to improve outcomes compared with intravitreal bevacizumab monotherapy.[ 200 ] The addition of an intravitreal dexamethasone sustained release device to a regimen of ranibizumab injections did not improve visual acuity outcomes at 24 weeks, although macular thinning was greater than with intravitreal ranibizumab (IVR) alone.[ 96 ]

The idea that vitreomacular adhesion might promote DME arose from the observation that eyes with DME have a lower prevalence of posterior vitreous detachment than eyes without DME.[ 24 ] The subsequent observation that resolution of DME could occur after posterior vitreous detachment strengthened the plausibility that surgical induction of a vitreomacular separation might improve DME.[ 201 , 202 ] With the advent of OCT, vitreomacular adhesion was shown to be a risk factor for DME.[ 87 ] Vitrectomy for DME was first reported in 1992.[ 203 ] Since then, many small retrospective and prospective case series, several small clinical trials, but no large, multi-centered, randomized, controlled trials of the approach have been published.[ 46 , 49 , 61 , 94 , 95 , 98 , 99 , 136 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 ] Vitrectomy was introduced for eyes with a taut posterior hyaloid adherent to the macula, often associated with shallow traction macular detachment, which had failed previous focal/grid laser.[ 45 , 48 , 99 , 136 , 203 , 216 ] Later, it was explored as a therapy for eyes with an attached but non-thickened, non-taut posterior hyaloid or for eyes with persistent DME despite previous focal laser or intravitreal triamcinolone injection regardless of the status of the posterior hyaloid [Figs. ​ [Figs.4 4 and ​ and5 5 ].[ 95 , 99 , 204 , 205 , 207 , 215 , 217 ] Most recently, the treatment has been studied as a potential primary therapy in eyes with more severe edema and greater visual acuity loss at presentation.[ 46 , 136 , 208 , 210 , 213 , 215 , 218 , 219 ] The relative frequencies of the various candidate groups have been reported as follows: refractory DME in eyes with attached but non-taut posterior hyaloid 68%, refractory DME in eyes with posterior vitreous detachment 22%, refractory DME in eyes with a taut posterior hyaloid 5%, and refractory DME in eyes with an epiretinal membrane 5%.[ 220 ]

Images of the left eye of a 21-year-old woman with type 1 diabetes mellitus with proliferative diabetic retinopathy and center-involved diabetic macular edema. Her best corrected visual acuity was 20/40. Because of documented poor adherence to scheduled clinic visits, vitrectomy rather than serial anti-VEGF injection therapy was chosen. (a) New vessels were present on the disc and in the midperiphery of all quadrants with a preretinal hemorrhage superiorly. (b) Fluorescein angiography shows leakage from new vessels and areas of capillary nonperfusion in the midperiphery. (c) Spectral domain-optical coherence tomography shows center-involved intraretinal fluid and subfoveal fluid. The ellipsoid zone is intact (yellow arrow)

Postoperative images from the same patient shown in Fig. 4 . (a) Following a single preoperative bevacizumab injection (to limit intraoperative bleeding), vitrectomy, internal limiting membrane peeling, and panretinal photocoagulation, the new vessels have regressed. (b) Five years later the center-involved diabetic macular edema remains resolved with no subsequent treatments. The best corrected visual acuity was 20/25.

A controversy exists regarding the effects of vitrectomy for DME. Several groups of investigators have reported data to suggest that vitrectomy reduces macular thickening but does not improve visual acuity.[ 135 , 211 , 215 , 218 , 220 ] Others report improved visual acuities simultaneous with decreases in macular thickening or lagging behind macular thinning by a few months.[ 94 , 136 , 208 , 221 ] Others report improved visual acuity in cases with macular traction, but no visual improvement in cases without traction.[ 48 , 222 ]

The largest prospective observational study with standardized data collection was performed by the DRCR network. In this study, which was not a randomized trial, 241 eyes were followed to a primary outcome visit at 6 months. Baseline median CSMT was 491 μm, interquartile range (IQR) (356, 586). Baseline visual acuity was 57 letters, IQR (45, 66). At 6 months follow-up, the median change in CSMT was -97 μm, IQR (−8, +10). The median change in ETDRS letter score was + 1 letter, IQR (−8, +10).

As has been reported for all other treatments for DME, recurrence of edema after initial improvement, incomplete resolution of macular thickening, and failure to respond at all to treatment also occur with vitrectomy, but the rates of these undesirable outcomes may be reduced compared with focal laser and intravitreal triamcinolone injections alone.[ 4 , 9 , 10 , 28 ]

Although there is general acceptance that vitrectomy has a role in the management of at least some cases of DME, there is also consensus that it has no role in many cases, including cases of mild edema with minimal visual compromise and in cases with large submacular hard exudates, in which chronic RPE atrophic changes limit the potential for improvement even after specifically removing these exudates through small retinotomies.[ 137 , 223 ] A prospective, multicenter, randomized clinical trial is needed to define the role of vitrectomy surgery in the management of DME.

Discrepancy between Outcomes in Randomized Controlled Trials and Real-World Conditions

The outcomes obtained in the treatment of DME in Randomized Controlled Trials (RCTs) and under real-world conditions are different. In real-world conditions, inferior visual acuity gains associated with less frequent intravitreal injections have been reported, a relationship that has been consistently noted internationally.[ 224 , 225 , 226 , 227 , 228 , 229 , 230 ] There are many factors that possibly explain the discrepancy. In clinical trials, patients are preselected for their commitment to complete the schedule of visits, costs are borne in most cases by the entity performing the study, and subsidies for travel are often provided. In real life, lack of time and means could contribute to lower treatment intensity, the nonmedical costs for patients are onerous especially for patients of lower economic means and who are motivated not to miss work for doctor visits, and the need to manage other comorbidities.[ 227 , 228 , 231 ] Both non-elderly and elderly patients with DME have higher rates of comorbidity and loss of work time and personal time compared with diabetic patients without DME.[ 232 ] For example, non-elderly patients with DME had an average of 24.7 annual days with healthcare visits compared with 14.4 for age-matched controls with diabetes but no DME.[ 232 ] The average direct medical cost ratio, adjusted for age, sex, race, geographic region, and comorbidity, for Medicare patients with DME over 3 years was 1.31 times that for diabetic controls without DME.[ 233 ] In a retrospective claims analysis of 2,733 newly diagnosed patients with DME conducted over the interval 2008 through 2010, the mean annual numbers of bevacizumab injections were 2.2, 2.5, and 3.6 for the years 2008, 2009, and 2010, respectively, fewer than in major clinical trials of anti-VEGF agents.[ 227 ] Similarly, in a retrospective study of 121 eyes of 110 patients with a new diagnosis of DME receiving anti-VEGF injection therapy for the first time between 2007 and 2012 from the Geisinger Health System database, a mean of 3.1 ± 2.4 injections per study eye were given in the first year of treatment. The mean change in corrected visual acuity was 4.7 ± 12.3 approximate ETDRS letters, where approximate ETDRS letters are calculated from Snellen visual acuity. Higher numbers of anti-VEGF injections in the first 12 months after diagnosis correlate with improved visual outcomes, implying that real-world outcomes usually lag those in RCTs.[ 227 ] Other factors that may contribute to the discrepancies include lack of protocol refractions in many real-world visits, and the variability in treatment regimens and follow-up used by real-world clinicians compared with standardized regimens in clinical trials.[ 228 ]

In a German study looking at pooled anti-VEGF injections for DME, the mean change in VA at 12 months was -1.3 letters with a median of 6 injections.[ 225 ] Both the number of injections and the visual acuity outcomes are inferior to those reported in RCTs. In a study of Medicare claims data from 2008 through 2010, the mean number of claims per year for anti-VEGF injections for DME was 3.1–4.6.[ 226 ] A US commercial database claims study over 2008 through 2010 reported mean numbers of bevacizumab injections for DME varying from 2.2 to 3.6.[ 227 ] By comparison, the number of injections of ranibizumab in RISE and RIDE was 12 in the first year, and of ranibizumab, bevacizumab, or aflibercept was 9–10 in DRCR protocol T.[ 174 , 178 ] A Danish study of IVR for DME at 12 months reported a median number of injections of 5 and a median change in BCVA of +5 ETDRS letters.[ 229 ] An Italian study of IVR for eyes with unilateral DME reported a mean ± SD number of injections of 4.15 ± 1.99 over 18 months of follow-up with a worsening of visual acuity on average.[ 230 ]

New Directions

Genetic mutations that render patients more or less susceptible to DME as a complication of diabetes mellitus are likely to be defined. The physiological pathways contributing to DME and not mediated by VEGF are a likely focus of future research. Using OCT and OCT angiography, it should be possible to define at almost histological levels the retinal changes occurring in DME and determine, which if any changes associate with visual outcomes. Clinical trials of new drugs initiated by drug companies and comparative effectiveness research by organizations like the DRCR network will provide an evidential basis for rational therapy. Efforts to close the gap between randomized clinical trials and real-world outcomes and to reduce the cost of care will draw increasing attention.

Summary of Key Points

• The prevalence of DME is increasing worldwide, mainly because of increasing type 2 diabetes.
• Understanding retinal anatomy helps in analyzing clinical presentations of DME based on the effects of the avascularity of the central macula, the locations of the microvessels in the inner retinal layers, the importance of the pigment epithelial layer, and the role of the vitreoretinal interface.
• The oxygen theory of DME is the most comprehensive pathophysiologic schema and VEGF is the single most important mediator in that pathway, although not the sole mediator.
• OCT is critical in managing DME.
• Macular thickening has an imperfect correlation with visual acuity probably due to factors currently difficult to assess such as duration of edema and degree of macular ischemia.
• Metabolic control of blood glucose, blood pressure, and serum lipids is the foundation of therapy for DME, and specific ocular treatments are most effective when this foundation is optimized first.
• Serial injections of anti-VEGF drugs are first-line therapy for DME. Focal/grid laser, intravitreal injections of corticosteroids, and vitrectomy have secondary roles in particular cases.

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• Published: 29 October 2019

Management of patients with diabetic macular oedema and good visual acuity: new findings from Protocol V

• Giuseppe Querques 1 ,
• Enrico Borrelli   ORCID: orcid.org/0000-0003-2815-5031 1 ,
• Riccardo Sacconi   ORCID: orcid.org/0000-0003-2891-2012 1 &
• Francesco Bandello 1  

Eye volume  34 ,  pages 792–794 ( 2020 ) Cite this article

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• Diabetes complications
• Eye diseases

As we observe a dramatic increase in diabetes prevalence worldwide, diabetes-associated eye complications are rapidly emerging as a global health issue that may threaten patients’ visual acuity [ 1 ]. Even though treatment of diabetic retinopathy (DR) can reduce the risk of visual loss by 60% [ 2 ], this disorder still remains the leading cause of blindness among working-age adults.

Diabetic macular oedema (DMO) is a major cause of vision decrease in these patients and may occur at any stage of DR. In 1985, the Early Treatment Diabetic Retinopathy Study reported on the use of laser photocoagulation to treat DMO [ 3 ]. The latter trial enrolled 1122 patients with DMO and demonstrated that the laser treatment effects in a reduced risk of moderate vision loss. Until the introduction of intravitreal anti-vascular endothelial growth factor (VEGF) injections, laser had been thus considered as the treatment of choice for eyes with DMO. Since 2010, several evidences have suggested that anti-VEGF agents may be considered as an effective and safe treatment in eyes with DMO and impaired vision [ 4 , 5 , 6 , 7 , 8 ]. To simplify, anti-VEGF therapies demonstrated a better improvement in visual acuity in comparison with focal/grid laser therapy. Nonetheless, the anti-VEGF treatment was also displayed to produce an amelioration in DR severity [ 9 ], even without an enhancement in retinal perfusion [ 10 ]. Of note, in a number of cases the anti-VEGF treatment may be ineffective and in these cases a switch to other treatments, including intravitreal dexamethasone, was proved to be potentially effective, especially in presence of definite imaging biomarkers [ 11 ].

Thanks to the support of the National Eye Institute, National Institutes of Health, the Diabetic Retinopathy Clinical Research (DRCR) Retina Network has organized and realized different important clinical trials which delineated guidelines for patients with DMO. In detail, in a study on 854 eyes with DMO, they provided evidence that intravitreal ranibizumab is superior in gaining visual acuity, with 30% of eyes increasing by three lines of visual acuity and 50% increasing by two lines at 1 year [ 4 ]. Successively, the DRCR Retina Network compared the three available anti-VEGF drugs in 660 DMO eyes with moderate to severe visual impairment [ 12 , 13 ]. The latter clinical trial demonstrated that all the three agents cause VA improvement from baseline to 1 and 2 years with a decreased number of injections in the second year [ 12 , 13 ]. However, aflibercept was displayed to be more efficacious at improving vision at 1 year in eyes with severe visual impairment (20/50 to 20/320 Snellen equivalent) [ 12 , 14 ]. Among these eyes with worse baseline visual acuity, aflibercept had superior visual outcomes at 2 years compared with bevacizumab, while superiority of aflibercept over ranibizumab, noted at 1 year, was no longer displayed [ 13 , 14 ].

Limited data was however available on the most appropriate therapeutic approach for eyes with DMO and good visual acuity. This aspect is crucial, assuming that these patients represent a main portion of DR population [ 15 ]. Recently, the DRCR Retina Network investigators reported significant results from Protocol V which specifically sought to address this critical debate [ 16 ]. This study included patients with centre-involved DMO and good visual acuity (20/25 or better) who were divided into three arms: prompt laser photocoagulation, prompt aflibercept therapy, or observation. Furthermore, this trial allowed eyes randomized to observation or laser to receive aflibercept rescue if visual acuity decreased from baseline by ≥10 letters at one visit or by 5–9 letters at two following visits [ 16 ]. This study concluded that the proportion of eyes experiencing a reduction in visual acuity by five letters at 2 years was similar independently on the assigned group [ 16 ]. Moreover, data from this trial also demonstrated that prompt treatment with aflibercept does not cause a significant reduction in the risk of a five letter or more loss, as this outcome was reached in 19%, 17%, and 16% in the observation, laser and aflibercept groups, respectively [ 16 ]. Importantly, ~10% of patients within the observation group experienced a two-step improvement in visual acuity, which was similar to that exhibited in the other two groups [ 16 ]. Taking all these results together, the investigators concluded that postponing treatment in centre-involved DMO and good visual acuity does not effect in a worse prognosis, as compared with prompt laser or intravitreal treatment.

Assuming that the cost of the drugs would be avoided, these results may have a huge impact on cost and burden of care delivery for patients and the health care system. Nonetheless, a reduction of the psychological burden for patients and their families would also be obtained. Importantly, we might avoid treatment-related unnecessary risks to patients, including the injection procedure itself. All these aspects emphasize the importance of these results and clinicians must recognize their relevance and accordingly employ a conservative management in patients with DMO and good visual acuity, at least until there is recorded reduction in visual acuity.

To completely comprehend these evidences from Protocol V, it is worth noting that included patients in this trial were characterized by a good metabolic and blood pressure control, as well as they routinely attended their follow-up visits. Although it might be said that these subjects do not necessarily reflect the profile of diabetic patients in real-world practice, the OBTAIN study recently reported on real-world data and similarly showed that visual acuity is maintained over a 1 year of follow-up in DMO patients with good visual acuity [ 17 ]. However, future studies are needed to reveal whether this conservative management might impact clinic attendance and long-term follow-up care among these patients.

Finally, future developments of more lasting and less invasive therapies might encourage to consider starting treatment earlier. Moreover, further development of novel-emerging therapies for DMO [ 18 ], including subthreshold laser treatment whose beneficial effect has already been demonstrated [ 19 ], may also modify the treatment threshold for these patients. Also, new discovered imaging biomarkers might allow the identification of a sub-group of patients with DMO and good visual acuity who may actually benefit from an early treatment.

Querques G. Eye complications of diabetes. Acta Diabetol. 2019;56:971–971. http://www.ncbi.nlm.nih.gov/pubmed/31201573 . Accessed 12 Aug 2019.

Article   Google Scholar  

American Diabetes Association AD. Standards of medical care in diabetes–2010. Diabetes Care. 2010;33:S11–61. http://www.ncbi.nlm.nih.gov/pubmed/20042772 . Accessed 2 Jun 2019.

Photocoagulation for diabetic macular edema: early treatment diabetic retinopathy study report number 1 early treatment diabetic retinopathy study research group. Arch Ophthalmol. 1985;103:1796–806.

Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema - the diabetic retinopathy clinical research network. Ophthalmology. 2011;118:609–14.

Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT Study). 12-month data: report 2. Ophthalmology. 2010;117:1078–e2.

Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL, Friedman SM, et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118:609–14.

Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615–25.

Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, et al. Ranibizumab for diabetic macular edema: Results from 2 phase iii randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789–801.

Ip MS, Zhang J, Ehrlich JS. The clinical importance of changes in diabetic retinopathy severity score. Ophthalmology. 2017;124:596–603.

Bonnin S, Dupas B, Lavia C, Erginay A, Dhundass M, Couturier A, et al. Anti–vascular endothelial growth factor therapy can improve diabetic retinopathy score without change in retinal perfusion. Retina. 2019;39:426–34.

Article   CAS   Google Scholar  

Cavalleri M, Cicinelli MV, Parravano M, Varano M, De Geronimo D, Sacconi R, et al. Prognostic role of optical coherence tomography after switch to dexamethasone in diabetic macular edema. Acta Diabetol. 2019: 1–9. http://link.springer.com/10.1007/s00592-019-01389-4 . Accessed 12 Aug 2019.

Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193–203. http://www.ncbi.nlm.nih.gov/pubmed/25692915 . Accessed 11 Aug 2019.

Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. Ophthalmology. 2016;123:1351–9. https://linkinghub.elsevier.com/retrieve/pii/S0161642016002062 . Accessed 11 Aug 2019.

Ashraf M, Souka A, Adelman R, Forster SH. Aflibercept in diabetic macular edema: evaluating efficacy as a primary and secondary therapeutic option. Eye. 2016;30:1531–41.

Bressler NM, Varma R, Doan QV, Gleeson M, Danese M, Bower JK, et al. Underuse of the health care system by persons with diabetes mellitus and diabetic macular edema in the United States. JAMA Ophthalmol. 2014;132:168–73.

Baker CW, Glassman AR, Beaulieu WT, Antoszyk AN, Browning DJ, Chalam KV, et al. Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial. JAMA. 2019;321:1880–94.

Busch C, Fraser-Bell S, Zur D, Rodríguez-Valdés PJ, Cebeci Z, Lupidi M, et al. Real-world outcomes of observation and treatment in diabetic macular edema with very good visual acuity: the OBTAIN study. Acta Diabetol. 2019;56:777–84.

Sacconi R, Giuffrè C, Corbelli E, Borrelli E, Querques G, Bandello F. Emerging therapies in the management of macular edema: a review. F1000Research 2019;8:1413 https://f1000research.com/articles/8-1413/v1 . Accessed 12 Aug 2019.

Mansouri A, Sampat KM, Malik KJ, Steiner JN, Glaser BM. Efficacy of subthreshold micropulse laser in the treatment of diabetic macular edema is influenced by pre-treatment central foveal thickness. Eye. 2014;28:1418–24.

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Giuseppe Querques, Enrico Borrelli, Riccardo Sacconi & Francesco Bandello

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FB is a consultant for: Alcon (Fort Worth,Texas,USA), Alimera Sciences (Alpharetta, Georgia, USA), Allergan Inc (Irvine, California,USA), Bayer Shering-Pharma (Berlin, Germany), Bausch and Lomb (Rochester, New York, USA), Genentech (San Francisco, California, USA), Hoffmann-La-Roche (Basel, Switzerland), NovagaliPharma (Évry, France), Novartis (Basel, Switzerland), Sanofi-Aventis (Paris, France), Thea (Clermont-Ferrand, France), Thrombogenics (Heverlee,Belgium), and Zeiss (Dublin, USA). GQ is a consultant for: Alimera Sciences (Alpharetta, Georgia, USA), Allergan Inc (Irvine, California, USA), Amgen (Thousand Oaks,USA), Bayer Shering-Pharma (Berlin, Germany), Bausch and Lomb (Rochester, New York, USA), Heidelberg (Germany), KBH (Chengdu; China), Hoffmann-La-Roche (Basel, Switzerland), LEH Pharma (London, UK), Lumithera (Poulsbo; USA), Novartis (Basel, Switzerland), Topcon (Tokyo, Japan), Sandoz (Berlin, Germany), Sifi (Catania, Italy), Sooft-Fidea (Abano, Italy), Thea (Clermont-Ferrand, France), and Zeiss (Dublin, USA). The remaining authors declare that they have no conflict of intetrest.

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Querques, G., Borrelli, E., Sacconi, R. et al. Management of patients with diabetic macular oedema and good visual acuity: new findings from Protocol V. Eye 34 , 792–794 (2020). https://doi.org/10.1038/s41433-019-0658-x

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Diabetic Macular Edema: Current Understanding, Molecular Mechanisms and Therapeutic Implications

Affiliations.

• 1 Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), School of Medicine, Shanghai Jiao Tong University, 100 Haining Road, Hongkou District, Shanghai 200080, China.
• 2 National Clinical Research Center for Eye Diseases, Shanghai 200080, China.
• 3 Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China.
• 4 Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China.
• 5 Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai 200080, China.
• 6 Nursing Department, People's Hospital of Huangdao District, Qingdao 266400, China.
• 7 Department of Ophthalmology, Shanghai Aier Eye Hospital, Shanghai 200336, China.
• PMID: 36359761
• PMCID: PMC9655436
• DOI: 10.3390/cells11213362

Diabetic retinopathy (DR), with increasing incidence, is the major cause of vision loss and blindness worldwide in working-age adults. Diabetic macular edema (DME) remains the main cause of vision impairment in diabetic patients, with its pathogenesis still not completely elucidated. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of DR and DME. Currently, intravitreal injection of anti-VEGF agents remains as the first-line therapy in DME treatment due to the superior anatomic and functional outcomes. However, some patients do not respond satisfactorily to anti-VEGF injections. More than 30% patients still exist with persistent DME even after regular intravitreal injection for at least 4 injections within 24 weeks, suggesting other pathogenic factors, beyond VEGF, might contribute to the pathogenesis of DME. Recent advances showed nearly all the retinal cells are involved in DR and DME, including breakdown of blood-retinal barrier (BRB), drainage dysfunction of Müller glia and retinal pigment epithelium (RPE), involvement of inflammation, oxidative stress, and neurodegeneration, all complicating the pathogenesis of DME. The profound understanding of the changes in proteomics and metabolomics helps improve the elucidation of the pathogenesis of DR and DME and leads to the identification of novel targets, biomarkers and potential therapeutic strategies for DME treatment. The present review aimed to summarize the current understanding of DME, the involved molecular mechanisms, and the changes in proteomics and metabolomics, thus to propose the potential therapeutic recommendations for personalized treatment of DME.

Keywords: anti-VEGF; blood-retinal barrier breakdown; diabetic macular edema; diabetic retinopathy; drainage dysfunction; inflammation; metabolomics; proteomics.

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• Research Support, Non-U.S. Gov't
• Angiogenesis Inhibitors / therapeutic use
• Diabetes Mellitus* / drug therapy
• Diabetic Retinopathy* / drug therapy
• Diabetic Retinopathy* / metabolism
• Intravitreal Injections
• Macular Edema* / drug therapy
• Vascular Endothelial Growth Factor A / metabolism
• Vascular Endothelial Growth Factor A
• Angiogenesis Inhibitors

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Introduction

Research design and methods, conclusions, article information, trends in the prevalence and treatment of diabetic macular edema and vision-threatening diabetic retinopathy among commercially insured adults aged <65 years.

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Elizabeth A. Lundeen , Minchul Kim , David B. Rein , John S. Wittenborn , Jinan Saaddine , Joshua R. Ehrlich , Christopher S. Holliday; Trends in the Prevalence and Treatment of Diabetic Macular Edema and Vision-Threatening Diabetic Retinopathy Among Commercially Insured Adults Aged <65 Years. Diabetes Care 1 April 2023; 46 (4): 687–696. https://doi.org/10.2337/dc22-1834

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Examine the 10-year trend in the prevalence and treatment of diabetic macular edema (DME) and vision-threatening diabetic retinopathy (VTDR) among commercially insured adults with diabetes.

We analyzed the 10-year trend (2009–2018) in health care claims for adults aged 18–64 years using the IBM MarketScan Database, a national convenience sample of employer-sponsored health insurance. We included patients continuously enrolled in commercial fee-for-service health insurance for 24 months who had a diabetes ICD-9/10-CM code on one or more inpatient or two or more different-day outpatient claims in the index year or previous calendar year. We used diagnosis and procedure codes to calculate the annual prevalence of patients with one or more claims for 1 ) any DME, 2 ) either DME or VTDR, and 3 ) antivascular endothelial growth factor (anti-VEGF) injections and laser photocoagulation treatment, stratified by any DME, VTDR with DME, and VTDR without DME. We calculated the average annual percent change (AAPC).

From 2009 to 2018, there was an increase in the annual prevalence of patients with DME or VTDR (2.1% to 3.4%; AAPC 7.5%; P < 0.001) and any DME (0.7% to 2.6%; AAPC 19.8%; P < 0.001). There were sex differences in the annual prevalence of DME or VTDR and any DME, with men having a higher prevalence than women. Annual claims for anti-VEGF injections increased among patients with any DME (327%) and VTDR with DME (206%); laser photocoagulation decreased among patients with any DME (−68%), VTDR with DME (−54%), and VTDR without DME (−62%).

Annual claims for DME or VTDR and anti-VEGF injections increased whereas those for laser photocoagulation decreased among commercially insured adults with diabetes.

Graphical Abstract

More than 37 million adults aged ≥18 years in the U.S. have diabetes ( 1 ), putting them at risk for serious complications like diabetic retinopathy (DR), the leading cause of incident blindness among U.S. adults aged 20–74 years ( 2 ). DR occurs when prolonged exposure to high blood glucose levels damages blood vessels in the retina. Risk of DR is primarily influenced by diabetes duration and long-term glycemic control ( 3 – 7 ). DR is estimated to affect 28.5% of U.S. adults aged ≥40 years who have diabetes ( 8 ). Vision-threatening DR (VTDR) includes severe nonproliferative DR and proliferative DR. Diabetic macular edema (DME), which can be present alone or with any stage of DR, is a vision-threatening condition that occurs when blood vessels in the retina leak fluid into the macula. Nationally representative data show that VTDR and DME affect 4.4% and 3.8%, respectively, of U.S. adults aged ≥40 years who have diabetes ( 3 , 8 ).

Studies have documented an increase in diabetes prevalence among U.S. adults in the past two decades ( 9 , 10 ). Data from the National Health and Nutrition Examination Survey (NHANES) show that the prevalence of diabetes among U.S. adults aged ≥18 years increased from 9.8% (95% CI 8.6–11.1%) in 1999–2000 to 14.3% (95% CI 12.9–15.8%) in 2017–2018 ( 10 ). Additionally, the prevalence of HbA 1c <7% among US adults aged ≥20 years who have diabetes decreased from 57.4% (95% CI 52.9–61.8%) in 2007–2010 to 50.5% (95% CI 45.8–55.3%) in 2015–2018 ( 11 ). These recent trends in the prevalence of diabetes and glucose control merit the examination of trends in DR and DME among adults with diabetes to help inform prevention and treatment interventions.

Early detection and timely treatment of diabetes-related eye diseases can reduce the risk of permanent vision loss. Without treatment, a person who develops proliferative DR has a 50% chance of becoming blind within 5 years ( 12 , 13 ). The past 20 years have seen the emergence of new treatments, particularly for DME, that show superior effectiveness in reducing vision loss. For decades, laser photocoagulation was the mainstay of treatment for VTDR and DME. Specifically, the preferred treatment for proliferative DR is panretinal laser photocoagulation (i.e., scatter laser surgery) and the standard of care for non–center-involved DME was focal laser photocoagulation surgery ( 5 , 14 , 15 ). In the early 2000s, ophthalmologists began treating center-involved DME using intravitreal injections of antivascular endothelial growth factor (anti-VEGF) agents (namely, ranibizumab, bevacizumab, and later, aflibercept). A meta-analysis of randomized clinical trials of the efficacy of these three anti-VEGF agents in treating moderate vision loss among patients with DME found they were all superior in improving vision after 1 year compared with laser photocoagulation treatment ( 16 ). Studies have also demonstrated that intravitreal injections of anti-VEGF therapies can be alternatives to panretinal laser photocoagulation for proliferative DR ( 17 , 18 ).

Previous studies on the prevalence of DR and DME in the United States are limited by older data. The only nationally representative, objectively measured data on the prevalence of DR and DME among adults aged ≥40 years are from NHANES, which last fielded this information from 2005 to 2008 ( 3 , 8 ). Few studies have examined recent trends in the prevalence and treatment of diabetes-related eye diseases. Previously, we described an increase from 2009 to 2018 in the annual prevalence of Medicare Part B fee-for-service beneficiaries aged ≥65 years who had a claim for DME or VTDR (from 2.8 to 4.3%) as well as significant changes in the use of different treatment modalities during this period ( 19 ). However, to our knowledge, similar studies of people aged <65 years have not been conducted. It is important to also understand these trends in patients with diabetes aged <65 years as this age group is in their prime working years and has experienced greater growth in the prevalence of diabetes from 1999–2002 to 2015–2018 ( 10 ). In this article, we examine the 10-year trend (2009–2018) in the annual prevalence of commercially insured adults aged 18–64 years who have diabetes and who have payment claims for DME or VTDR, the annual prevalence of treatment, and differences in prevalence of DME or VTDR by age and sex groups.

We analyzed annual trends in health care claims from 2009 to 2018 for adults aged 18–64 years, using the IBM MarketScan Database, a national convenience sample of employer-sponsored health insurance beneficiaries ( 20 ). Patients were retained in the analytic sample for each index year if they were continuously enrolled in commercial noncapitated (i.e., fee-for-service) health insurance for 24 months, consisting of the index year and the previous calendar year. The analytic sample for each year was further restricted to patients with diabetes (all types), defined using the Chronic Conditions Data Warehouse algorithm as those who had an International Classification of Diseases 9th Revision (ICD-9-CM) or 10th Revision (ICD-10-CM) diabetes diagnosis code on one or more inpatient or two or more different-day outpatient claims in the index year or previous calendar year ( 21 ).

In each index year, we determined the annual prevalence of patients with diabetes who had one or more claims for DME or VTDR (hereafter, DME/VTDR), defined using ICD-9-CM and ICD-10-CM diagnosis codes ( Supplementary Table 1 ). Annual prevalence of DME/VTDR was calculated as the number of patients with one or more claims with a diagnosis of DME/VTDR in the index year divided by the number of patients with diabetes in that year. Because of the emergence of new therapies for DME, we also separately calculated the annual prevalence of patients with diabetes with one or more claims for any DME (hereafter, any DME), with or without any stage of DR, using ICD diagnosis codes ( Supplementary Table 2 ). Last, we present the annual prevalence of patients with diabetes with one or more claims for non–vision-threatening diabetes-related eye diseases, defined using ICD diagnosis codes ( Supplementary Table 3 ) as background DR, nonproliferative DR (not otherwise specified), unspecified DR without macular edema, mild nonproliferative DR (without DME), moderate nonproliferative DR (without DME), diabetes with ophthalmic manifestations, and other diabetic ophthalmic complications. The annual prevalence of these three categories of disease (i.e., DME/VTDR, any DME, and diabetes with non–vision-threatening diabetes-related eye diseases) is presented overall, stratified by sex and age groups (18–44, 45–54, and 55–64 years), and cross-stratified by age group and sex.

We also examined trends in the annual prevalence of four types of treatment: anti-VEGF injections, laser photocoagulation, retinal detachment repair, and vitrectomy. Patients were defined as having ach of these treatment types if they had one or more claims in the index year with the Current Procedural Terminology codes or Healthcare Common Procedure Coding System codes for these procedures ( Supplementary Table 4 ). The annual prevalence for each of the four treatment types is presented for three groups of patients: those with any DME, VTDR with DME, and VTDR without DME ( Supplementary Tables 5 – 7 ). All prevalence figures were standardized using the direct method to the age and sex distribution of the analytic sample in 2009 to account for differences in the age and sex composition of the study population when assessing trends over time. Analyses were performed using Stata 16 (StataCorp, College Station, TX) and SAS 9.4 (SAS Institute, Cary, NC). To assess trends in the annual prevalence of DME/VTDR, any DME, non–vision-threatening diabetes-related eye diseases, and the four treatment types, we used the Joinpoint Regression Program, version 4.8.0.1 (National Cancer Institute). This software uses permutation tests to find points where the trend changes significantly and calculates the annual percentage change (APC) for each segment of the trend, as well as the average annual percent change (AAPC), which is a summary measure of the trend over the entire period. Last, differences by age and sex in the annual prevalence of DME/VTDR, any DME, and non–vision-threatening diabetes-related eye disease were tested for statistical significance using the Wald test ( Supplementary Tables 8 – 10 ). Confidence intervals for the statistics presented in all figures are shown in Supplementary Tables 11 – 14 .

This research was considered exempt from institutional review board review under 45 Code of Federal Regulations 46.101[b][5], which covers Department of Health and Human Services research and demonstration projects that are designed to study, evaluate, or examine public benefit or service programs. Findings of this study are reported in accordance with Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.

From 2009 to 2018, among commercially insured adults aged 18–64 years, approximately 1 in 15 patients had diabetes (range: 6.83% [95% CI 6.82–6.85] in 2013 to 7.51% [95% CI 7.49–7.53] in 2017) ( Supplementary Table 15 ). The size of the patient population with diabetes was 1.12 million in 2009 and 779,212 in 2018. The age and sex distribution of the population remained stable over the 10-year period, with approximately half of the patients being female and half aged 55–64 years.

The annual prevalence of patients with diabetes who had DME/VTDR increased significantly from 2.07% (95% CI 2.05–2.10) in 2009 to 3.38% (95% CI 3.33–3.42) in 2018 (AAPC 7.5%; P < 0.001) ( Fig. 1 ). An inflection point in the trend was found at 2011, with the annual prevalence decreasing nonsignificantly from 2009 to 2011 (APC −4.2%; P = 0.60) and then increasing significantly from 2011 to 2018 (APC 9.6%; P < 0.001). The prevalence of DME/VTDR was significantly higher among men compared with women from 2010 to 2018 (all P ≤ 0.01 ( Fig. 1 , Supplementary Table 8 ). Beginning in 2010, the prevalence of DME/VTDR was highest among men and women aged 55–64 years and men 45–54 years, compared with the other age and sex groups (all P ≤ 0.05) ( Fig. 1 ).

Annual prevalence of having one or more claims for DME/VTDR among adults 18–64 years of age with diabetes, according to the IBM MarketScan Database (2009–2018) ( 20 ). DME or VTDR was defined as DME, severe nonproliferative DR (with or without DME), or proliferative DR (with or without DME).

Similarly, the annual prevalence of patients with diabetes who had any DME increased significantly from 0.67% (95% CI 0.65–0.68) in 2009 to 2.60% (95% CI 2.57–2.64) in 2018 (AAPC 19.8%; P < 0.001) ( Fig. 2 ). From 2010 to 2018, the prevalence of any DME was significantly higher among men compared with women (all P < 0.01) ( Fig. 2 ), and the prevalence was highest among men and women aged 55–64 years and men aged 45–54 years (all P ≤ 0.01) ( Fig. 2 , Supplementary Table 9 ). Conversely, from 2009 to 2018, the annual prevalence of non–vision-threatening diabetes-related eye diseases among patients with diabetes decreased significantly from 8.93% (95% CI 8.88–8.99) in 2009 to 5.96% (95% CI 5.91–6.01] in 2018 (AAPC −4.9%; P < 0.001) ( Fig. 3 ). An inflection point in the trend was detected at 2014, with the annual prevalence decreasing nonsignificantly from 2009 to 2014 (APC −0.9%; P = 0.60) and then decreasing significantly from 2014 to 2018 (APC −9.6%; P < 0.001). From 2009 to 2018, the prevalence of non–vision-threatening diabetes-related eye disease was significantly higher among men compared with women (all P < 0.01) ( Fig. 3 ), and the prevalence was highest among men and women aged 55–64 years and men aged 45–54 years (all P ≤ 0.01) ( Fig. 3 , Supplementary Table 10 ).

Annual prevalence of having one or more claims for any DME among adults 18–64 years of age with diabetes, according to the IBM MarketScan Database (2009–2018) ( 20 ). Any DME was characterized as any diagnosis of DME, by itself or with any stage of DR.

Annual prevalence of having one or more claims for non–vision-threatening diabetes-related eye disease among adults 18–64 years of age with diabetes, according to the IBM MarketScan Database (2009–2018) ( 20 ). Non–vision-threatening diabetes-related eye disease was characterized as background DR, nonproliferative DR (not otherwise specified), unspecified DR without macular edema, mild nonproliferative DR (without DME), moderate nonproliferative DR (without DME), diabetes with ophthalmic manifestations, or other diabetic ophthalmic complication.

From 2009 to 2018, the annual prevalence of having laser photocoagulation decreased significantly among all three groups: those with any DME (51.32% [95% CI 49.80–52.83] to 16.56% [95% CI 15.96–17.18]; AAPC −11.7%; P < 0.001); VTDR with DME (68.31% [95% CI 66.71–69.87] to 31.45% [95% CI 30.52–32.39]; AAPC −8.0%; P < 0.001); and VTDR without DME (33.03% [95% CI 32.30–33.77] to 12.7% [95% CI 11.89–13.57]; AAPC −9.2%; P < 0.001) ( Fig. 4 ). During this period, the annual prevalence of having anti-VEGF injections increased significantly among those with any DME (7.95% [95% CI 7.16–8.81] to 33.74% [95% CI 32.97–34.52]; AAPC 6.3%; P < 0.001) and those having VTDR with DME (18.66% [95% CI 17.37–20.02] to 57.32% [95% CI 56.32–58.31]; AAPC 5.6%; P < 0.001). Among those with VTDR with DME, joinpoint regression detected two distinct trend lines, with the annual anti-VEGF prevalence increasing significantly and steeply from 2009 to 2012 (APC 26.8%; P < 0.001) and still increasing, but less steeply, from 2012 to 2018 (APC 3.1%; P < 0.001). By 2018, more than half of patients with VTDR with DME received treatment using anti-VEGF injections. Over the 10-year period, among those with VTDR without DME, there was a trend of increasing annual prevalence of having received anti-VEGF injections, but this increase was not significant (APC 7.0%; P = 0.1).

Annual prevalence of having one or more claims for treatment among adults 18–64 years with diabetes, according to the IBM MarketScan Database (2009–2018) ( 20 ). VTDR was defined as severe nonproliferative DR or proliferative DR.

Vitrectomy and retinal detachment repair were less common procedures overall, as expected, and were most frequently performed among patients with VTDR with DME (range in annual prevalence across the 10-year period: from 7.04% [95% CI 6.54–7.58] in 2018 to 13.78% [95% CI 12.62–15.02] in 2010; and from 5.00% [95% CI 4.57–5.47] in 2018 to 6.89% [95% CI 6.05–7.84] in 2010, respectively). From 2009 to 2018, the annual prevalence of having a vitrectomy significantly decreased among patients with VTDR with DME (from 12.94% [95% CI 11.84–14.13] to 7.04% [95% CI 6.54–7.58]; AAPC −7.1%; P < 0.001) and those with VTDR without DME (9.33% [95% CI 8.89–9.79] to 4.16% [95% CI 3.68–4.70]; AAPC −7.9%; P < 0.001). Annual prevalence of retinal detachment repair declined only among patients with VTDR without DME.

From 2009 to 2018, we found a 62% increase in the annual prevalence of commercially insured adults with diabetes who had a claim for DME or VTDR. We found significant age and sex differences from 2010 to 2018, with the annual prevalence of having a claim for DME/VTDR higher among men than women and highest among men and women aged 55–64 years and men aged 45–54 years compared with the other age and sex groups. There were marked changes during this time in the use of different treatment modalities for DME and VTDR, including a substantial increase in the annual prevalence of having a claim for anti-VEGF injections, particularly among those with any DME and those with VTDR with DME (a 327% and 206% increase, respectively). Among all three groups of patients—those with any DME, VTDR with DME, and VTDR without DME—there was a similarly pronounced decline (68%, 54%, and 62%, respectively) in the annual prevalence of having a claim for laser photocoagulation.

To our knowledge, there are no comparable published data on trends in the prevalence of DR and DME among adults aged <65 years. Our prevalence estimates are similar to those published using the 2005–2008 NHANES data, which showed that VTDR and DME affect 4.4% and 3.8%, respectively, of U.S. adults aged ≥40 years who have diabetes ( 3 , 8 ). Using identical case definitions as the present study, we published a study describing very similar trends from 2009 to 2018 in the annual prevalence of Medicare Part B fee-for-service beneficiaries aged ≥65 years who had a claim for DME/VTDR (from 2.8 to 4.3%) or any DME (1.0% to 3.3%) ( 19 ). The reasons for the trends we observed that show an increase in annual claims for vision-threatening diabetes-related eye disease are unknown. Diabetes duration and long-term glycemic control are primary risk factors for DR and DME ( 3 – 7 ). The significant decrease in age at diagnosis of type 2 diabetes seen in the 1990s in the U.S. could have contributed to our observed trends in complications as people are living longer with diabetes ( 22 ). Another contributing factor might be the documented trends showing continued poor glycemic control among adults with diabetes during this period ( 10 , 11 ). A study using MarketScan data with linked claims and electronic health records found that from 2012 to 2019, there was a decrease in the percentage of adults aged ≥18 years with diabetes who achieved a HbA 1c <7% ( 23 ). However, we cannot discount the possibility that improvements in screening, imaging technology, diagnosis, or medical coding over the past decade may have influenced these trends.

We documented statistically significant differences in the prevalence of annual claims for DME/VTDR, any DME, and non–vision-threatening diabetes-related eye disease by sex, with men having a higher prevalence than women; however, these differences by sex are small and may not be clinically meaningful. Several U.S. examination-based population studies have stratified the prevalence of diabetes-related eye disease by sex; however, the older age and small sample size of some of these studies make a direct comparison with our study results difficult ( 24 – 28 ). A study using data from the New Jersey 725 study and the Wisconsin Epidemiologic Study of Diabetic Retinopathy examined the prevalence of DR among adults with type 1 diabetes and found that men were more likely to have VTDR than women (relative risk 1.17; 95% CI 1.01–1.36) ( 24 ). The Chinese American Eye Study found that men had a higher prevalence than women of moderate DR (15.0% vs. 9.2%, respectively; P = 0.02) and proliferative DR (3.6% vs. 1.4%, respectively; P = 0.049), even after adjusting for age ( 25 ). A retrospective study in Puerto Rico examined eye-clinic health records collected through a screening program for patients with diabetes and found that DR was more common in men (47.2%) than women (33.7%; P = 0.004) ( 26 ). Other population-based studies have found no difference by sex in the prevalence of any DR ( 27 ) and proliferative DR ( 28 ). The most recent nationally representative NHANES data showed that among adults aged ≥40 years with diabetes, the prevalence of DR was higher in men (31.6%; 95% CI 26.8–36.8) than women (25.7% [95% CI 21.7–30.1], P = 0.04; adjusted odds ratio [OR] 2.07 [95% CI 1.39–3.10]) ( 8 ). However, there was no difference in the prevalence of VTDR among men (4.2%; 95% CI 2.8–6.1) compared with women (4.7% [95% CI 3.2–6.9], P = 0.67; adjusted OR 1.79 [95% CI 0.67–4.80]) ( 8 ); the same was true for the prevalence of DME ( 3 ).

A previously published analysis by Benoit et al. ( 29 ), using the IBM MarketScan Database of health care claims, documented sex differences in DR that were similar to our findings. They examined claims for DR, VTDR, and eye examinations among a cohort of patients with type 1 and type 2 diabetes who were continuously enrolled in health insurance from 2010 to 2014. Benoit et al. ( 29 ) found that among patients with type 2 diabetes, the 5-year period prevalence of DR and VTDR was 24.4% and 8.3%, respectively, and that men had a higher prevalence than women of both DR (27.3% vs. 21.7%; P < 0.0001) and VTDR (9.3% vs. 7.3%; P < 0.0001). Among patients with type 1 diabetes, the 5-year period prevalence of DR and VTDR was 54.0% and 24.3%, respectively, and in this population, men also had a higher prevalence than women of both DR (56.1% vs. 51.8%; P < 0.0001) and VTDR (25.4% vs. 23.2%; P < 0.01).

Reasons for the observed differences in the prevalence of DME/VTDR and any DME by sex are unknown. A higher prevalence among men of risk factors such as hypertension could be a contributing factor ( 30 ). It is recommended that individuals with diabetes receive annual or biennial dilated-eye examinations as early detection and timely treatment of DR are vital for preventing disease progression and preserving vision ( 31 – 34 ). Benoit et al. ( 29 ) found that among patients with type 2 diabetes, 14.7% of men and 15.8% of women met the American Diabetes Association recommendations for annual or biennial eye examinations; among those with type 1 diabetes this prevalence was 24.3% among men and 28.4% among women. Another study used 2007–2015 data from a nationwide commercial claims database to determine the rate of eye examinations and diabetes-related eye disease in the first 5 years after diagnosis of type 2 diabetes among adults ( 35 ). The authors found that men had lower odds of receiving an annual eye examination (OR 0.84; P < 0.01) and higher odds of developing DR within 5 years (OR 1.17; P < 0.01) than women. If men with diabetes meet guidelines for routine eye examinations at a lower rate than women, this could translate to men’s eye disease being diagnosed at a more advanced stage, which could contribute to the sex differences we observed in the prevalence of annual claims for DME/VTDR and any DME. An important risk factor for the development of DR is glycemic control. However, pooled data from the 2007–2010 NHANES showed no difference in having poor glycemic control by sex ( 36 ), and a study using 2007–2012 NHANES data found no differences by sex in meeting individualized HbA 1c targets ( 37 ).

We observed a precipitous increase in the annual prevalence of having a claim for anti-VEGF injections from 2009 to 2018, a period during which physicians began to replace laser photocoagulation treatment with the injections in response to studies documenting superior efficacy of anti-VEGF injections for DME ( 16 ). In 2012, the Food and Drug Administration approved the anti-VEGF drug ranibizumab for DME treatment (38), and later approved aflibercept for DME treatment in 2014 (39) and ranibizumab and aflibercept for the treatment of DR in patients with DME in 2015 (40,41). Other U.S. studies have documented similar increases in the use of anti-VEGF treatment for DME during this period. Recently published data using claims for Medicare Part B fee-for-service beneficiaries aged ≥65 years with diabetes showed an increase from 2009 to 2018 in the annual prevalence of anti-VEGF treatment, particularly among patients with any DME (15.7% to 35.2%) or VTDR with DME (20.2% to 47.6%); this increase coincided with a decrease in the annual prevalence of laser photocoagulation among those with any DME (45.5% to 12.5%), VTDR with DME (54.0% to 20.3%), and VTDR without DME (22.5% to 5.8%) ( 19 ).

An earlier study using a nationally representative sample of Medicare beneficiaries found that the use of laser photocoagulation for patients with DME decreased from 43% of patients receiving laser photocoagulation in 2000 to only 30% of patients in 2004, compared with an increase in receipt of intravitreal injection from 1% to 13% of patients in this period ( 42 ). Another study using administrative claims for patients with DME and either commercial health insurance or government insurance (i.e., Medicaid, Medicare, and Medicare Advantage) found that the prevalence of receiving anti-VEGF treatments increased from 5.0% of patients in 2009 to 27.1% in 2014, and that anti-VEGF treatments, as a proportion of all DME treatments, increased from 11.6% in 2009 to 61.9% in 2014 (compared with a decrease in focal laser procedures from 75.3% of all DME treatments in 2009 to 24.0% in 2014) ( 43 ). One study combined health care claims data from commercial health insurance and Medicare Advantage for adults aged ≥18 years and found that the annual use of anti-VEGF treatment, measured as the number of injections per 1,000 patients with diabetes-related retinal disease, increased from 2006 to 2015, and this trend was particularly pronounced for bevacizumab, the use of which increased from 2.4 injections/1,000 patients with DR in 2009 to 13.6 injections/1,000 patients in 2015 ( 44 ). An interesting finding of this research was that female patients received 57.1% of the administered anti-VEGF injections and male patients received 42.9%, documenting important differences in treatment by sex that could have implications for progression and severity of eye disease.

This analysis is subject to several limitations. Although the MarketScan database of administrative claims provides a robust sample size with patients from all U.S. states, the data are a national convenience sample of individuals who are commercially insured through their employers; therefore, our findings are not generalizable to all U.S. adults aged <65 years. Second, the trends described in this analysis are based on the annual prevalence of having a health care claim for diabetes-related eye disease and can be influenced by changes in coding and treatment practices. Our estimates are likely an underestimate as they are less accurate than those based on the measured presence of eye disease in examination-based studies. Third, our study period overlapped with the 2015 transition from ICD-9-CM to ICD-10-CM diagnosis coding, and we cannot discount the possibility that these coding changes influenced the observed trends. ICD-10-CM codes provide substantially more granular detail on the nature of the diabetes-related eye disease, including laterality information. This could have affected our prevalence estimates in either direction, resulting in under- or overreporting of DME/VTDR prevalence. Fourth, our analytic sample size declined from 16.1 million to 10.6 million patients from 2009 to 2018, due to loss of data in the MarketScan database from a participating insurance provider. Last, the data allowed for a description of important differences in diabetes-related eye disease by sex; however, we were not able to explore disparities by other important factors such as race, ethnicity, and income because of the absence of this information in MarketScan.

In summary, from 2009 to 2018, we observed a significant increase in the annual prevalence of having a health care claim for vision-threatening diabetes-related eye disease among commercially insured adults aged 18–64 years with diabetes. We also documented important differences in disease prevalence by sex, with men having a higher prevalence, and marked changes over this decade in the use of different treatment modalities, with anti-VEGF surpassing laser photocoagulation as the most-used treatment for DME/VTDR. Future research could explore causes of the observed differences in eye disease by sex, as well as the barriers to eye care and treatment, to inform prevention interventions.

This article contains supplementary material online at https://doi.org/10.2337/figshare.21793130 .

Funding. This work was a collaborative effort between the US Centers for Disease Control and Prevention and the National Opinion Research Center as a part of the cooperative agreement DP-19-005/U01 DP006444-01 “Research to Enhance the US Vision and Eye Health Surveillance System.”

Duality of Interest. J.R.E. is an Intergovernmental Personnel Act consultant to Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, and the Centers for Disease Control and Prevention.

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Author Contributions. E.A.L. led the design of the study methodology, interpretation of the findings, and writing of the manuscript, and takes full responsibility for the contents of this article. M.K. led the data analysis and reviewed and edited the manuscript. D.B.R., J.S.W., J.R.E., C.S.H., and J.S. participated in the design of the study methodology, interpretation of the findings, and reviewed and edited the manuscript.

Prior Presentation. An abstract based on this analysis was presented virtually as a poster at the 81st American Diabetes Association Scientific Sessions, 25–29 June 2021.

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ESASO classification relevance in the diagnosis and evolution in diabetic macular edema patients after dexamethasone implant treatment

• Retinal Disorders
• Published: 04 April 2024

Cite this article

• Almudena Moreno-Martínez   ORCID: orcid.org/0000-0002-4788-9850 1 ,
• Cristina Blanco-Marchite 1 ,
• Fernando Andres-Pretel 1 ,
• Francisco López-Martínez 1 ,
• Antonio Donate-Tercero 1 ,
• Eva González-Aquino 1 ,
• Carlos Cava-Valenciano 1 ,
• Giacomo Panozzo 2 &
• Sergio Copete 1  

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To assess the clinical relevance of The European School for Advanced Studies in Ophthalmology (ESASO) classification in patients with diabetic macular edema (DME) after their first dexamethasone implant (DEXI) treatment.

Retrospective real-world study conducted on consecutive DME patients who underwent DEXI treatment and were controlled at month-2. Subjects were initially classified according to the ESASO classification stages. The outcomes were anatomical biomarkers with spectral-domain optical coherence tomography (SD-OCT) and best-corrected visual acuity (BCVA).

A total of 128 patients were classified according to ESASO classification stages as early (7; 5.5%), advanced (100; 78.1%), and severe (21; 16.4%). At baseline, there were significant differences between stages in BCVA, central macular thickness (CMT), and tomography anatomical biomarkers ( p  < 0.05). Initial BCVA (logMAR) was 0.33 ± 0.10, 0.58 ± 0.34, and 0.71 ± 0.35 in the early, advanced, and severe stages, respectively ( p  < 0.05). At month-2, BCVA was 0.17 ± 0.15, 0.46 ± 0.29, and 0.69 ± 0.27 in those classified as early, advanced, and severe stages, respectively. At month-2, DME was resolved or improved in 6 (85.7%), 60 (60%), and 12 (60%) patients classified as early, advanced, and severe stages, respectively.

Conclusions

There was a good correlation between BCVA and ESASO classification stages. Patients in the severe stage did not achieve visual acuity improvement over the study period.

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Rathmann W, Giani G (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27:2568–2569. https://doi.org/10.2337/diacare.27.10.2568 . (author reply 2569)

Article   PubMed   Google Scholar  

Sabanayagam C, Yip W, Ting DSW et al (2016) Ten emerging trends in the epidemiology of diabetic retinopathy. Ophthalmic Epidemiol 23:209–222. https://doi.org/10.1080/09286586.2016.1193618

Virgili G, Menchini F, Casazza G et al (2015) Optical coherence tomography (OCT) for detection of macular oedema in patients with diabetic retinopathy. Cochrane Database Syst Rev 1:CD008081. https://doi.org/10.1002/14651858.CD008081.pub3

Das A, McGuire PG, Rangasamy S (2015) Diabetic macular edema: pathophysiology and novel therapeutic targets. Ophthalmology 122:1375–1394. https://doi.org/10.1016/j.ophtha.2015.03.024

Tang J, Kern TS (2011) Inflammation in diabetic retinopathy. Prog Retin Eye Res 30:343–358. https://doi.org/10.1016/j.preteyeres.2011.05.002

Article   CAS   PubMed   PubMed Central   Google Scholar  

Panozzo G, Cicinelli MV, Augustin AJ et al (2020) An optical coherence tomography-based grading of diabetic maculopathy proposed by an international expert panel: the European School for Advanced Studies in Ophthalmology classification. Eur J Ophthalmol 30:8–18. https://doi.org/10.1177/1120672119880394

Schmidt-Erfurth U, Garcia-Arumi J, Bandello F et al (2017) Guidelines for the management of diabetic macular edema by the European Society of Retina Specialists (EURETINA). Ophthalmologica 237:185–222. https://doi.org/10.1159/000458539

Boyer DS, Yoon YH, Belfort R et al (2014) Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 121:1904–1914. https://doi.org/10.1016/j.ophtha.2014.04.024

Munk MR, Somfai GM, de Smet MD et al (2022) The role of intravitreal corticosteroids in the treatment of DME: predictive OCT biomarkers. Int J Mol Sci 23:7585. https://doi.org/10.3390/ijms23147585

Udaondo P, Adan A, Arias-Barquet L et al (2021) Challenges in diabetic macular edema management: an expert consensus report. Clin Ophthalmol 15:3183–3195. https://doi.org/10.2147/OPTH.S320948

Article   PubMed   PubMed Central   Google Scholar  

Kodjikian L, Bellocq D, Bandello F et al (2019) First-line treatment algorithm and guidelines in center-involving diabetic macular edema. Eur J Ophthalmol 29:573–584. https://doi.org/10.1177/1120672119857511

Starace V, Battista M, Brambati M et al (2021) The role of inflammation and neurodegeneration in diabetic macular edema. Ther Adv Ophthalmol 13:25158414211055964. https://doi.org/10.1177/25158414211055963

Usui Y (2020) Elucidation of pathophysiology and novel treatment for diabetic macular edema derived from the concept of neurovascular unit. JMA J 3:201–207. https://doi.org/10.31662/jmaj.2020-0022

Usui Y, Westenskow PD, Kurihara T et al (2015) Neurovascular crosstalk between interneurons and capillaries is required for vision. J Clin Invest 125:2335–2346. https://doi.org/10.1172/JCI80297

Sonoda S, Sakamoto T, Shirasawa M et al (2013) Correlation between reflectivity of subretinal fluid in OCT images and concentration of intravitreal VEGF in eyes with diabetic macular edema. Invest Ophthalmol Vis Sci 54:5367–5374. https://doi.org/10.1167/iovs.13-12382

Article   CAS   PubMed   Google Scholar  

Strimbu K, Tavel JA (2010) What are biomarkers? Curr Opin HIV AIDS 5:463–466. https://doi.org/10.1097/COH.0b013e32833ed177

Zur D, Iglicki M, Busch C et al (2018) OCT Biomarkers as functional outcome predictors in diabetic macular edema treated with dexamethasone implant. Ophthalmology 125:267–275. https://doi.org/10.1016/j.ophtha.2017.08.031

Huang Y-T, Chang Y-C, Meng P-P et al (2022) Optical coherence tomography biomarkers in predicting treatment outcomes of diabetic macular edema after dexamethasone implants. Front Med (Lausanne) 9:852022. https://doi.org/10.3389/fmed.2022.852022

Castro-Navarro V, Cervera-Taulet E, Navarro-Palop C et al (2020) Analysis of anatomical biomarkers in subtypes of diabetic macular edema refractory to anti-vascular endothelial growth factor treated with dexamethasone implant. Eur J Ophthalmol 30:764–769. https://doi.org/10.1177/1120672119834182

Kwon J-W, Kim B, Jee D et al (2021) Aqueous humor analyses of diabetic macular edema patients with subretinal fluid. Sci Rep 11:20985. https://doi.org/10.1038/s41598-021-00442-z

Eandi CM, De Geronimo D, Giannini D et al (2020) Baseline SD-OCT characteristics of diabetic macular oedema patterns can predict morphological features and timing of recurrence in patients treated with dexamethasone intravitreal implants. Acta Diabetol 57:867–874. https://doi.org/10.1007/s00592-020-01504-w

Munk MR, Ram R, Rademaker A et al (2015) Influence of the vitreomacular interface on the efficacy of intravitreal therapy for uveitis-associated cystoid macular oedema. Acta Ophthalmol 93:e561-567. https://doi.org/10.1111/aos.12699

Kessler LJ, Auffarth GU, Bagautdinov D et al (2021) Ellipsoid zone integrity and visual acuity changes during diabetic macular edema therapy: a longitudinal study. J Diabetes Res 2021:8117650. https://doi.org/10.1155/2021/8117650

Vujosevic S, Toma C, Villani E et al (2020) Diabetic macular edema with neuroretinal detachment: OCT and OCT-angiography biomarkers of treatment response to anti-VEGF and steroids. Acta Diabetol 57:287–296. https://doi.org/10.1007/s00592-019-01424-4

Bonfiglio V, Reibaldi M, Pizzo A et al (2019) Dexamethasone for unresponsive diabetic macular oedema: optical coherence tomography biomarkers. Acta Ophthalmol 97:e540–e544. https://doi.org/10.1111/aos.13935

Panozzo G, Mura GD, Franzolin E et al (2022) Early DMO: a predictor of poor outcomes following cataract surgery in diabetic patients. The DICAT-II study Eye (Lond) 36:1687–1693. https://doi.org/10.1038/s41433-021-01718-4

Feng Y, Busch S, Gretz N et al (2012) Crosstalk in the retinal neurovascular unit - lessons for the diabetic retina. Exp Clin Endocrinol Diabetes 120:199–201. https://doi.org/10.1055/s-0032-1304571

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Department of Ophthalmology, Albacete University Hospital Complex, C/ Seminario, 4, E-02006, Albacete, Spain

Almudena Moreno-Martínez, Cristina Blanco-Marchite, Fernando Andres-Pretel, Francisco López-Martínez, Antonio Donate-Tercero, Eva González-Aquino, Carlos Cava-Valenciano & Sergio Copete

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Conceptualization: AMM, CBM, and SC; data analysis and interpretation: AMM, FAP, and SC; collect data for investigation: AMM, CBM, and SC; methodology and project administration: AMM, CBM, and SC; supervision: AMM, CBM, and SC; writing—original draft: AMM, CBM, and SC; writing—review, editing and final approval of the version: AMM, CBM, FAP, FLM, ADT, EGA, GP, CCV, and SC.

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Moreno-Martínez, A., Blanco-Marchite, C., Andres-Pretel, F. et al. ESASO classification relevance in the diagnosis and evolution in diabetic macular edema patients after dexamethasone implant treatment. Graefes Arch Clin Exp Ophthalmol (2024). https://doi.org/10.1007/s00417-024-06473-2

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Received : 11 October 2023

Revised : 04 March 2024

Accepted : 28 March 2024

Published : 04 April 2024

DOI : https://doi.org/10.1007/s00417-024-06473-2

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