Management of Diabetic Macular Edema: Guidelines from the Emirates Society of Ophthalmology.

In the United Arab Emirates, retinopathy has been shown to be present in 19% of the diabetic population, with diabetes identified in up to 40% of individuals aged over 55 years. Despite the prevalence of diabetic retinal diseases, there are no unified national guidelines on the management of diabetic macular edema (DME). These published guidelines are based on evidence taken from the literature and published trials of therapies, and consensus opinion of a representative expert panel with an interest in this condition, convened by the Emirates Society of Ophthalmology. The aim is to provide evidence-based, clinical guidance for the best management of different aspects of DME, with a special focus on vision-threatening diabetic retinopathy. Treatment should be initiated in patients with best-corrected visual acuity 20/30 or worse, and/or features of DME as seen on optical coherence tomography (OCT) with central retinal thickness (CRT) of at least 300 μm or in symptomatic patients with vision better than 20/25, and/or CRT less than 300 μm where there are OCT features consistent with center-involving macular edema. The treatment of DME is effective irrespective of glycated hemoglobin (HbA1c) level, and treatment must not be denied or delayed in order to optimize systemic parameters. All ophthalmic treatment options should be discussed with the patient for better compliance and expectations. Non-center-involving DME can be initially observed until progression toward the center is documented. Macular laser no longer has a primary role in center-involving DME, and anti-vascular endothelial growth factor (anti-VEGF) therapy should be considered as first-line treatment for all patients, unless contraindicated. If anti-VEGF is contraindicated, a steroid dexamethasone implant can be considered for first-line treatment. Recommendations for the treatment of DME in special circumstances and in relapsing and refractory DME are also discussed.

Key Summary Points

Introduction

Diabetic macular edema (DME) is becoming an increasing concern for ophthalmologists around the globe, driven by the increasing prevalence of diabetes. In the United Arab Emirates (UAE), rapid urbanization and socioeconomic development have led to the widespread adoption of a sedentary lifestyle and Westernized diet in the local population; consequently, there is a high prevalence of both obesity and diabetes. In 2019, International Diabetes Federation (IDF) statistics reported a diabetes prevalence rate of 16.3% for the adult population in the UAE aged between 20 and 79 years, and higher than for other Middle East and North Africa countries [1]. A survey of Emiratis and expatriates in 1999–2000 reported a 20.0% rate in the 20–64-years age group, using the oral glucose tolerance test, similar to rates reported in neighboring Middle East and North Africa countries [2]. Since then, there have been few studies on diabetes prevalence in the UAE.

The Weqaya screening program conducted in Abu Dhabi collected data from 50,138 participants between 2008 and 2010 [3]. This showed age-standardized prevalence rates of 17.6% for diabetes and 27.1% for pre-diabetes. More recently, a study of UAE citizens in the Northern Emirates found that the prevalence of diabetes was 25.1% [4]. It was higher in UAE citizens than in expatriates (25% versus 13–19% depending on the country) [1, 2, 5]. The prevalence of diabetes rose with age to a maximum of 40% after the age of 55 years, and the prevalence of impaired fasting glycemia was 5% in men and 7% in women. Overall, 41% of individuals with diabetes were undiagnosed prior to the survey [2]. Obesity was common in all ethnic groups and the presence of diabetes was associated with increasing waist-to-hip ratio, age, and systolic blood pressure and ethnicity [2]. Comorbidity with glucose intolerance occurred with obesity in 8% of individuals and with hypertension in 5%.

The aim of these guidelines on the management of DME is to continuously advance the standard of ophthalmology practice in the UAE, in order to improve eye and visual health in the UAE community and beyond, and to provide evidence-based, clinical guidance for the best management of different aspects of diabetic eye disease. The foundations of the guidelines are based on evidence taken from the literature and published trials of therapies, as well as consensus opinion of a representative expert panel convened by the Emirates Society of Ophthalmology in the second half of 2019 with an interest in this condition. As this article is based on previously conducted studies, it does not contain any studies with human participants or animals performed by any of the authors.

The scope of the guidelines is limited to management of DME with a special focus on vision-threatening diabetic retinopathy. The guidelines offer recommendations regarding service provision to facilitate delivery of optimal clinical care for patients and have been prepared primarily for ophthalmologists. They are, however, also relevant for other healthcare professionals, service providers, and commissioning organizations, such as insurance companies, as well as patient groups. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Recommendations

Treatment Initiation

DME should be treated to improve vision when it is decreased, to maintain vision, and to prevent structural damage to the macula [6]. Treatment is initiated on the basis of careful assessment of the structure and function of the macula [7]. Conditions needed to initiate treatment are best-corrected visual acuity 20/30 or worse, and/or features of DME as seen on optical coherence tomography (OCT) with central retinal thickness (CRT) of at least 300 μm [6, 8] or symptomatic patients with vision better than 20/25 [9], and/or CRT less than 300 μm [8, 9] with OCT features consistent with center-involving macular edema. OCT intra-device reproducibility is satisfactory; however, CRT cutoffs are devise-specific [9] since retinal thickness and volume measurements differ between systems [10].

Once the decision to treat has been made, it is recommended that visual acuity be assessed before initiation of treatment, after the initial loading dose of 3–6 intravitreal anti-vascular endothelial growth factor (VEGF) injections, at monthly intervals, and periodically during treatment, as per physician’s discretion [11, 12]. It may, however, be assessed at every visit. It is also recommended to check intraocular pressure (IOP) before initiation of treatment, after loading dose, and periodically during treatment, as per physician’s discretion [6, 13]. Again, this may be carried out at every visit [6, 13]. Spectral-domain OCT is recommended before the initiation of treatment, after loading dose, and periodically during treatment, as per physician’s discretion [14, 15]. Ocular fundus exam is recommended before the initiation of treatment and periodically during treatment, as per physician’s discretion [15], and fundus fluorescein angiography (FFA) may be carried out before the initiation of treatment and periodically to assess the macular perfusion and/or peripheral ischemia [6, 15]. OCT angiography can be used for evaluation of macular blood supply and the presence of macular ischemia [15].

General Guidance in DME Management

The treatment of DME is effective irrespective of glycated hemoglobin (HbA1c) level, and treatment must not be denied or delayed in order to optimize systemic parameters [16-18]; although it is recommended to check for other ocular causes of vision loss such as cataract progression.

Systemic management of patients with DME consists of optimal control of diabetes mellitus and HbA1c [16-18], arterial hypertension [19-21], dyslipidemia [22-27], smoking cessation [24, 28], weight loss if required for a normal body mass index [28], renal impairment [24, 28], and sleep apnea [28], as all are factors associated with better management of DME. Patients should therefore be encouraged to pursue this with their diabetologist. Fenofibrate [29] and statins [30] can be recommended to the family physicians/endocrinologists as anti-dyslipidemia medication, as both have a positive effect on diabetic retinopathy and DME. We recommend also checking for any new medications that can exacerbate DME, such as glitazones [17, 28, 31].

It is important to perform FFA and/or OCT angiography in order to assess macular ischemia in those cases where there is no improvement in visual acuity despite a reduction in macular thickness after a loading dose with anti-VEGF injections or a dexamethasone implant [32, 33]. Importantly, all ophthalmic treatment options should be discussed with the patient for better compliance and expectations [34].

Clinically significant macular edema is retinal thickening at or within 500 μm of the center of the macula; and/or hard exudates at or within 500 μm of the center of the macula if associated with thickening of the adjacent retina, and/or zone(s) of retinal thickening one disc area in size, any part of which is within one disc diameter from the center of the macula [35]. A flowchart for the management of DME is shown in Fig. 1.

Fig. 1

Flowchart for DME management. *Rule out contraindications for anti-VEGF. **Rule out contraindications for dexamethasone implant. ***Poor response: failure to gain at least 5 letters of vision; failure to reduce CRT by 10%. ****Rule out contraindications for fluocinolone implant. BCVA best-corrected visual acuity, CRT central retinal thickness, dex, dexamethasone, DME diabetic macular edema, FFA fundus fluorescein angiography, IOP intraocular pressure, MI myocardial infarction, OCT optical coherence tomography, OCTA optical coherence tomography angiography, PRN pro re nata, VEGF vascular endothelial growth factor

Treatment Recommendations for Non-Center-Involving DME

Non-center-involving DME is retinal thickening in the macula that does not involve the central subfield zone, 1 mm in diameter on OCT [6]. It can be initially observed until progression toward the center is documented. Anti-VEGF therapy can be initiated, or FFA-guided focal laser treatment administered to leaking microaneurysms at least 300–500 μm from the center of the macula [36]. Focal laser treatment should, however, only be performed by a retina specialist in specific circumstances [36, 37].

Treatment Recommendation for Center-Involving DME

Center-involving macular edema is retinal thickening in the macula that involves the central subfield zone, 1 mm in diameter on OCT [6]. Macular laser no longer has a primary role in center-involving DME [36] and anti-VEGF therapy should be considered as first-line treatment for all patients, unless contraindicated [38, 39]. A steroid dexamethasone implant can be used as a first-line treatment if anti-VEGF is contraindicated, or if there is poor compliance with the anti-VEGF regimen treatment, and may be recommended in patients who are vitrectomized, pseudophakic, or with chronic DME [40, 41]. IOP should be monitored in patients in whom a steroid implant is used [41].

Intravitreal Anti-VEGF Therapy

Treatment goals and strategy should be discussed with patients [28] and treatment algorithms may vary according to patient’s and physician’s preference [42]. Physicians should also ensure the patient’s systemic diseases, particularly dyslipidemia and hypertension, are well controlled [15]. Fixed, pro re nata, and treat-and-extend dosing (based on visual acuity and OCT) can be considered [43]. Only licensed and approved anti-VEGF agents, such as intravitreally administered aflibercept and ranibizumab, should be used, and no biosimilars/medicines are allowed to be imported to the country and used other than what is legally distributed [44, 45].

All patients treated with anti-VEGF agents should have a loading dose of 3–6 injections [44, 46]. The loading dose, 3–6 injections at monthly intervals, is based on the treatment response assessed by visual acuity and OCT [44, 46], keeping inter-OCT variability and device-specific measurements in consideration throughout patient follow-up [10]. The estimated number of optimal anti-VEGF injections is 8–9 injections in the first year of treatment (including the loading dose), and 5–6 injections in the second year [44, 46].

A poor response to anti-VEGF treatment, after the loading dose of 3–6 injections at monthly intervals, is defined as failure to gain at least five letters of vision and/or reduce CRT by 10% [47]. These criteria should be considered before switching, which may include switching to another anti-VEGF agent or to steroids after the loading phase has been completed [47]. Caution is warranted when considering switching therapies for persistent DME following three or more injections; improvements can be achieved with continued anti-VEGF treatment rather than switching therapies [48].

Physicians should consider assessing macular ischemia with FFA or OCT angiography [6, 15, 49], and OCT should be used to rule out epiretinal membrane and/or vitreomacular traction [15]. As a safety practice, it is advised not to treat with anti-VEGF agents for a minimum of 3 months after myocardial infarction or stroke [50]. Anti-VEGF treatment is not recommended during pregnancy or while breast-feeding [51]. In such cases, steroid should be used as first-line treatment [52]. Intravitreal anti-VEGF and steroid therapy should also be deferred in case of active infection [52].

Steroid Implants

Physicians should be aware that a dexamethasone implant does not usually last for more than 4 months, with a peak effect at 6–8 weeks [53-57]. Thus, the estimated number of dexamethasone implants is 3–4 injections over 12 months. In cases where there is a good response and if DME recurrence is less frequent than every 6 months, it is recommended to continue with dexamethasone implants [56]. The frequent recurrence of fluids (less than 3 months) after dexamethasone implant necessitates further discussion and likely a switch to anti-VEGF therapy.

If the patient does not wish to receive implants every 4 months, switching to a fluocinolone implant should be considered [47, 58–60]. Prior to a fluocinolone implant, a steroid challenge may be needed (i.e., starting with a dexamethasone implant, or alternatively topical steroid eye drops in compliant patients) [61-63]. A wide range of OCT/OCT angiography biomarkers exist for predicting treatment outcomes in DME; patients with submacular fluid, hyperreflective foci, intra-retinal cysts, and a disorganization of the continuous inner retinal layer (also referred to as DRIL) may respond better to dexamethasone implants than those without these features [64] and vessel density and foveal avascular zone may also be useful in predicting response to treatment [32]. Not every responder to dexamethasone implants will respond to fluocinolone implants, and top-up treatment may be required in addition to the fluocinolone implant, including anti-VEGF treatment and dexamethasone implants [31, 65]. Furthermore, around 10% of patients treated with dexamethasone implants will have an IOP increase of greater than 25 mmHg. If a patient develops elevated IOP with dexamethasone implants, it is not recommended to use a fluocinolone implant [66-68].

Pseudophakic patients are preferred for the use of steroids, otherwise patients have to be informed about the high risk for cataract surgery [15], and it is known that cataract surgery predisposes to, or worsens DME [31]. Contraindications to dexamethasone and fluocinolone acetonide intravitreal implants are eyes with active or suspected ocular or periocular infection; advanced glaucoma (requiring more than three medications), non-intact posterior capsule (yttrium aluminum garnet [YAG] capsulotomy excluded), eyes with aphakia, and hypersensitivity to dexamethasone implant or a fluocinolone acetonide intravitreal implant [58, 69].

Relapsing and Refractory DME

Relapsing DME (recurrence of DME after 3–6 months from last intravitreal anti-VEGF injection) allows the repetition of the same treatment used previously if there is clear evidence of a previous response; otherwise, the patient should be treated as being a new patient, starting with any available treatment option (i.e., anti-VEGF or dexamethasone implant) [6]. Refractory DME is defined as DME not responding to a full course of anti-VEGF agents and steroid implants. A combination therapy with anti-VEGF and steroids might be considered, although there is no strong evidence for an additional benefit with combination therapy, and referral to a retinal surgeon for vitrectomy if epiretinal membrane or vitreomacular traction is confirmed on OCT [70-72].

Treatment of DME in Special Circumstances

DME and Proliferative Diabetic Retinopathy

Physicians should initially assess visual acuity and conduct a fully dilated fundus exam [36].

Anti-VEGF agents are recommended in the first-line treatment of center-involving DME unless contraindicated, and in cases of non-center-involving DME and proliferative diabetic retinopathy, the use of either anti-VEGF treatment or pan-retinal photocoagulation (PRP) are valid options [73].

PRP remains the gold standard treatment for proliferative diabetic retinopathy (PDR). Navigated laser treatment achieves more uniform laser burns with less pain during shorter treatment duration in comparison with conventional pattern laser [74]. Anti-VEGF agents and PRP are both licensed treatments for the condition, and their combination can be used while the addition of laser can reduce the frequency of injections [73].

After the proliferative diabetic retinopathy is treated, anti-VEGF injections may continue for the treatment of DME. When choosing between anti-VEGF and PRP as first-line therapy for PDR, treatment decisions should be guided by consideration of the relative advantages of each therapeutic modality and anticipated patient compliance with follow-up and treatment recommendations [73]. Core management of the retinopathy status is recommended either by continuing anti-VEGF injections or initiating PRP [73].

Cataract Surgery

In order to stabilize DME in planning for cataract surgery, it is recommended to give either anti-VEGF injections or steroids 1–2 weeks preoperatively or at the time of surgery [75, 76]. The use of non-steroidal anti-inflammatory drug topical eye drops is recommended postoperatively [75, 77].

Fibrovascular Membranes and Tractional Retinal Detachment Near or Involving the Macula

It is recommended not to give any anti-VEGF injections, unless the physician is planning vitreoretinal surgery or has planned access to a retinal surgery service or to a retina surgeon [78].

Vitreomacular Traction/Epiretinal Membrane

Physicians should consult with the vitreoretinal surgeon before giving injections in patients with diabetes in whom a vitreomacular traction or epiretinal membrane is shown [79].

Vitreous Hemorrhage in Patients with DME

Vitreous hemorrhage is frequent in PDR and, in the absence of vitreomacular traction, many vitreous hemorrhages do not need vitreoretinal surgery. Physicians should consult with the vitreoretinal surgeon for patients with DME and vitreous hemorrhage [80].

DME and Pregnancy

For DME in pregnancy, first-line treatments should remain as blood glucose control and laser therapy. Pregnancy is a contraindication for anti-VEGF treatment for DME [81-83]. Intravitreal dexamethasone implant may be a safe and effective treatment modality for managing severe DME as first-line treatment [81, 84, 85]. Laser is another option for non-center-involving macular edema [86]. Alternatively, treatment can be deferred until after delivery. Steroid treatment should be offered only in the second or third trimesters, while the risks of IOP elevation, cataract development, and the remote risk of fetal harm should be fully discussed with the patient [81, 84, 85].

Bilateral Injection

The decision of unilateral versus bilateral injections should be at the surgeon’s discretion [87]. All risks and benefits of the procedure should be well explained to the patient, and the option of unilateral injection should be properly explained [87]. The surgeon should take the maximum precautions to avoid all risks of bilateral injection complications, as every eye should be treated as a separate procedure: precautions also can include (but are not limited to) separate gloves; separate vials with different patch number; separate surgical mask; and separate needles, syringes, and speculums, as this should be used for each eye with full preparation [36, 88].

Iodine

The use of 5% iodine in the fornix for 60 s per eye is recommended [89-91]. In cases of clear allergy to iodine, chlorhexidine 0.1% aqueous solution can be used with caution and warning of endophthalmitis [92].

Injection Room and International and Local Infection Control

Anti-VEGF and steroid injections can be given either in theater or in a dedicated clean room that meets international and local infection control guidelines [92-94]. The clean room should be separated from the examination room, adequately equipped, and approved by the appropriate hospital teams (microbiology/infection control/health and safety). The details of such specifications should be discussed with the local health and safety representatives. Any room where minor operations take place is suitable as long as infected cases are excluded.

Mask and Gloves

The physician must wear a mask and sterile gloves [88], and the patient must wear a mask covering the nose or a drape [95]. The InVitrea device can be used instead of lid speculum and caliper [95], and the physician should ensure sterility of the periorbital skin with 10% povidone-iodine [88]. Prior to the procedure, the patient should be advised to avoid talking while lying down and prior to mask/drape placement, to avoid air droplet contamination [88, 95, 96].

Post-Injection Management and Follow-up

Antibiotics are not recommended, either pre- or post-injection [88, 97]. Patients should be given information about postoperative complications and a telephone number to contact in case of symptoms including increase in redness, eye pain, vision reduction, or any symptoms of endophthalmitis [98].

Summary

The Emirates Society of Ophthalmology clarifies that these guidelines are made by retinal specialists on the basis of international guidelines and studies, and clinical trials, which have been fully acknowledged. These include recommendations from the International Diabetes Federation in 2019 [28], and from the European Society of Retina Specialists and International Council of Ophthalmology in 2017 [15, 36]. As such, these guidelines developed by the Emirates Society of Ophthalmology may also be applicable in other regions of the world, especially where country- or region-specific guidelines do not exist.

It is our hope that consensus guidelines will assist in advancing the standard of ophthalmology practice in the UAE, and consequently improve eye and visual health in the UAE community.

The authors have made considerable efforts to ensure that the information upon which the recommendations are based is current and accurate. The guidelines do not cover rare, complex, complicated, or unusual cases and it is recommended that readers refer to other relevant sources of information such as summaries of product characteristics for pharmaceutical products, as well as other clinical literature or guidelines where necessary. In all cases, the management of each individual patient should be individualized on the basis of their specific disease characteristics, treatment requirements, and subsequent responses to therapy.

Driven by the increasing prevalence of diabetes, diabetic macular edema (DME) is becoming an increasing concern for ophthalmologists around the globe and particularly in the United Arab Emirates (UAE).

These guidelines provide treatment recommendations for both center-involving and non-center-involving DME, including the use of anti-vascular endothelial growth factor (VEGF) injections, and the treatment of DME in special circumstances.

The aim of these guidelines on the management of DME is to continuously advance the standard of ophthalmology practice in the UAE, in order to improve eye and visual health in the UAE community and beyond.