Disease Prevalence and Incidence
Diabetes mellitus is a metabolic disease that is characterized by persistent elevations in blood glucose (hyperglycemia). The persistent elevation of blood glucose can cause damage to blood vessels on a microvascular level such as those in the eye resulting in diabetic retinopathy (DR).25 Some patients with DR and continued poorly managed blood glucose can experience swelling in the retina, known as diabetic macular edema (DME).1 Generally, DME manifests as a slowly progressive vision loss. The Early Treatment for Diabetic Retinopathy Study (ETDRS) chart is the gold standard in measuring changes in best-corrected visual acuity (BCVA).26 Each line contains five letters, which proportionally decrease in size as the patient reads down the chart. The degree of vision loss can vary considerably and depends on the severity, duration, and location of intraretinal fluid, among other factors. Clinically significant macular edema can be defined by retinal thickening at or within 500 µm of the center of the macula.2,4,11 Signs of DME include blurred vision, retinal hemorrhages, retinal detachment, colours appearing “washed out” or faded, changes in contrast sensitivity, impaired colour vision, gaps in vision (scotomas), and potentially permanent vision loss. The development of hard exudates are typically the culprit in the significant vision impairment associated with DME.27 Untreated DME is considered the leading cause of visual loss, visual disability, and legal blindness in people with diabetes mellitus.1,27,28 The Eye Diseases Prevalence Research Group reported that the prevalence of DR for adults in the US was 40.3%; whereas, sight-threatening retinopathy occurred in 8.2% of such individuals.29 Prevalence of macular edema in patients with type 1 diabetes, patients with type 2 diabetes treated with insulin therapy, and patients treated with antihyperglycemic therapies were 11%, 15% and 4%, respectively.30 Furthermore, higher prevalence rates were identified in First Nations populations in Canada.31,32 An observational retrospective study using records from the Southwestern Ontario database suggested that the prevalence of DME was estimated to be 15.7% and of these, 2.56% experienced vision loss that required treatment.2 Given that the prevalence of diabetes in Canada is 9.2%, it is estimated that there are 528,524 patients with DME across Canada, 13,530 of whom experienced vision impairment.2,3 Overall, more than 50% of patients with DME experiencing vision loss were older than 60 years, and more than 22% of patients with DME experiencing vision loss are patients within the First Nation community.2 Furthermore, patients with DME who are pseudophakic (natural lens surgically replaced with an artificial lens) would therefore only comprise a subset of the overall DME population.
Generally, vision loss is associated with significant morbidity, including increased falls, hip fracture and mortality.33 In addition, it has been suggested that amputation and visual loss due to DR are independent predictors of early death among patients with type 1 diabetes.34 Such progressive visual impairment typically results in significant decrements in daily functioning and quality of life and indirect costs due to lost productivity are high if left untreated.35–37 Therefore, early detection and treatment of DME is vital.26,38
Vascular endothelial growth factor (VEGF) and inflammation (as a result from damaged retinal blood vessels caused by chronic hyperglycemia) are the leading factors in the pathophysiology of DME.39 Specifically, VEGF induces angiogenesis/neovascularization, and increases vascular permeability. Besides VEGF, hypoxia-induced placental growth factor is instrumental in contributing to vascular permeability.40 Hypoxia induces influx of leukocytes into the retina, another potential source of leakage-promoting proteins.41 It acts in synergy with VEGF and contributes to the vessel abnormalities and retinal changes occurring in early DR. Recent evidence also highlights the role of inflammation in the development of DME. Inflammation due to leukostasis (accumulation of leukocytes on the surface of retinal capillaries) leads to the upregulation of intracellular adhesion molecule (ICAM)-1, found to further enhance retinal leukostasis and vascular permeability.41 Therefore, suppression of inflammatory mediators and other permeability factors in addition to VEGF is a more comprehensive treatment strategy for DME.
Standards of Therapy
The treatment strategies for DME encompass lifestyle modification including diet and exercise, smoking cessation as well as better blood sugar, blood pressure, blood lipids, and body mass index control. Current therapies for DME can be categorized into non-pharmacological and pharmacological interventions. Non-pharmacological therapies include laser photocoagulation and surgery (vitrectomy). While approved pharmacological treatments include an anti-VEGF drugs (ranibizumab, aflibercept).
Macular laser photocoagulation (including focal or grid laser) therapy for DME was the standard of care for more than 25 years before the introduction of anti-VEGF drugs, and is still widely used following anti-VEGF therapy.4 Laser therapy has been shown to slow and/or stabilize vision loss, but has been minimally effective in restoring vision.42 Laser therapy also has the disadvantage of causing permanent destruction of retinal tissue during treatment.43–45 Recently, clinical studies have shown robust efficacy and safety data for frequent (monthly or bimonthly) anti-VEGF injections for the treatment of DME patients.5–8 However, there is limited evidence of benefit and risk of continuous anti-VEGF injections among patients who did not respond well to prior anti-VEGF therapy.9 The results from these trials demonstrated that treatment with anti-VEGF drugs substantially improved visual and anatomic outcomes compared with laser photocoagulation, and avoids the ocular side effects associated with laser treatment. Canadian evidence based guidelines and clinical treatment algorithm recommend anti-VEGF injections as therapy for most patients with clinically significant DME involving central vision. If there is no response after six months treatment, patients should switch to intravitreal steroids, vitrectomy, or laser.10,11 The first of the anti-VEGF drugs to be approved in Canada for the treatment of DME was ranibizumab (a humanized recombinant monoclonal antibody fragment with anti-VEGF activity) and has since become standard of care.4,46 The recommended dose of ranibizumab is 0.5 mg administered as a single intravitreal injection monthly until stable visual acuity is achieved for three consecutive monthly assessments. This is followed by monthly monitoring and a “treatment as-needed” regimen.46 Other anti-VEGF therapies include aflibercept at the recommended dose of 2.0 mg administered by intravitreal injection monthly for the first five consecutive doses, followed by one injection every two months.47 Bevacizumab, another anti-VEGF drug approved for the treatment of cancers such as colorectal and lung cancer, has been used off label as monotherapy as an intravitreal treatment for macular edema in some Canadian jurisdictions. Although not approved for use in DME patients in Canada, the 2016 CADTH Therapeutic Review examined the evidence on age-related macular edema, diabetic macular edema, retinal vein occlusion, or choroidal neovascularization due to pathologic myopia, and issued a recommendation suggesting bevacizumab as the preferred initial anti-VEGF therapy, based on similar clinical effectiveness and lower cost compared with other anti-VEGF treatments.48 Triamcinolone acetonide monotherapy administered as an intravitreal steroid injection is also considered for off label in Canada for the treatment of macular edema according to the clinical expert consulted for this CDR review.
Although anti-VEGF therapies are widely accepted as the standard of care for patients with DME, they require frequent (eight to 12 injections per eye, per year) to achieve desirable outcomes, acting as a barrier to compliance. Anti-VEGF therapies are also associated with an increased risk of cerebro- and cardiovascular events such as thromboembolic events; therefore, they may not be appropriate in all DME patients. Furthermore, studies have shown that around 40% of patients on anti-VEGF therapy have inadequate response to treatment.9
Drug
Dexamethasone is a synthetic glucocorticoid receptor agonist, analogue to the naturally occurring glucocorticoids hydrocortisone and cortisone and is administered into the vitreous on an as-needed basis to mitigate the effects of DME.12 Corticosteroids target multiple mediators in DME, possessing anti-inflammatory, anti-vascular permeability, and anti-angiogenic properties.13 These drugs act by decreasing the production of mediators such as interleukin-6 and VEGF, and may also directly stabilize the blood-retinal barrier.14 In contrast to anti-VEGF drugs which inhibit the actions of synthesized VEGF, corticosteroids act to directly decrease the synthesis of VEGF.15 Additionally, corticosteroids prevent the release of prostaglandins, some of which have been identified as mediators of cystoid macular edema.16–18
According to the Health Canada–approved product monograph, dexamethasone can be used for the treatment of macular edema following central retinal vein occlusion, noninfectious uveitis affecting the posterior segment of the eye and adult patients with DME who are pseudophakic.12 The indication under review is limited to the latter (for the treatment of adult patients with DME who are pseudophakic).12 Dexamethasone is administered using the Dexamethasone Posterior Segment Drug Delivery System (DEX PS DDS), which consists of a sterile, single-use system intended to deliver one biodegradable implant into the vitreous, and was designed to prolong the duration of the dexamethasone effect in the eye. The biodegradable implant delivers a 700 mcg dose of dexamethasone to the vitreous with gradual release over time allowing for sustained drug levels to the target areas. Patients are eligible for retreatment on an as-needed basis. According to the product monograph of dexamethasone implant, no more than two consecutive injections should be used, and an interval of approximately six months should be allowed between the two injections.12 In general, treatment with dexamethasone is associated with elevated intraocular pressure (IOP) and cataracts, which is consistent with the AEs profile of intravitreal steroid therapies.12,19 There are currently no other approved steroids for the treatment of DME in Canada, however, according to the clinical expert consulted for this CDR review, triamcinolone acetonide may be considered for off label use.
Dexamethasone is contraindicated in patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases, patients with advanced glaucoma, patients with known hypersensitivity to any components of this product or to other corticosteroids, patients who have aphakic eyes with rupture of the posterior lens capsule and patients with anterior chamber intraocular lens and rupture of the posterior lens capsule.12
