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Diabetes mellitus (“diabetes”) is a growing worldwide epidemic, affecting largely a working age population. By 2035, it is estimated close to 600 million people worldwide will be living with diabetes, a marked increase from the 382 million in 2013. 1 Patients with diabetes are at an increased risk of several morbid and chronic conditions, among them acute coronary syndrome, hypertension, and retinopathy. 2-4
If not treated properly, one ocular manifestation of the systemic disorder, diabetic macular edema (DME), progresses to proliferative diabetic retinopathy (DR) and retinal neovascularization, hemorrhaging, and permanent loss of vision. About 50% of untreated patients with proliferative DR will become blind within 5 years of the initial diagnosis. 5
As with any medical therapy for a systemic disorder that impacts other organs in the body, the importance of patient education about treatment options and expected disease impact along with potential short vs. long-term risks is inherent to the process of determining and delivering appropriate treatment. For ophthalmologists, an understanding of the complications of diabetes is crucial to the overall management of the systemic disease and the preservation of vision after diagnosis. Further, treatment options and dosing strategies can be impacted by the cost and burden of treatment, which continue to be a major factor in treatment planning. 6-9
Concerns about the systemic safety of the anti-vascular endothelial growth factor (VEGF) treatments—which have become the first-line treatment option—also are heightened in the vasculopathic DME population. In this patient group, a decrease in retrobulbar blood flow parameters, retinal arteriolar vasoconstriction, and worsening of macular ischemia after intravitreal anti-VEGF administration has been reported. 10 As might be expected, chronic use of the anti-VEGF agents in this patient population warrants close monitoring by fluorescein angiography or optical coherence tomography.
As new therapies enter the market, treatment options and dosing strategies can be impacted by the cost of treatment, which continues to be a major factor in treatment planning. 6-9 Clinicians need to consider multiple treatment options in order to properly gauge the right treatment plan for any given patient’s needs. Ophthalmologists are also only one part of the treatment paradigm for patients with diabetes; as previously described these patients tend to have other manifestations of the systemic disorder and treatment is multifactorial.
Current treatments for ocular disorders associated with diabetes (DME/DR)
Both decreased vision and decreased vision-related quality of life can be modified by treatment, including newer modalities that provide practitioners with the flexibility of customizing management based on each patient’s individual needs.
Focal macular laser photocoagulation (FML) had been the primary treatment for DME for more than 2 decades. The Early Treatment Diabetic Retinopathy Study (ETDRS) outcomes focused on the preservation of vision, finding a 50% reduction in the likelihood of severe vision loss with grid-style FML. 11 In 2010, the Diabetic Retinopathy Clinical Research Network (DRCR.net) reported a 10-letter gain in nearly one-third of patients treated with laser, but 19% of subjects experienced progressive visual loss. 12
As a result, researchers and clinicians alike demanded better treatment options. Within the past few years, VEGF inhibitors–such as ranibizumab (Lucentis, Genentech), aflibercept (Eylea, Regeneron/Bayer Healthcare) and pegaptanib sodium (Macugen, Valeant Pharmaceuticals)–and intravitreal delivery systems that release corticosteroids–such as fluocinolone acetonide (Iluvien, Alimera), dexamethasone (Ozurdex, Allergan, Inc.), and triamcinolone acetonide (I-vation SurModics)–have been investigated for the treatment of DME and all but triamcinolone have been approved for the treatment of DME. There are two commercially available triamcinolone products (Triesence, Alcon; Trivaris, Allergan) but neither of those is approved for the treatment of DME. (Of note, another anti-VEGF intravitreal drug, bevacizumab, is often used off-label in the treatment of DME. Clinicians cite its pricing as a primary reason for endorsement. Another fluocinolone acetonide implant, Retisert (Bausch + Lomb), is approved only for non-infectious uveitis).
Interpreting the analysis of ocular and systemic VEGF load before and during anti-VEGF therapy is a complex issue for clinicians. Potentially complicating the issue for retinal specialists is that anti-VEGFs agents designed for use in cancer treatments are associated with several adverse events, including thromboembolic events, myocardial infarction, stroke, hypertension, gastrointestinal perforations, and kidney disease. Since the intravitreal formulation of these agents can also be detected systemically, the potential exists for systemic adverse events after intravitreal anti-VEGF use. 10 Both ranibizumab and aflibercept were approved for treatment of DME by the FDA in 2014.
The RESTORE study demonstrated superior gains in best-corrected visual acuity at 1 year with ranibizumab with or without laser vs. laser monotherapy. The study authors found greater reduction in foveal thickness in the anti-VEGF groups, as well as better vision-related quality of life. 13
RISE and RIDE, which also focused on the treatment of DME, evaluated 0.3-mg and 0.5-mg doses of ranibizumab compared to sham injections. Subjects were randomized to sham treatments or focal/grid laser photocoagulation. 14, 15 The RISE and RIDE studies clearly demonstrated that monthly injections of ranibizumab were associated with significant improvement in visual acuity: 40% to 45% of patients gained 3 or more ETDRS lines of vision. 14, 15 Besides the gain in visual acuity, patients who were treated with ranibizumab overall had fewer complications from their underlying DR and less progression of the DR than those who were treated with sham injections. Another finding of the RISE and RIDE studies was that no statistically significant differences in side effects or serious systemic or ocular adverse events were associated with subjects treated with ranibizumab injections or sham injections.
In the DaVINCI studies, intravitreal aflibercept resulted in VA gains of up to 8.5 letters, with 34% of patients gaining 15 or more letters. 16 However, common systemic adverse events included hypertension, nausea, and congestive heart failure after intravitreal aflibercept, although the study was not powered to sufficiently uncover associations. 17 Although there was a higher incidence of cardiac events/deaths in the aflibercept groups, the baseline characteristics showed the aflibercept groups to have roughly twice the prior incidence of cardiac disease than the laser group, which may have been reflected in the systemic adverse events. 16 The phase 3 studies of Eylea for DME (Study of Intravitreal Administration of VEGF Trap-Eye (BAY86-5321) in Patients with Diabetic Macular Edema (VISTA DME), VEGF Trap-Eye in Vision Impairment Due to DME (VIVID-DME) and VIVID Japan) found no increased rates of death, stroke, or myocardial infarction in the aflibercept groups; safety outcomes across all groups were similar. 18
Corticosteroids are also approved for the treatment of DME, 19, 20 but bring with them a concern about cataract formation and increased intraocular pressure levels that do not exist with the anti-VEGF treatments. 21, 22
The PLACID study demonstrated higher gains in BCVA up to 9 months post-treatment for diffuse DME in patients receiving dexamethasone intravitreal implant 0.7 mg combined with laser photocoagulation compared with laser alone, but no significant between-group differences at 12 months. 23 The dexamethasone intravitreal implant 0.7 mg (Ozurdex, Allergan) was approved in 2014 for the treatment of DME, but was initially granted approval only in select patient groups (pseudophakes and phakic patients scheduled to undergo cataract surgery). 19 Approval had been limited because of the increased number of adverse events—namely, cataract formation and intraocular pressure spikes. 21 The FDA removed the restrictions on lens status in October 2014.
Fluocinolone acetonide (Iluvien, Alimera Sciences) has been approved for the treatment of DME.20 A 3-year efficacy and safety study comparing eyes with refractory DME treated with either fluocinolone acetonide or standard of care (SOC; additional laser/observation) found VA improved ≥3 lines in 16.8% of implanted eyes at 6 months compared to 1.4% in the SOC group, which increased to 31.1% at 3 years in the implanted group and 20% in the SOC group. 24
As with the other steroids, however, Iluvien is associated with increased cataract formation, increased IOP, and the necessity for surgical treatment of elevated IOP. 22 As a result, its approval has been limited to patients who have previously shown no significant rise in IOP. 20
An overview of these two corticosteroids in 2014 suggested the durability of the treatments may be best used as foundational therapy, with patients then relegated to receive intravitreal anti-VEGFs less frequently. 25
Intravitreal triamcinolone (Triesence, Alcon; Trivaris, Allergan) has been shown in a few smaller studies to improve VA in eyes with recalcitrant diffuse DME, but results have been inconclusive when compared to laser photocoagulation. 22 Further, people treated with the steroid had significantly higher rates of increased intraocular pressure and close to 50% of study patients developed cataract while on the steroid.
As the complexity of treatment options also involves the cost and timing of repeated patient treatments, ophthalmologists need to update their knowledge in order to provide their patients with the best understanding of treatment expectations and minimization of risks, and to reduce treatment burden and cost for patients and the healthcare system.
Additional Statement of Need:
There may presently be a significant knowledge gap in retina specialists’ understanding of the dynamics of steroid-induced IOP elevation. Understanding of the dose- and exposure-dependent relationship between corticosteroid use and IOP elevation would be beneficial for the total care of patients. Equally, knowledge of appropriate management strategies would equip ophthalmologists who regularly use corticosteroid therapy with confidence in dealing with the most common potential complication.
Left untreated, elevation of IOP has the potential to damage the optic nerve, which, in turn, may lead to irreversible loss of visual acuity. However, most cases of corticosteroid-induced IOP elevation can be effectively managed with topical therapy, similar to that used for treating glaucoma.26,27,28,29 In each of these studies, the initiation of antihypotensive therapy was deemed necessary for some patients, and the initiation of this strategy was effective in reducing pressures to acceptable levels.
Incisional surgery to manage IOP elevation secondary to corticosteroid use may still be required in some cases.26,27,28,29 Discussions of surgical intervention may engender additional fears of intra- and postoperative complications. However, new understanding of the surgical management of glaucoma may add context to the associated risk when weighing a patient’s candidacy for surgery. For example, long-term follow up in the Tube Versus Trabeculectomy Study suggests that shunts may confer a comparatively lower failure rate and a reduced rate of postoperative complications.13 Thus, even if IOP elevation secondary to corticosteroid use is deemed serious enough to warrant surgical intervention, there are strategies available to minimize the attendant risks.
A full knowledge of the dynamics of corticosteroid-induced complications will be beneficial for arming clinicians who use these drugs with a more complete understanding when counseling patients and for understanding when to initiate additional therapeutic options. It is hoped that providing this education would remove a potential barrier to greater acceptance of this class of drugs. Finally, in the interest of providing more complete care to patients, providing clinicians with insight into the management strategies for corticosteroid-induced complications might engender greater collaboration with colleagues in other subspecialties.
The views and opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of The Dulaney Foundation.