Treatment modalities for diabetic retinopathy include retinal photocoagulation, intraocular injection of pharmacological agents and vitreoretinal surgery.
Laser therapy
As determined in the Diabetic Retinopathy Study (DRS) and the Early Treatment Diabetic Retinopathy Study (ETDRS), panretinal laser photocoagulation to the retinal periphery reduces severe visual loss and reduces legal blindness by 90% in people with severe nonproliferative or proliferative retinopathy (10–12). As determined by the ETDRS, focal laser treatment to the macula for CSME reduces the incidence of moderate visual loss by 50% (9). Long-term follow-up studies to the original laser photocoagulation trials confirm its benefit over several decades (57).
Local (intraocular) pharmacological intervention
The cytokine, vascular endothelial growth factor (VEGF), is a potent vascular permeability and angiogenic factor. Increased VEGF expression has been demonstrated to play a pivotal role in the development of diabetic retinopathy and, in particular, DME. Treatment of centre-involving DME with intravitreal anti-VEGF agents has been associated with improved vision and reduction of macular edema (thickening), unlike focal macular laser where the effect is to reduce the probability of further vision loss. Thus, anti-VEGF drugs have become first-line therapy in the management of centre-involving DME, and focal macular laser continues to be used when central vision is not involved. Three anti-VEGF agents are available, namely, ranibizumab, aflibercept and off-label use of bevacizumab.
Two masked, phase III, randomized clinical trials, A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus (RISE) and A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus (RIDE), using monthly ranibizumab, a humanized recombinant anti-VEGF antibody fragment, with or without prompt laser, improved visual acuity compared against sham over the 2 years of study (58). In the RISE trial, 44% and 39% of participants receiving 0.3 or 0.5 mg ranibizumab, respectively, gained 15 letters or more (3 lines) of acuity vs. 18% of those in the control arm. In the RIDE study, 33% or 45% of participants gained 15 letters or more at doses of 0.3 or 0.5 mg, respectively. RISE and RIDE open-label extension trials showed visual acuity gains and safety profiles were maintained with a marked reduction in subsequent treatment frequency (59).
Furthermore, 1-year results of a phase III clinical trial, Ranibizumab Monotherapy or Combined with Laser versus Laser Monotherapy for Diabetic Macular Edema (RESTORE), using an initial loading dose of 3 monthly injections of 0.5 mg ranibizumab, and as-needed treatment thereafter, likewise demonstrated improvement in the primary and secondary outcome measures of best corrected visual acuity and reduction in central macular thickness. In all studies, the effect(s) of ranibizumab were consistent when used as monotherapy or in conjunction with macular photocoagulation. In the RESTORE study, 37% to 43% of ranibizumab-treated participants improved vision by 10 letters or more compared to 16% with focal macular laser (60). Three-year extension results maintained similar outcomes (61).
Similar positive results were obtained by the Diabetic Retinopathy Clinical Research Network (DRCR.net) (Protocol I - 5-year results) using flexible ranibizumab plus prompt or deferred laser treatment algorithms (62,63).
Aflibercept is a recombinant fusion protein comprised of the highest-affinity binding site from VEGF receptor 1 and 2, fused to the constant region (Fc) of immunoglobulin G1, and binds or traps VEGF and PlGF (Placental Growth Factor). Two masked phase III randomized clinical trials, Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema (VISTA DME) and Intravitreal Aflibercept Injection in Vision Impairment Due to DME (VIVID-DME), evaluated aflibercept at 2 different dosing intervals (2q4 and 2q8) vs. macular laser photocoagulation. The 52-week visual and anatomic superiority of aflibercept over laser control was sustained through week 100, with similar efficacy in the 2q4 and 2q8 groups. Mean BCVA gain from baseline to week 100 with aflibercept 2q4, 2q8 and laser control was 11.5, 11.1 and 0.9 letters (p<0.0001) in VISTA and 11.4, 9.4 and 0.7 letters (p<0.0001) in VIVID, respectively (64).
A similar outcome was noted when comparing intraocular injection of bevacizumab (a full-length antibody against VEGF) to macular laser. Two-year results of A Prospective Randomized Trial of Intravitreal Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema (BOLT), a phase 3 clinical trial, demonstrated a gain of at least 15 letters or more in 32% of participants receiving 1.25 mg bevacizumab compared to 4% in the control arm (65). However, unlike ranibizumab and aflibercept, intraocular injection of bevacizumab in diabetic retinopathy constitutes off-label use of the drug in Canada.
A head-to-head randomized clinical trial, Diabetic Retinopathy Clinical Research Network Protocol T study, was carried out comparing the 3 anti-VEGF agents—aflibercept, bevacizumab and ranibizumab—in the treatment of centre-involving DME. All 3 agents demonstrated improvement of visual acuity and reduction in central macular thickness both at year 1 (66) and year 2. Superiority of aflibercept was noted in the group of participants with worse baseline visual acuity. This superiority of aflibercept at year 2 with gains of 18.1 letters in aflibercept, 13.3 letters in bevacizumab and 16.1 letters in ranibizumab groups at 2 years (aflibercept vs. bevacizumab, p=0.02, aflibercept vs. ranibizumab, p=0.18, and ranibizumab vs. bevacizumab, p=0.18).
Steroids are an alternate class of drug utilized in the management of DME. Injectable agents include triamcinolone, dexamethasone and fluocinolone.
Intravitreal injection of triamcinolone combined with prompt macular laser was as effective as ranibizumab in a single subgroup of people characterized by previous cataract surgery (62).
The Macular Edema: Assessment of Implantable Dexamethasone in Diabetes (MEAD) study group showed positive visual results with the dexamethasone (DEX) implant over a 3-year follow-up period. The percentage of participants with ≥15-letter improvement in BCVA from baseline at study end was greater with DEX implant 0.7 mg (22.2%) and DEX implant 0.35 mg (18.4%) than sham (12.0%, p≤0.018) (67).
The fluocinolone implant for DME has been studied (68,69) and more recently was studied vs. sham in the Fluocinolone Acetonide for Macular Edema (FAME) study, a phase III clinical trial consisting of 2 3-year pivotal trials. The percentage of participants with improvement from baseline letter score of 15 or more at month 24 was 28.7% and 28.6% in the low- and high-dose insert groups, respectively, compared with 16.2% in the sham group (p=0.002 for each) (70).
However, treatments with intraocular steroids are associated with increased rates of glaucoma and cataract formation.
Randomized-controlled trials evaluating anti-VEGF therapy for the treatment of centre-involving DME have noted improved diabetic retinopathy severity scale (DRSS). Progression of DRSS severity has been associated with an increased risk of development of proliferative diabetic retinopathy and DME (71). In nonproliferative diabetic retinopathy, ranibizumab (RISE/RIDE phase IV trial) demonstrated ≥2 step improvement in DRSS at year 3 (p=0.0003). Similarly, with aflibercept, a significant proportion of eyes demonstrated ≥2 step improvement in DRSS in the VISTA trial (p=0.0001) and VIVID trial (p=0.0004) (64). In proliferative diabetic retinopathy, ranibizumab demonstrated to be not inferior to PRP (panretinal photocoagulation) with 47% of eyes demonstrating ≥2 step improvement in DRSS (72). Thus, future randomized controlled trials may further evaluate DRSS as a primary endpoint in the prevention or regression of diabetic retinopathy.
Surgical intervention
Vitreoretinal surgery in diabetes is necessary for retinopathy complicated with non-clearing vitreous bleeding, persistent neovascularization (especially post PRP laser +/- VEGF injectables) and vitreoretinal traction, especially with retinal detachment threatening the macula. The Diabetic Retinopathy Vitrectomy Study (DRVS) Group evaluated the benefit of early vitrectomy (<6 months) in the treatment of severe vitreous hemorrhage (73) and very severe proliferative diabetic retinopathy (74). People with type 1 diabetes of <20 years' duration and severe vitreous hemorrhage were more likely to achieve good vision with early vitrectomy compared to conventional management (73). Similarly, early vitrectomy was associated with higher chance of visual recovery in people with either type 1 or 2 diabetes with very severe proliferative diabetic retinopathy (74). More recent surgical advances and instrumentation in vitrectomy since the DRVS trials have demonstrated reduced side effects with more consistent favourable visual outcomes, thus supporting vitrectomy in advanced proliferative diabetic retinopathy (75). Furthermore, these advances have expanded surgical indications to include earlier vitrectomy for diffuse macular edema, particularly with vitreomacular traction (76). It is worth noting that the use of perioperative ASA (77–79) and warfarin therapy (80) for persons undergoing ophthalmic surgery does not appear to raise the risk of hemorrhagic complications.
Overall, the last few years have seen significant advances in systemic, local and surgical treatments of diabetic eye disease, with significantly improved visual outcome. Most notably, long-term follow up to early laser studies confirm their sustained efficacy in preserving vision (57). Pharmacologic therapies, especially VEGF and steroid agents, demonstrate both preservation and recovery of vision in persons with DME. Despite these successes, it is important to encourage people with even moderate visual loss to seek assistance from community services that provide spectacle correction, enhanced magnification, vision aids and measures to encourage independence and ongoing quality of life (81,82).