The Evolving Treatment of Diabetic Retinopathy

Abstract

Purpose: To review the current therapeutic options for the management of diabetic retinopathy (DR) and diabetic macular edema (DME) and examine the evidence for integration of laser and pharmacotherapy.

Methods: A review of the PubMed database was performed using the search terms diabetic retinopathy, diabetic macular edema, neovascularization, laser photocoagulation, intravitreal injection, vascular endothelial growth factor (VEGF), vitrectomy, pars plana vitreous surgery, antiangiogenic therapy. With additional cross-referencing, this yielded 835 publications of which 301 were selected based on content and relevance.

Results: Many recent studies have evaluated the pharmacological, laser and surgical therapeutic strategies for the treatment and prevention of DR and DME. Several newer diagnostic systems such as optical coherence tomography (OCT), microperimetry, and multifocal electroretinography (mfERG) are also assisting in further refinements in the staging and classification of DR and DME. Pharmacological therapies for both DR and DME include both systemic and ocular agents. Systemic agents that promote intensive glycemic control, control of dyslipidemia and antagonists of the renin-angiotensin system demonstrate beneficial effects for both DR and DME. Ocular therapies include anti-VEGF agents, corticosteroids and nonsteroidal anti-inflammatory drugs. Laser therapy, both as panretinal and focal or grid applications continue to be employed in management of DR and DME. Refinements in laser devices have yielded more tissue-sparing (subthreshold) modes in which many of the benefits of conventional continuous wave (CW) lasers can be obtained without the adverse side effects. Recent attempts to lessen the burden of anti-VEGF injections by integrating laser therapy have met with mixed results. Increasingly, vitreoretinal surgical techniques are employed for less advanced stages of DR and DME. The development and use of smaller gauge instrumentation and advanced anesthesia agents have been associated with a trend toward earlier surgical intervention for diabetic retinopathy. Several novel drug delivery strategies are currently being examined with the goal of decreasing the therapeutic burden of monthly intravitreal injections. These fall into one of the five categories: non-biodegradable polymeric drug delivery systems, biodegradable polymeric drug delivery systems, nanoparticle-based drug delivery systems, ocular injection devices and with sustained release refillable devices. At present, there remains no one single strategy for the management of the particular stages of DR and DME as there are many options that have not been rigorously tested through large, randomized, controlled clinical trials.

Conclusion: Pharmacotherapy, both ocular and systemic, will be the primary mode of intervention in the management of DR and DME in many cases when cost and treatment burden are less constrained. Conventional laser therapy has become a secondary intervention in these instances, but remains a first-line option when cost and treatment burden are more constrained. Results with subthreshold laser appear promising but will require more rigorous study to establish its role as adjunctive therapy. Evidence to support an optimal integration of the various treatment options is lacking. Central to the widespread adoption of any therapeutic regimen for DR and DME is substantiation of safety, efficacy, and cost-effectiveness by a body of sound clinical trials.

Keywords: antiangiogenic therapy; diabetes; diabetic macular edema; diabetic retinopathy; intravitreal injection; laser photocoagulation; neovascularization; retina; vascular endothelial growth factor; vitrectomy pars plana vitreous surgery.

Figure 1

(A) Suggested treatment decision tree for the clinical scenario of proliferative diabetic retinopathy without diabetic macular edema. (B) Suggested treatment decision tree for the clinical scenario of proliferative diabetic retinopathy with center-involved diabetic macular edema. (C) Suggested treatment decision tree for the scenario of clinically significant diabetic macular edema. CSDME=clinically significant diabetic macular edema, which falls into 3 subcategories: edema of 1 disc area or more within 1 disc diameter of the fovea; foveal or parafoveal hard lipid with adjacent macular thickening; or foveal thickening. Focal laser means modified focal-grid laser in the manner outlined by the diabetic retinopathy clinical research network. Subthreshold laser may eventually gain a place in this block, but currently, the evidence is not strong enough to merit commensurate standing with focal laser. Abbreviations: PDR, proliferative diabetic retinopathy; DME, diabetic macular edema; PRP, panretinal photocoagulation; VEGF, vascular endothelial growth factor; CI-DME, center-involved diabetic macular edema.