Therapies for DME and Rationale for Combination Therapy
Therapies for DME and Rationale for Combination Therapy
Diabetic macular oedema (DMO) is responsible for significant visual impairment in diabetic patients. The primary cause of DMO is fluid leakage resulting from increased vascular permeability through contributory anatomical and biochemical changes. These include endothelial cell (EC) death or dysfunction, pericyte loss or dysfunction, thickened basement membrane, loss or dysfunction of glial cells, and loss/change of EC Glycocalyx. The molecular changes include increased reactive oxygen species, pro-inflammatory changes: advanced glycation end products, intracellular adhesion molecule-1, Complement 5–9 deposition and cytokines, which result in increased paracellular permeability, tight junction disruption, and increased transcellular permeability. Laser photocoagulation has been the mainstay of treatment until recently when pharmacological treatments were introduced. The current treatments for DMO target reducing vascular leak in the macula once it has occurred, they do not attempt to treat the underlying pathology. These pharmacological treatments are aimed at antagonising vascular endothelial growth factor (VEGF) or non-VEGF inflammatory pathways, and include intravitreal injections of anti-VEGFs (ranibizumab, aflibercept or bevacizumab) or steroids (fluocinolone, dexamethasone or triamcinolone) as single therapies. The available evidence suggests that each individual treatment modality in DMO does not result in a completely dry macula in most cases. The ideal treatment for DMO should improve vision and improve morphological changes in the macular (eg, reduce macular oedema) for a significant duration, reduced adverse events, reduced treatment burden and costs, and be well tolerated by patients. This review evaluates the individual treatments available as monotherapies, and discusses the rationale and potential for combination therapy in DMO. A comprehensive review of clinical trials related to DMO and their outcomes was completed. Where phase III randomised control trials were available, these were referenced, if not available, phase II trials have been included.
In 2002, it was reported that diabetes affected 220 million people worldwide, and anticipated that the prevalence of diabetes will double within the next 10 years. More recent estimates indicate that the prevalence of diabetes in adults (aged 20–79 years) worldwide was 382 million people in 2012, and that this would likely increase to 592 million in 2035.
Diabetic retinopathy (DR) has been extensively studied over the years, and its incidence correlates with poor glycaemic control and hyperlipidaemia. Diabetic choroidopathy is a less well-studied entity, and is thought to occur in the advanced stages of diabetic eye disease. As such, the retinal and choroidal vascular beds seem to be affected differently by diabetes. Diabetes and hyperglycaemia have obvious effects on intraocular vascular endothelial cell (EC) permeability, adhesion to leukocytes, as well as angiogenesis. These alterations result in increased vascular leakage (increased permeability), vascular occlusions, ischaemia, and angiogenesis. However, the exact mechanisms underlying these changes are not fully understood, and require further elucidation.
Diabetic macular oedema (DMO) is responsible for significant visual impairment in diabetic patients. In the retina, leakage is due to increased permeability that occurs at the retinal 'neurovascular' unit, which consists of single layer of tightly adherent ECs, basal lamina, surrounding pericytes, astrocytes, and microglia leading to increased EC trans- or paracellular permeability, as summarised in the recent review by Klaassen et al. There are contributory anatomical and biochemical changes that are interlinked (Figure 1). The anatomic changes include EC damage—death or dysfunction, pericyte loss or dysfunction, thickened basement membrane, loss or dysfunction of glial cells, and loss/change of EC Glycocalyx. The molecular changes include increased reactive oxygen species, pro-inflammatory changes: advanced glycation end products, intracellular adhesion molecule-1 (ICAM-1), Complement 5–9 (C5–9) deposition, cytokines, which result in increased paracellular permeability—small molecules and water: tight junction (TJ) disruption—and increased transcellular permeability—large molecules and water: caveolar transport, aquaporins, plasmalemmal vesicle-associated protein. The increased intraretinal fluid leads to progressive retinal dysfunction (see Klaassen et al review). The contributions of the choroidal vasculature to the clinical disease of DR are less well understood, but again will be largely contributed to by the choroidal EC (CEC) alterations. It is known that retinal vascular leakage in DMO is contributed to by vascular endothelial growth factor (VEGF) upregulation as well as non-VEGF-dependent inflammatory pathways, so that chronic subclinical inflammation is important in the pathogenesis of DR. An early event in the pathogenesis of diabetic vasculopathy is leukocyte adherence to retinal vascular endothelium, resulting in EC death, vascular leakage, and capillary closure (Figure 2).
(Enlarge Image)
Figure 1.
Pathogenesis of diabetic vasculopathy. DMO, diabetic macular oedema; Ang-2, Angiopoietin-2; EC, endothelial cell; ICAM, intercellular adhesion molecule; IP, interferon-induced protein; MMP, metallic metalloproteinase; VEGF, vascular endothelial growth factor; VE, vascular endothelial; PDGF, platelet-derived growth factor; TJ, tight junction, bFGF, basic fibroblast growth factor.
(Enlarge Image)
Figure 2.
Pathophysiology and treatment mechanisms in diabetic macular oedema (DMO). AGE, advanced glycation products; Ang-2, Angiopoietin-2; EC, endothelial cell; C, complement; ICAM, intercellular adhesion molecule; IL, interleukin; MCP, monocyte chemotactic protein; IP, interferon-induced protein; MMP, metallic metalloproteinase; NO, nitric oxide; NOS, nitric oxide synthase; RAGE, receptor for advanced glycation products; VEGF, vascular endothelial growth factor; VE, vascular endothelial; ROS, reactive oxygen species; PDGF, platelet-derived growth factor; PKC, protein kinase C; BRB, blood–retinal barrier.
The current treatments for DMO at reducing vascular leak in the macula once it has occurred, and aim for a dry macular subsequently. No attempt is made at addressing the underlying pathology, although it is possible that some of these treatments may alter retinal function in other ways (such as neurodegeneration) in addition to reducing vascular leakage.
This review evaluates the individual treatments available, and discusses the rationale and potential for combination therapy in DMO.
Abstract and Introduction
Abstract
Diabetic macular oedema (DMO) is responsible for significant visual impairment in diabetic patients. The primary cause of DMO is fluid leakage resulting from increased vascular permeability through contributory anatomical and biochemical changes. These include endothelial cell (EC) death or dysfunction, pericyte loss or dysfunction, thickened basement membrane, loss or dysfunction of glial cells, and loss/change of EC Glycocalyx. The molecular changes include increased reactive oxygen species, pro-inflammatory changes: advanced glycation end products, intracellular adhesion molecule-1, Complement 5–9 deposition and cytokines, which result in increased paracellular permeability, tight junction disruption, and increased transcellular permeability. Laser photocoagulation has been the mainstay of treatment until recently when pharmacological treatments were introduced. The current treatments for DMO target reducing vascular leak in the macula once it has occurred, they do not attempt to treat the underlying pathology. These pharmacological treatments are aimed at antagonising vascular endothelial growth factor (VEGF) or non-VEGF inflammatory pathways, and include intravitreal injections of anti-VEGFs (ranibizumab, aflibercept or bevacizumab) or steroids (fluocinolone, dexamethasone or triamcinolone) as single therapies. The available evidence suggests that each individual treatment modality in DMO does not result in a completely dry macula in most cases. The ideal treatment for DMO should improve vision and improve morphological changes in the macular (eg, reduce macular oedema) for a significant duration, reduced adverse events, reduced treatment burden and costs, and be well tolerated by patients. This review evaluates the individual treatments available as monotherapies, and discusses the rationale and potential for combination therapy in DMO. A comprehensive review of clinical trials related to DMO and their outcomes was completed. Where phase III randomised control trials were available, these were referenced, if not available, phase II trials have been included.
Introduction
In 2002, it was reported that diabetes affected 220 million people worldwide, and anticipated that the prevalence of diabetes will double within the next 10 years. More recent estimates indicate that the prevalence of diabetes in adults (aged 20–79 years) worldwide was 382 million people in 2012, and that this would likely increase to 592 million in 2035.
Diabetic retinopathy (DR) has been extensively studied over the years, and its incidence correlates with poor glycaemic control and hyperlipidaemia. Diabetic choroidopathy is a less well-studied entity, and is thought to occur in the advanced stages of diabetic eye disease. As such, the retinal and choroidal vascular beds seem to be affected differently by diabetes. Diabetes and hyperglycaemia have obvious effects on intraocular vascular endothelial cell (EC) permeability, adhesion to leukocytes, as well as angiogenesis. These alterations result in increased vascular leakage (increased permeability), vascular occlusions, ischaemia, and angiogenesis. However, the exact mechanisms underlying these changes are not fully understood, and require further elucidation.
Diabetic macular oedema (DMO) is responsible for significant visual impairment in diabetic patients. In the retina, leakage is due to increased permeability that occurs at the retinal 'neurovascular' unit, which consists of single layer of tightly adherent ECs, basal lamina, surrounding pericytes, astrocytes, and microglia leading to increased EC trans- or paracellular permeability, as summarised in the recent review by Klaassen et al. There are contributory anatomical and biochemical changes that are interlinked (Figure 1). The anatomic changes include EC damage—death or dysfunction, pericyte loss or dysfunction, thickened basement membrane, loss or dysfunction of glial cells, and loss/change of EC Glycocalyx. The molecular changes include increased reactive oxygen species, pro-inflammatory changes: advanced glycation end products, intracellular adhesion molecule-1 (ICAM-1), Complement 5–9 (C5–9) deposition, cytokines, which result in increased paracellular permeability—small molecules and water: tight junction (TJ) disruption—and increased transcellular permeability—large molecules and water: caveolar transport, aquaporins, plasmalemmal vesicle-associated protein. The increased intraretinal fluid leads to progressive retinal dysfunction (see Klaassen et al review). The contributions of the choroidal vasculature to the clinical disease of DR are less well understood, but again will be largely contributed to by the choroidal EC (CEC) alterations. It is known that retinal vascular leakage in DMO is contributed to by vascular endothelial growth factor (VEGF) upregulation as well as non-VEGF-dependent inflammatory pathways, so that chronic subclinical inflammation is important in the pathogenesis of DR. An early event in the pathogenesis of diabetic vasculopathy is leukocyte adherence to retinal vascular endothelium, resulting in EC death, vascular leakage, and capillary closure (Figure 2).
(Enlarge Image)
Figure 1.
Pathogenesis of diabetic vasculopathy. DMO, diabetic macular oedema; Ang-2, Angiopoietin-2; EC, endothelial cell; ICAM, intercellular adhesion molecule; IP, interferon-induced protein; MMP, metallic metalloproteinase; VEGF, vascular endothelial growth factor; VE, vascular endothelial; PDGF, platelet-derived growth factor; TJ, tight junction, bFGF, basic fibroblast growth factor.
(Enlarge Image)
Figure 2.
Pathophysiology and treatment mechanisms in diabetic macular oedema (DMO). AGE, advanced glycation products; Ang-2, Angiopoietin-2; EC, endothelial cell; C, complement; ICAM, intercellular adhesion molecule; IL, interleukin; MCP, monocyte chemotactic protein; IP, interferon-induced protein; MMP, metallic metalloproteinase; NO, nitric oxide; NOS, nitric oxide synthase; RAGE, receptor for advanced glycation products; VEGF, vascular endothelial growth factor; VE, vascular endothelial; ROS, reactive oxygen species; PDGF, platelet-derived growth factor; PKC, protein kinase C; BRB, blood–retinal barrier.
The current treatments for DMO at reducing vascular leak in the macula once it has occurred, and aim for a dry macular subsequently. No attempt is made at addressing the underlying pathology, although it is possible that some of these treatments may alter retinal function in other ways (such as neurodegeneration) in addition to reducing vascular leakage.
This review evaluates the individual treatments available, and discusses the rationale and potential for combination therapy in DMO.
Source...